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1
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Atallah A, Slama SB, Guelbi M, Hadrich Z, Megdiche S, Omrani S. Voluminous fibrolamellar carcinoma in a young adult: A case report. Int J Surg Case Rep 2025; 131:111355. [PMID: 40288144 PMCID: PMC12059704 DOI: 10.1016/j.ijscr.2025.111355] [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: 03/17/2025] [Revised: 04/13/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025] Open
Abstract
INTRODUCTION Fibrolamellar carcinoma (FLC) is a rare primary liver cancer, typically presenting as a solitary nodule in young adults without underlying liver disease. Surgical resection is currently the only curative treatment. PRESENTATION OF CASE We report a 27-year-old woman with a 6-month history of moderate epigastric pain, right upper quadrant heaviness, and a 20-kg weight loss. Imaging studies (ultrasound, CT, and MRI) revealed an 11-cm mass in the right liver featuring a central scar and calcifications, highly suggestive of FLC. A liver biopsy confirmed the diagnosis. The patient subsequently underwent a right hepatectomy with en bloc resection of an adherent diaphragmatic collar and lymphadenectomy. Her postoperative course was uneventful, leading to discharge on postoperative day 10. DISCUSSION FLC accounts for less than 1 % of primary liver tumors and is distinct from conventional hepatocellular carcinoma, primarily due to its occurrence in non-cirrhotic, younger patients. Characteristic radiologic findings include a well-circumscribed, large lesion with a central fibrous scar and occasional calcifications. Although the prognosis post-resection is generally favorable, recurrence rates exceed 60 %, emphasizing the need for aggressive surgical management and vigilant long-term follow-up. CONCLUSION FLC is a distinct clinical entity with improved surgical outcomes compared to classical hepatocellular carcinoma. Nonetheless, its high recurrence potential necessitates continued surveillance and further research to optimize treatment strategies.
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Affiliation(s)
- Aziz Atallah
- Department of Surgery, Mongi Slim Hospital, Marsa, Tunisia
| | - Sana Ben Slama
- Department of Pathology, Mongi Slim Hospital, Marsa, Tunisia
| | - Mohamed Guelbi
- Department of Surgery, Mongi Slim Hospital, Marsa, Tunisia.
| | - Zied Hadrich
- Department of Surgery, Mongi Slim Hospital, Marsa, Tunisia
| | - Sadok Megdiche
- Department of Surgery, Mongi Slim Hospital, Marsa, Tunisia
| | - Sahir Omrani
- Department of Surgery, Mongi Slim Hospital, Marsa, Tunisia
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2
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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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3
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Farghli AR, Chan M, Sherman MS, Dickerson LK, Shui B, Nukaya M, Stephanou A, Ma RK, Pepe-Mooney BJ, Smith CJ, Long D, Munn PR, McNairn A, Grenier JK, Karski M, Ronnekleiv-Kelly SM, Pillarisetty VG, Goessling W, Gujral TS, Vakili K, Sethupathy P. Single-cell multi-omic analysis of fibrolamellar carcinoma reveals rewired cell-to-cell communication patterns and unique vulnerabilities. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.11.627911. [PMID: 39713360 PMCID: PMC11661214 DOI: 10.1101/2024.12.11.627911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Fibrolamellar carcinoma (FLC) is a rare malignancy disproportionately affecting adolescents and young adults with no standard of care. FLC is characterized by thick stroma, which has long suggested an important role of the tumor microenvironment. Over the past decade, several studies have revealed aberrant markers and pathways in FLC. However, a significant drawback of these efforts is that they were conducted on bulk tumor samples. Consequently, identities and roles of distinct cell types within the tumor milieu, and the patterns of intercellular communication, have yet to be explored. In this study we unveil cell-type specific gene signatures, transcription factor networks, and super-enhancers in FLC using a multi-omics strategy that leverages both single-nucleus ATAC-seq and single-nucleus RNA-seq. We also infer completely rewired cell-to-cell communication patterns in FLC including signaling mediated by SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, and FGF7-FGFR. Finally, we validate findings with loss-of-function studies in several models including patient tissue slices, identifying vulnerabilities that merit further investigation as candidate therapeutic targets in FLC.
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4
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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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5
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Matteini F, Cannella R, Garzelli L, Dioguardi Burgio M, Sartoris R, Brancatelli G, Vilgrain V, Ronot M, Vernuccio F. Benign and malignant focal liver lesions displaying rim arterial phase hyperenhancement on CT and MRI. Insights Imaging 2024; 15:178. [PMID: 39020233 PMCID: PMC11254889 DOI: 10.1186/s13244-024-01756-y] [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: 04/22/2024] [Accepted: 06/22/2024] [Indexed: 07/19/2024] Open
Abstract
Rim arterial phase hyperenhancement is an imaging feature commonly encountered on contrast-enhanced CT and MRI in focal liver lesions. Rim arterial phase hyperenhancement is a subtype of arterial phase hyperenhancement mainly present at the periphery of lesions on the arterial phase. It is caused by a relative arterialization of the periphery compared with the center of the lesion and needs to be differentiated from other patterns of peripheral enhancement, including the peripheral discontinuous nodular enhancement and the corona enhancement. Rim arterial phase hyperenhancement may be a typical or an atypical imaging presentation of many benign and malignant focal liver lesions, challenging the radiologists during imaging interpretation. Benign focal liver lesions that may show rim arterial phase hyperenhancement may have a vascular, infectious, or inflammatory origin. Malignant focal liver lesions displaying rim arterial phase hyperenhancement may have a vascular, hepatocellular, biliary, lymphoid, or secondary origin. The differences in imaging characteristics on contrast-enhanced CT may be subtle, and a multiparametric approach on MRI may be helpful to narrow the list of differentials. This article aims to review the broad spectrum of focal liver lesions that may show rim arterial phase hyperenhancement, using an approach based on the benign and malignant nature of lesions and their histologic origin. CRITICAL RELEVANCE STATEMENT: Rim arterial phase hyperenhancement may be an imaging feature encountered in benign and malignant focal liver lesions and the diagnostic algorithm approach provided in this educational review may guide toward the final diagnosis. KEY POINTS: Several focal liver lesions may demonstrate rim arterial phase hyperenhancement. Rim arterial phase hyperenhancement may occur in vascular, inflammatory, and neoplastic lesions. Rim arterial phase hyperenhancement may challenge radiologists during image interpretation.
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Affiliation(s)
- Francesco Matteini
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University Hospital of Palermo, Palermo, Italy
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Roberto Cannella
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University Hospital of Palermo, Palermo, Italy
| | - Lorenzo Garzelli
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Paris, France
- Université Paris Cité, INSERM U1149, "Centre de Recherche sur l'Inflammation"; CRI, Paris, France
| | - Marco Dioguardi Burgio
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Paris, France
- Université Paris Cité, INSERM U1149, "Centre de Recherche sur l'Inflammation"; CRI, Paris, France
| | - Riccardo Sartoris
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Paris, France
- Université Paris Cité, INSERM U1149, "Centre de Recherche sur l'Inflammation"; CRI, Paris, France
| | - Giuseppe Brancatelli
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University Hospital of Palermo, Palermo, Italy
| | - Valérie Vilgrain
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Paris, France
- Université Paris Cité, INSERM U1149, "Centre de Recherche sur l'Inflammation"; CRI, Paris, France
| | - Maxime Ronot
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Paris, France
- Université Paris Cité, INSERM U1149, "Centre de Recherche sur l'Inflammation"; CRI, Paris, France
| | - Federica Vernuccio
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University Hospital of Palermo, Palermo, Italy.
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6
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Ruiz E, Honles J, Fernández R, Uribe K, Cerapio JP, Cancino K, Contreras-Mancilla J, Casavilca-Zambrano S, Berrospi F, Pineau P, Bertani S. A preoperative risk score based on early recurrence for estimating outcomes after resection of hepatocellular carcinoma in the non-cirrhotic liver. HPB (Oxford) 2024; 26:691-702. [PMID: 38431511 DOI: 10.1016/j.hpb.2024.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 01/15/2024] [Accepted: 02/12/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Liver resection is the mainstay treatment option for patients with hepatocellular carcinoma in the non-cirrhotic liver (NCL-HCC), but almost half of these patients will experience a recurrence within five years of surgery. Therefore, we aimed to develop a rationale-based risk evaluation tool to assist surgeons in recurrence-related treatment planning for NCL-HCC. METHODS We analyzed single-center data from 263 patients who underwent liver resection for NCL-HCC. Using machine learning modeling, we first determined an optimal cut-off point to discriminate early versus late relapses based on time to recurrence. We then constructed a risk score based on preoperative variables to forecast outcomes according to recurrence-free survival. RESULTS We computed an optimal cut-off point for early recurrence at 12 months post-surgery. We identified macroscopic vascular invasion, multifocal tumor, and spontaneous tumor rupture as predictor variables of outcomes associated with early recurrence and integrated them into a scoring system. We thus stratified, with high concordance, three groups of patients on a graduated scale of recurrence-related survival. CONCLUSION We constructed a preoperative risk score to estimate outcomes after liver resection in NCL-HCC patients. Hence, this score makes it possible to rationally stratify patients based on recurrence risk assessment for better treatment planning.
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Affiliation(s)
- Eloy Ruiz
- Departamento de Cirugía en Abdomen, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru.
| | - Jorge Honles
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; UMR 152 PHARMADEV, Université de Toulouse, IRD, Toulouse, France
| | - Ramiro Fernández
- Departamento de Cirugía en Abdomen, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru
| | - Karla Uribe
- Departamento de Cirugía en Abdomen, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - Juan P Cerapio
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; UMR 1037 CRCT, Université de Toulouse, INSERM, Toulouse, France
| | - Karina Cancino
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; UMR 152 PHARMADEV, Université de Toulouse, IRD, Toulouse, France; UMR 1037 CRCT, Université de Toulouse, INSERM, Toulouse, France
| | - Juan Contreras-Mancilla
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; Laboratorio de Investigación Traslacional y Biología Computacional, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Sandro Casavilca-Zambrano
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; Departamento de Patología, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Facultad de Ciencias de la Salud, Universidad de Huánuco, Huánuco, Peru
| | - Francisco Berrospi
- Departamento de Cirugía en Abdomen, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - Pascal Pineau
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; Unité Organisation Nucléaire et Oncogenèse, INSERM, Institut Pasteur, Paris, France
| | - Stéphane Bertani
- International Joint Laboratory of Molecular Anthropological Oncology, INEN, IRD, Lima, Peru; UMR 152 PHARMADEV, Université de Toulouse, IRD, Toulouse, France.
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7
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Taheri N, Graham RP. How Molecular Discoveries Have Changed Liver Tumor Pathology: A Brief Review. Arch Pathol Lab Med 2024; 148:e96-e102. [PMID: 37639429 DOI: 10.5858/arpa.2023-0099-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 08/31/2023]
Abstract
CONTEXT Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. OBJECTIVE To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. DATA SOURCES First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. CONCLUSIONS Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors.
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MESH Headings
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/diagnosis
- Cholangiocarcinoma/genetics
- Cholangiocarcinoma/pathology
- Cholangiocarcinoma/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/diagnosis
- Hemangioendothelioma, Epithelioid/genetics
- Hemangioendothelioma, Epithelioid/pathology
- Hemangioendothelioma, Epithelioid/diagnosis
- Adenoma, Liver Cell/pathology
- Adenoma, Liver Cell/genetics
- Adenoma, Liver Cell/diagnosis
- Bile Duct Neoplasms/genetics
- Bile Duct Neoplasms/pathology
- Bile Duct Neoplasms/diagnosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Molecular Diagnostic Techniques
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Affiliation(s)
- Negar Taheri
- From the Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering (Taheri)
- the Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota(Taheri)
| | - Rondell P Graham
- the Divisions of Anatomic Pathology, , Mayo Clinic, Rochester, Minnesota(Graham)
- Laboratory Genetics and Genomics, Mayo Clinic, Rochester, Minnesota(Graham)
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8
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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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9
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Ma RK, Tsai PY, Farghli AR, Shumway A, Kanke M, Gordan JD, Gujral TS, Vakili K, Nukaya M, Noetzli L, Ronnekleiv-Kelly S, Broom W, Barrow J, Sethupathy P. DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma. PLoS Genet 2024; 20:e1011216. [PMID: 38512964 PMCID: PMC11020935 DOI: 10.1371/journal.pgen.1011216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 04/16/2024] [Accepted: 03/08/2024] [Indexed: 03/23/2024] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.
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Affiliation(s)
- Rosanna K. Ma
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Pei-Yin Tsai
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America
| | - Alaa R. Farghli
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Alexandria Shumway
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Matt Kanke
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - John D. Gordan
- Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, United States of America
| | - Taranjit S. Gujral
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America
| | - Khashayar Vakili
- Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Manabu Nukaya
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Leila Noetzli
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States of America
| | - Sean Ronnekleiv-Kelly
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Wendy Broom
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, United States of America
| | - Joeva Barrow
- Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America
| | - Praveen Sethupathy
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
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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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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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van der Meeren PE, de Wilde RF, Sprengers D, IJzermans JNM. Benefit and harm of waiting time in liver transplantation for HCC. Hepatology 2023:01515467-990000000-00646. [PMID: 37972979 DOI: 10.1097/hep.0000000000000668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023]
Abstract
Liver transplantation is the most successful treatment for limited-stage HCC. The waiting time for liver transplantation (LT) can be a critical factor affecting the oncological prognosis and outcome of patients with HCC. Efficient strategies to optimize waiting time are essential to maximize the benefits of LT and to reduce the harm of delay in transplantation. The ever-increasing demand for donor livers emphasizes the need to improve the organization of the waiting list for transplantation and to optimize organ availability for patients with and without HCC. Current progress in innovations to expand the donor pool includes the implementation of living donor LT and the use of grafts from extended donors. By expanding selection criteria, an increased number of patients are eligible for transplantation, which necessitates criteria to prevent futile transplantations. Thus, the selection criteria for LT have evolved to include not only tumor characteristics but biomarkers as well. Enhancing our understanding of HCC tumor biology through the analysis of subtypes and molecular genetics holds significant promise in advancing the personalized approach for patients. In this review, the effect of waiting time duration on outcome in patients with HCC enlisted for LT is discussed.
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Affiliation(s)
- Pam Elisabeth van der Meeren
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Roeland Frederik de Wilde
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Dave Sprengers
- Department of Gastroenterology & Hepatology, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Jan Nicolaas Maria IJzermans
- Department of Surgery, Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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13
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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: 3] [Impact Index Per Article: 1.5] [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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14
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Aloysius MM, Iskander P, Ahmed K, Asija U, Mohammed E, Iskander A, Shah NJ, Goyal H, Khurana V, Simin N, Aswath G, John S. Fibrolamellar hepatocellular carcinoma: An epidemiologic and 5-year cancer survival assessment based off SEER data. Clin Res Hepatol Gastroenterol 2023; 47:102162. [PMID: 37307948 DOI: 10.1016/j.clinre.2023.102162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
The fibrolamellar variant of hepatocellular carcinoma makes up a small percentage of liver tumors. Despite being a subset, it has been noted in the literature to have variations in terms of its epidemiology and intervention recommendations. Using the Surveillance, Epidemiology, and End Results database, 339 cases from 1988 to 2016 were studied. Favorable prognostic epidemiological factors included male sex, younger ages, and white race. Those who underwent any lymph node resection (combined with liver resection) did better than those without lymph node resection; chemotherapy proved beneficial for those where surgery was contraindicated. To our knowledge, this report is the largest conglomerate dataset analyzing prognostic profiles and treatment strategies for fibrolamellar hepatocellular carcinoma.
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Affiliation(s)
- Mark M Aloysius
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Peter Iskander
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States.
| | - Khalid Ahmed
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Udit Asija
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Elmkdad Mohammed
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Anthony Iskander
- Xavier University School of Medicine Aruba, Santa Helenastraat 23, Oranjestad, Aruba
| | - Niraj James Shah
- University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States
| | - Hemant Goyal
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Vikas Khurana
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Nasr Simin
- The Wright Center for Graduate Medical Education, 501 S Washington Avenue, Scranton, PA, United States
| | - Ganesh Aswath
- Upstate University Hospital, 750 East Adams Street, Syracuse, NY 13210, United States
| | - Savio John
- Upstate University Hospital, 750 East Adams Street, Syracuse, NY 13210, United States
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15
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Alshareefy Y, Shen CY, Prekash RJ. Exploring the molecular pathogenesis, diagnosis and treatment of fibrolamellar hepatocellular carcinoma: A state of art review of the current literature. Pathol Res Pract 2023; 248:154655. [PMID: 37429175 DOI: 10.1016/j.prp.2023.154655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 06/25/2023] [Indexed: 07/12/2023]
Abstract
This paper aims to present a detailed overview of fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC) that accounts for approximately 1-9% of all cases a. according to the SEER database. Despite ongoing research, the aetiology of FLC tumours remains unclear. Nevertheless, FLC is believed to have a better overall prognosis than other primary liver tumours, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. This study aims to present a comprehensive overview of fibrolamellar carcinoma (FLC), with a focus on its epidemiology, pathogenesis, diagnosis, treatment, and prognosis. FLC frequently incorporate features of stomach pain, weight loss, and malaise in their clinical signs and symptoms, which are generally nonspecific Ultimately, the most common physical finding is an abdominal mass or hepatomegaly. With this said, several unusual presentations have been documented such as Budd Chiari syndrome, severe anaemia, non-bacterial thrombotic endocarditis and many more. In regards to this tumour's genetic analysis, it is characterised by a 400 kb deletion on chromosome 19 leading to a functional DNAJB1-PRKACA chimeric transcript in addition to tetraploidy in 50% of cases. FLC is chromosomally stable as compared to typical HCC. mTOR pathway activation has also been found to play a critical role in 47% of these tumours and EFGR over-expression is also evident. Fibrolamellar carcinomas (FLCs) exhibit a distinctive gross appearance, characterized by a yellow to pale tan colour, with a consistency that can vary from soft to firm and hard. In addition, a central scar is observed in 60-70% of FLC cases. The central scar is typically white or grey in colour and has a fibrous appearance, which is often surrounded by nodular, tumour-like tissue. Its histologic appearance is characterized by large polygonal cells with abundant eosinophilic cytoplasm, large vesiculated nuclei, large nucleoli, and arranged in lamellar bands of collagen fibres. Lamellar bands of fibrosis, consisting of collagen type I, III and IV, have also been identified as a distinctive histologic feature that is observed under low power magnification. Ultrasound, CT and MRI along with image guided biopsy are the primary modalities in diagnosis. Current management options include systemic therapy which has thus far been unremarkable with platinum-based therapies as well combination therapy with interferon alpha-2b being the most successful options. Surgical resection remains the primary treatment modality and there have been no advances in targeted therapies. Although the prognosis for FLC is favourable as compared to other hepatic cancer subtypes such as intrahepatic cholangiocarcinoma, there is a high rate of recurrence ranging from 33% to 100% with a median recurrence-free survival of 20-48 months. As a result of this there is a low overall cure rate associated with this tumour type and much more research is required to gain an in-depth understanding of the molecular mechanisms occurring in order to provide more adequate treatment to patients who suffer from this condition.
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Affiliation(s)
- Yasir Alshareefy
- School of Medicine, Trinity College Dublin, University of Dublin, Ireland.
| | - Chai Yu Shen
- Department of Medicine, Manipal University College, Malaysia
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16
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Qiu S, Chen R, Hu J, Han T. The prognosis of fibrolamellar carcinoma versus conventional hepatocellular carcinoma: a study based on propensity score matching. Scand J Gastroenterol 2023; 58:1351-1358. [PMID: 37353942 DOI: 10.1080/00365521.2023.2227305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 06/25/2023]
Abstract
BACKGROUND The prognosis of fibrolamellar carcinoma (FLC) versus conventional hepatocellular carcinoma (HCC) remains controversial. Thus, this study aimed to compare the prognosis of FLC and HCC. METHODS Patients with FLC and HCC in the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2015 were included. Propensity score matching (PSM) was performed to balance the clinical characteristics between FLC and HCC. Cox regression and Kaplan-Meier analysis were applied to identify the effect of pathology in prognosis before and after match in the whole cohort, as well as in subgroups of fibrosis score, AJCC stage and therapy. RESULTS A total of 213 patients with FLC and 33365 patients with HCC between 2000 and 2015 were identified. Before matching, the overall survival (OS) and cancer-specific survival (CSS) were significantly better in FLC than HCC. After matching, FLC patients had better OS than HCC patients, but the CSS was similar between groups. Further analyses found that in patients at early stage (AJCC I-III) and/or accepted curative therapy, the prognosis was comparable between HCC and FLC. In patients without cirrhosis (F0), the HCC patients had similar prognosis with FLC patients. Prognosis benefit of FLC was observed in subgroups of AJCC stage IV and non-curative therapy, however, the concomitant diseases may affect the results. CONCLUSIONS The prognosis of FLC was significantly better than HCC before matching. However, after matching for clinical characteristics, the CSS was comparable between FLC and HCC.
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Affiliation(s)
- Shaotian Qiu
- The School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Gastroenterology and Hepatology, Tianjin Union Medical Center Affiliated to Nankai University, Tianjin, P.R. China
| | - Rui Chen
- Department of Gastroenterology and Hepatology, Tianjin Union Medical Center of Tianjin Medical University, Tianjin, P.R. China
| | - Jiaxuan Hu
- The School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Gastroenterology and Hepatology, Tianjin Union Medical Center Affiliated to Nankai University, Tianjin, P.R. China
| | - Tao Han
- The School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Gastroenterology and Hepatology, Tianjin Union Medical Center Affiliated to Nankai University, Tianjin, P.R. China
- Department of Gastroenterology and Hepatology, Tianjin Union Medical Center of Tianjin Medical University, Tianjin, P.R. China
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Abstract
The fight against rare cancers faces myriad challenges, including missed or wrong diagnoses, lack of information and diagnostic tools, too few samples and too little funding. Yet many advances in cancer biology, such as the realization that there are tumour suppressor genes, have come from studying well-defined, albeit rare, cancers. Fibrolamellar hepatocellular carcinoma (FLC), a typically lethal liver cancer, mainly affects adolescents and young adults. FLC is both rare, 1 in 5 million, and problematic to diagnose. From the paucity of data, it was not known whether FLC was one cancer or a collection with similar phenotypes, or whether it was genetically inherited or the result of a somatic mutation. A personal journey through a decade of work reveals answers to these questions and a road map of steps and missteps in our fight against a rare cancer.
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18
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Zeng H, Su K, Chen X, Li X, Wen L, Song Y, Chen L, Li H, Guo L, Han Y. A propensity score matching study on survival benefits of radiotherapy in patients with inoperable hepatocellular carcinoma. Sci Rep 2023; 13:6879. [PMID: 37106014 PMCID: PMC10140032 DOI: 10.1038/s41598-023-34135-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/25/2023] [Indexed: 04/29/2023] Open
Abstract
With the advancements in radiotherapy (RT) in recent years, several studies have shown that RT can significantly prolong the survival of patients with hepatocellular carcinoma (HCC). As a noninvasive treatment option, the application of RT for the treatment of HCC is garnering increasing attention. In this retrospective study, we included data from 13,878 patients with HCC from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019 and 325 patients with HCC treated in three tertiary hospitals in China between 2015 and 2021. Patient data were divided into RT and non-RT groups based on whether the patients underwent RT. Propensity score matching analysis was performed to minimize the deviation between the RT and non-RT groups, and the Kaplan-Meier method, Cox proportional hazard model, and nomogram were used to assess the efficacy of undergoing RT. The median overall survival (mOS) of the RT group was significantly longer compared with that of the non-RT group for the SEER data (16 months versus 9 months, p < 0.01). Similarly, the survival benefit was more significant in the RT group than in the non-RT group at our hospitals (34.1 months versus 15.4 months, p < 0.01). Furthermore, multivariate Cox analysis revealed that factors, including tumor (T) stage, patient age, tumor grade, serum AFP level, and chemotherapy, also affected patient survival. Moreover, these factors were also used to construct a nomogram. Subgroup analysis of these factors showed that RT was effective in prolonging patient survival in different populations. RT significantly improves the survival time of patients with inoperable HCC, thereby providing a basis for selecting HCC patients who can benefit from RT.
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Affiliation(s)
- Hao Zeng
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, No.25 Taiping Street, Luzhou, Sichuan Province, China
| | - Ke Su
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, No.25 Taiping Street, Luzhou, Sichuan Province, China
| | - Xiaojing Chen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, No.25 Taiping Street, Luzhou, Sichuan Province, China
| | - Xueting Li
- Department of Oncology, 363 Hospital, Chengdu, China
| | - Lianbin Wen
- Department of Geriatric Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Yanqiong Song
- Department of Radiotherapy, School of Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Lan Chen
- Department of Oncology and Hematology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Han Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, No.25 Taiping Street, Luzhou, Sichuan Province, China
| | - Lu Guo
- Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yunwei Han
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, No.25 Taiping Street, Luzhou, Sichuan Province, China.
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19
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Zack T, Losert KP, Maisel SM, Wild J, Yaqubie A, Herman M, Knox JJ, Mayer RJ, Venook AP, Butte A, O'Neill AF, Abou-Alfa GK, Gordan JD. Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data. NPJ Precis Oncol 2023; 7:29. [PMID: 36959495 PMCID: PMC10034241 DOI: 10.1038/s41698-023-00371-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 03/03/2023] [Indexed: 03/25/2023] Open
Abstract
The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates. By employing unsupervised learning on clinical laboratory data from patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in urea cycle disorders. Our findings demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.
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Affiliation(s)
- Travis Zack
- Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, CA, USA
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA
| | | | | | - Jennifer Wild
- Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Amin Yaqubie
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Herman
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Jennifer J Knox
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Robert J Mayer
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan P Venook
- Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Atul Butte
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA
| | - Allison F O'Neill
- Dana-Farber Cancer Institute/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Department of Pediatric Oncology, Boston, MA, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Weill Medical College at Cornell University, New York, NY, USA.
| | - John D Gordan
- Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, CA, USA.
- Quantitative Biosciences Institute, University of California, San Francisco, CA, USA.
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20
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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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21
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Berger R, Dinstag G, Tirosh O, Schiff E, Kleiner D, Aldape KD, Ruppin E, Beker T, Kurzrock R. Fibrolamellar carcinoma transcriptomic-based treatment prediction: complete response after nivolumab and ipilimumab. J Immunother Cancer 2022; 10:e005620. [PMID: 36600603 PMCID: PMC9743402 DOI: 10.1136/jitc-2022-005620] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 12/13/2022] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare cancer of the liver that most commonly affects children and young adults. There is no clear standard of care for the disease, whose response to treatment seems to be very different from that of hepatocellular carcinoma. We present a case of FLC in a patient in her mid 30s that recurred and persisted despite resection and multiple lines of treatment. Following transcriptomic analysis, a combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) led to complete remission, although common biomarkers for immune checkpoint blockade were all negative in this case. The patient is still in remission. Here, combined checkpoint blockade guided by novel transcriptomic analysis led to complete remission after failure of several lines of treatment.
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Affiliation(s)
- Raanan Berger
- Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | | | | | | | - David Kleiner
- Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | - Kenneth D Aldape
- Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | - Eytan Ruppin
- Cancer Data Science Lab, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | | | - Razelle Kurzrock
- Clinical Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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22
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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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23
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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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24
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Alsadery HA, Almaiman H, Alibrah R, Mnayan M, Alblowi A, Alzayyat R, Alshahrani A. Case Report of Fibrolamellar Hepatocellular Carcinoma in A 15-Year-old Male. Med Arch 2022; 76:387-390. [PMID: 36545449 PMCID: PMC9760234 DOI: 10.5455/medarh.2022.76.387-390] [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: 09/14/2022] [Accepted: 10/22/2022] [Indexed: 11/16/2022] Open
Abstract
Background A rare form of hepatocellular cancer is called fibrolamellar hepatocellular carcinoma (FL-HCC) which occurs mostly in young adults who are medically free, regardless of their gender. It usually presents with abdominal pain with right upper quadrant palpable mass, nausea, and weight loss associated with higher Alpha-Fetoprotein (AFP) in some cases. Objective We report a case of a 15-year-old male patient who was diagnosed with (FL-HCC), successfully treated with surgical resection and is currently free of relapses. Case presentation A 15-year-old male patient with no previous medical or surgical history, presented with recurrent vomiting for two months, weight loss, and loss of appetite. Patient presented with normal systemic examination except for abdominal examination which revealed a generalized distended abdomen with mild tenderness in the right upper quadrant with the presence of hepatomegaly. Laboratory and radiological investigation showed high level of (AFP). CT and liver MRI showed large right hepatic lobe lesion then TRU-CUT needle biopsy was performed which showed Fibrolamellar hepatocellular carcinoma and patient underwent surgical resection with no postoperative complication followed by multiple cycle of chemotherapy and no signs of relapse with 3 year follow up. Conclusion Fibrolamellar hepatocellular carcinoma is rear type hepatocellular carcinoma which occurs mostly in young adults who are medically free with vague symptom and to diagnose it need high index of suspicion and variers Laboratory and radiological investigation including biopsy. However, it can be treated successfully by surgical resection followed by chemotherapy in selected cases if diagnosis in timely manner.
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Affiliation(s)
- Humood Ahmed Alsadery
- Department of General Surgery, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, College of Medicine, Dammam, Saudi Arabia
| | - Hisham Almaiman
- Department of Surgery, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Rawan Alibrah
- Department of Surgery, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Marooh Mnayan
- Department of Surgery, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Abdulrahman Alblowi
- Department of General Surgery, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, College of Medicine, Dammam, Saudi Arabia
| | - Remah Alzayyat
- Department of General Surgery, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, College of Medicine, Dammam, Saudi Arabia
| | - Abdulwahab Alshahrani
- Department of General Surgery, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, College of Medicine, Dammam, Saudi Arabia,Department of Surgery, King Fahad Specialist Hospital, Dammam, Saudi Arabia
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25
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Na SK. Fibrolamellar hepatocellular carcinoma that was successfully treated with surgical resection: a case report. JOURNAL OF LIVER CANCER 2022; 22:178-182. [PMID: 37383417 PMCID: PMC10035731 DOI: 10.17998/jlc.2022.06.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/03/2022] [Accepted: 06/10/2022] [Indexed: 06/30/2023]
Abstract
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare malignant hepatic cancer with characteristics that differ from those of typical hepatocellular carcinoma (HCC). Unlike conventional HCC, FLHCC is common in young patients without any underlying liver disease and is known to be associated with a unique gene mutation. This cancer type is rare in Asia, with only a few cases being reported in Korea. We report a case of FLHCC in a young woman that successfully underwent surgical resection. The efficacy of alternative treatments, such as transarterial chemoembolization or systemic chemotherapies, has not yet been established. To conclude, early diagnosis and appropriate surgical resection are important for the treatment of FLHCC.
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Affiliation(s)
- Seong Kyun Na
- Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Korea
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26
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Narayan NJC, Requena D, Lalazar G, Ramos-Espiritu L, Ng D, Levin S, Shebl B, Wang R, Hammond WJ, Saltsman JA, Gehart H, Torbenson MS, Clevers H, LaQuaglia MP, Simon SM. Human liver organoids for disease modeling of fibrolamellar carcinoma. Stem Cell Reports 2022; 17:1874-1888. [PMID: 35803261 PMCID: PMC9391427 DOI: 10.1016/j.stemcr.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 11/29/2022] Open
Abstract
Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.
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Affiliation(s)
- Nicole J C Narayan
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - David Requena
- 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
| | - Lavoisier Ramos-Espiritu
- High Throughput and Spectroscopy Center, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Denise Ng
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Solomon Levin
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Bassem Shebl
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Ruisi Wang
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - William J Hammond
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 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, New York, NY, USA; Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Helmuth Gehart
- Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands
| | - Michael S Torbenson
- Department of Laboratory Medicine and Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Hans Clevers
- Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands
| | - Michael P LaQuaglia
- Pediatric Surgical Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sanford M Simon
- Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
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27
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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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28
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Sempokuya T, Forlemu A, Azawi M, Silangcruz K, Khoury N, Ma J, Wong LL. Survival characteristics of fibrolamellar hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results database study. World J Clin Oncol 2022; 13:352-365. [PMID: 35662983 PMCID: PMC9153071 DOI: 10.5306/wjco.v13.i5.352] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/29/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct type of hepatocellular carcinoma that frequently presents in an advanced stage in younger patients with no underlying liver disease. Currently, there is a limited understanding of factors that impact outcomes in FL-HCC.
AIM To characterize the survival of FL-HCC by age, race, and surgical intervention.
METHODS This is a retrospective study of The Surveillance, Epidemiology, and End Results database. We identified patients with FL-HCC between 2000-2018 by using an ICD-O-3 site code C22.0 and a histology code 8171/3: Hepatocellular carcinoma, fibrolamellar. In addition, demographics, tumor characteristics, types of surgical procedure, stages, and survival data were obtained. We conducted three separate survival analyses by age groups; ≤ 19, 20-59, and ≥ 60-year-old, and race; White, Black, Hispanic, Asian and Pacific islanders (API), and surgical types; Wedge resection or segmental resection, lobectomy, extended lobectomy (lobectomy + locoregional therapy or resection of the other lobe), and transplant. The Chi-Square test analyzed categorical variables, and continuous variables were examined using the Mann-Whitney U test. The Kaplan-Meier survival curve was used to compare survival. Multivariate analysis was done with Cox regression analysis.
RESULTS We identified 225 FL-HCC patients with a mean age of 36.9. Overall median survival was 34 (95%CI: 27-41) mo. Patients ≤ 19-years-old had more advanced disease with positive lymph nodes status. However, they received more surgical interventions such as a wedge, segmental resection, lobectomy, extended lobectomy, and transplant. Survival for ≤ 19 was 85 (95%CI: 37-137) mo, age 20-59 was 29 (95%CI: 18-41) mo, and age ≥ 60 years was 12 (95%CI: 7-31) mo (P < 0.001). There were no differences in stage, lymph node status, metastasis status, and surgical treatment among races. The median survival were; Whites had 39 (95%CI: 29-63), Blacks 26 (95%CI: 5-92), Hispanics 31 (95%CI: 11-54), and APIs 28 (95%CI: 5-39) mo (P = 0.28). Of 225 patients, 111 FL-HCC patients had surgical procedures. Median survivals for a wedge or segmental resection was 112 (95%CI: 78-NA), lobectomy was 92 (95%CI: 57-NA), extended lobectomy was 54 (95%CI: 23-NA), and a transplant was 63 (95%CI: 20-NA) mo (P < 0.001). The median survival was better in patients who had surgical treatments regardless of lymph nodes or metastasis status (P < 0.001).
CONCLUSION FL-HCC occurs in a primarily younger population, but survival can be prolonged despite the aggressive disease. There were no racial differences in the survival of FL-HCC; however, Asians with FL-HCC tended to be older than in other races. Surgical treatment provided better survival even in those patients with nodal disease or metastases. Although future studies are needed to explore other therapies for FL-HCC, surgical options should be considered in all cases of FL-HCC unless contraindicated.
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Affiliation(s)
- Tomoki Sempokuya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Arnold Forlemu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Muaataz Azawi
- Division of Gastroenterology and Hepatology, Sanford Center for Digestive Health, Sioux Falls, SD 57105, United States
| | - Krixie Silangcruz
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States
| | - Nathalie Khoury
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Jihyun Ma
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Linda L Wong
- Department of Surgery, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, United States
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29
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Kang S, Magliocca J, Sellers M, Roccaro G, Zheng W, Pectasides M, Draper A, Guadagno J, El-Rayes B, Akce M. Successful liver transplantation of recurrent fibrolamellar carcinoma following clinical and pathologic complete response to triple immunochemotherapy: A case report. Oncol Res Treat 2022; 45:430-437. [PMID: 35537414 DOI: 10.1159/000524872] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/01/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects younger patients without a history of liver disease. Surgical resection is the cornerstone of therapy and represents the best potentially curative treatment option. Modest objective responses with cytotoxic chemotherapy alone or combined with immune checkpoint inhibitors (ICIs) have been reported, however there are no established systemic therapy regimens for unresectable or metastatic FLC. CASE PRESENTATION We report a case of a 23-year-old woman with FLC who presented with a 11.5 x 8.3 cm left liver mass and subsequently underwent resection as initial therapy. Molecular analysis of her surgical tissue revealed a DNAJB1-PRKACA fusion gene. The patient developed biopsy-proven recurrent FLC with multiple liver lesions but without any distant metastatic disease only 3 months after initial resection. In light of emerging data, the patient was treated with a novel triple therapy regimen including 5-fluorouracil (5-FU), interferon (IFN) alfa-2b, and nivolumab. Partial radiographic response was achieved after 4 treatments and complete response was achieved after 12 cycles with the combination. The patient received 2 more doses of 5-FU/IFN alfa-2b without nivolumab, and underwent orthotopic liver transplantation (OLT) 6 months after the last dose of ICI. Pathological examination of the explanted liver remarkably confirmed pathologic complete response. She remains recurrence-free and is on active surveillance. DISCUSSION/CONCLUSION For patients with unresectable/recurrent FLC with no distant disease, the combination of 5-FU, IFN alfa-2b, and nivolumab could be an effective systemic therapy option. The use of this chemoimmunotherapy regimen to downstage FLC prior to OLT may be worth investigating further.
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Affiliation(s)
- Sandra Kang
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA,
| | - Joseph Magliocca
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Marty Sellers
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Giorgio Roccaro
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Wei Zheng
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Melina Pectasides
- Department of Radiology and Imaging Services, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Amber Draper
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Jessica Guadagno
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Bassel El-Rayes
- Division of Hematology and Oncology, Department of Internal Medicine, O Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA
| | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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30
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Satake T, Morizane C, Rikitake R, Higashi T, Okusaka T, Kawai A. The epidemiology of rare types of hepatobiliary and pancreatic cancer from national cancer registry. J Gastroenterol 2022; 57:890-901. [PMID: 36161533 PMCID: PMC9596567 DOI: 10.1007/s00535-022-01920-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/05/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Information on rare hepatobiliary and pancreatic (HBP) subtypes of cancer is scarce. We aimed to elucidate the incidence and clinical features of rare tumors in Japan using the National Cancer Registry (NCR), a new nationwide integrated population-based registry. METHODS The data of patients diagnosed in 2016-2017 were extracted from the NCR database, and classified by topography: liver cells, intrahepatic bile duct, gallbladder, extrahepatic bile duct, ampulla of Vater, and pancreas. Data were described and analyzed using the World Health Organization and General Rules tumor classifications. The incidences for all rare tumors including hepatoblastoma and adenosquamous cell carcinoma were calculated as the number of new cases divided by the corresponding total person years. RESULTS The NCR data yielded 8,239 patients with rare HBP tumors between 2016 and 2017. The ratios of rare tumors to all cancer types were 0.5%, 0.7%, 3.9%, 1.6%, 0.8%, and 7.2% in the liver, intrahepatic bile duct, gallbladder, extrahepatic bile duct, ampulla of Vater, and pancreas, respectively. Rare tumors occurred more frequently in men, except for gallbladder tumors. The main tumor stage was localized in liver cells (42.4%) and the intrahepatic bile duct (51.6%); more patients were diagnosed in advanced stage with gallbladder (84.1%) and extrahepatic bile duct (74.4%) tumors. Approximately equal percentage of patients were diagnosed at designated cancer care hospitals (DCCHs) and non-DCCHs, whereas 60% to 70% patients received treatment at DCCHs. CONCLUSION This is the first report to provide comprehensive information on the epidemiological status of rare HBP tumors in Japan by utilizing population-based NCR data.
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Affiliation(s)
- Tomoyuki Satake
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan.
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Rare Cancer Center, National Cancer Center, Tokyo, Japan
| | - Ryoko Rikitake
- Institute for Cancer Control, Division of Health Services Research, National Cancer Center, Tokyo, Japan
| | - Takahiro Higashi
- Rare Cancer Center, National Cancer Center, Tokyo, Japan
- Division of Health Services Research, National Cancer Center, Tokyo, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akira Kawai
- Rare Cancer Center, National Cancer Center, Tokyo, Japan
- Department of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital, Tokyo, Japan
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31
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Ding J, Wen Z. Survival improvement and prognosis for hepatocellular carcinoma: analysis of the SEER database. BMC Cancer 2021; 21:1157. [PMID: 34715816 PMCID: PMC8555190 DOI: 10.1186/s12885-021-08904-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 10/18/2021] [Indexed: 02/07/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) incidences have been increasing in the United States. This study aimed to examine temporal trend of HCC survival and determine prognostic factors influencing HCC survival within the U.S. population. Methods The Surveillance Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with primary HCC from 1988 to 2015. Overall survival (OS) and disease-specific survival (DSS) were calculated by the Kaplan-Meier method. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for prognostic factors and comparing survival between patients diagnosed at different periods (per 5-year interval). Results A total of 80,347 patients were included. The proportions of both young patients (< 45 years) and old patients (≥75 years) decreased over time (P < 0.001) and the male-to-female ratio increased over time (P < 0.001). Significant decreasing temporal trends were observed for HCC severity at diagnosis, including SEER stage, tumor size, tumor extent, and lymph node involvement (P < 0.001 for all). OS and DSS of patients with HCC improved over time (P < 0.001). After adjusting for patient and tumor characteristics and treatment difference, period of diagnosis retained an independent factor for improved DSS and its prognostic significance was evident for localized and regional HCC (P < 0.001), but not for distant HCC. On multivariate analyses, young age, female gender, Hispanic ethnicity, and married status were predictors favoring DSS, whereas a worse DSS was observed for patients with tumor > 5 cm, with vascular invasion, and with lymph node involvement. Patients treated with liver-directed therapy (HR = 0.54, 95% CI: 0.35–0.56), hepatic resection (HR = 0.35, 95% CI: 0.33–0.37), and transplantation (HR = 0.14, 95% CI: 0.13–0.15) had significantly longer DSS compared with those who received no surgery. In stratified analyses, the beneficial effects of surgical approach, regardless therapy type, were significant across all stages. Conclusions Our results indicate a significant improvement in survival for HCC patients from 1988 to 2015, which may be attributable to advances in early diagnosis and therapeutic approaches.
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Affiliation(s)
- Jingli Ding
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Hubei, Wuhan, 430071, China.,Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Jiangxi, Nanchang, 330006, China
| | - Zhili Wen
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Jiangxi, Nanchang, 330006, China.
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Lalazar G, Requena D, Ramos-Espiritu L, Ng D, Bhola PD, de Jong YP, Wang R, Narayan NJC, Shebl B, Levin S, Michailidis E, Kabbani M, Vercauteren KOA, Hurley AM, Farber BA, Hammond WJ, Saltsman JA, Weinberg EM, Glickman JF, Lyons BA, Ellison J, Schadde E, Hertl M, Leiting JL, Truty MJ, Smoot RL, Tierney F, Kato T, Wendel HG, LaQuaglia MP, Rice CM, Letai A, Coffino P, Torbenson MS, Ortiz MV, Simon SM. Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening. Cancer Discov 2021; 11:2544-2563. [PMID: 34127480 PMCID: PMC8734228 DOI: 10.1158/2159-8290.cd-20-0872] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 03/12/2021] [Accepted: 05/25/2021] [Indexed: 11/16/2022]
Abstract
To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.This article is highlighted in the In This Issue feature, p. 2355.
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Affiliation(s)
- Gadi Lalazar
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York
| | - David Requena
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
| | - Lavoisier Ramos-Espiritu
- High Throughput and Spectroscopy Resource Center, The Rockefeller University, New York, New York
| | - Denise Ng
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
| | - Patrick D Bhola
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ype P de Jong
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York
| | - Ruisi Wang
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
| | - Nicole J C Narayan
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
- Pediatric Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Bassem Shebl
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
| | - Solomon Levin
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
| | - Eleftherios Michailidis
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York
| | - Mohammad Kabbani
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York
| | - Koen O A Vercauteren
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York
- Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium
- Institute of Tropical Medicine, Antwerp, Belgium
| | - Arlene M Hurley
- Hospital Program Direction, The Rockefeller University, New York, New York
| | - Benjamin A Farber
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
- Department of Surgery, Division of Pediatric Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - William J Hammond
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
- Pediatric Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York
| | - James A Saltsman
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
- Pediatric Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Surgery, Mount Sinai Hospital, New York, New York
| | - Ethan M Weinberg
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - J Fraser Glickman
- High Throughput and Spectroscopy Resource Center, The Rockefeller University, New York, New York
| | - Barbara A Lyons
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico
| | - Jessica Ellison
- Division of Transplantation, Rush University Medical Center, Chicago, Illinois
| | - Erik Schadde
- Department of Surgery, Division of Transplantation and Division of Surgical Oncology, Rush University Medical Center, Chicago, Illinois
| | - Martin Hertl
- Division of Transplantation, Rush University Medical Center, Chicago, Illinois
| | - Jennifer L Leiting
- Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Mark J Truty
- Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Rory L Smoot
- Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Faith Tierney
- Division of Abdominal Organ Transplantation, New York-Presbyterian/Columbia University, New York, New York
| | - Tomoaki Kato
- Division of Abdominal Organ Transplantation, New York-Presbyterian/Columbia University, New York, New York
| | - Hans-Guido Wendel
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael P LaQuaglia
- Pediatric Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York
| | - Anthony Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Philip Coffino
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York
| | | | - Michael V Ortiz
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sanford M Simon
- Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York.
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Natarajan Y, El‐Serag HB. Risk Factors for Hepatocellular Carcinoma: A Historical Perspective. Clin Liver Dis (Hoboken) 2021; 18:1-13. [PMID: 34745580 PMCID: PMC8555458 DOI: 10.1002/cld.1042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/12/2020] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Audio Recording.
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Affiliation(s)
- Yamini Natarajan
- Section of Gastroenterology and HepatologyDepartment of MedicineMichael E DeBakey VA Medical Center and Baylor College of MedicineHoustonTX
| | - Hashem B. El‐Serag
- Section of Gastroenterology and HepatologyDepartment of MedicineMichael E DeBakey VA Medical Center and Baylor College of MedicineHoustonTX
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Takahashi A, Imamura H, Ito R, Kawano F, Gyoda Y, Ichida H, Yoshioka R, Mise Y, Fukumura Y, Sano K, Saiura A. A case report of fibrolamellar hepatocellular carcinoma, with particular reference to preoperative diagnosis, value of molecular genetic diagnosis, and cell origin. Surg Case Rep 2021; 7:208. [PMID: 34533614 PMCID: PMC8448801 DOI: 10.1186/s40792-021-01295-4] [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: 07/12/2021] [Accepted: 09/10/2021] [Indexed: 01/12/2023] Open
Abstract
Background Fibrolamellar hepatocellular carcinoma (FL-HCC) is a liver tumor that occurs almost exclusively in young adults without underlying liver disease. In spite of its distinct clinical characteristics and specific imaging findings, preoperative diagnosis is often difficult due to the extremely low incidence of the tumor. Although FL-HCC shows particular morphological features on H&E-stained tissue sections, differential diagnosis from ordinary HCC, especially the scirrhous variant of HCC, and intrahepatic cholangiocarcinoma needs additional immunohistochemical (IHC) analyses and/or molecular genetic testing. Case presentation A 21-year-old male patient was referred to our hospital for further evaluation of a large liver mass. Abdominal ultrasound examination, contrast-enhanced computed tomography, and magnetic resonance imaging revealed a well-defined hypervascular lobulated liver mass, 11 × 11 cm in diameter, with a central scar and calcification, in segments 5/8. Under the diagnosis of FL-HCC, we carried out extended anterior sectorectomy, including a part of segment 4. On microscopic examination, the tumor was composed of proliferating polygonal cells with abundant eosinophilic granular cytoplasm containing nuclei with vesicular chromatin and enlarged nucleoli, in an abundant stroma. Collagen fibers arranged in a parallel lamellar pattern were seen in the tumor stroma. These findings, together with the results of subsequent IHC analyses using HAS, CK7, and CD 67, we made the diagnosis of FL-HCC, which was further confirmed by detection of the DNAJB1-PRKACA fusion gene in the tumor cells by RT-PCR. Conclusion FL-HCC shows distinct imaging appearances. Although it also has characteristic morphological features, combined use of IHC and/or molecular genetic studies are necessary for the final diagnosis.
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Affiliation(s)
- Atsushi Takahashi
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Hiroshi Imamura
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Ryota Ito
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Fumihiro Kawano
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Yu Gyoda
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Hirofumi Ichida
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Ryuji Yoshioka
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Yoshihiro Mise
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Yuki Fukumura
- Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Katsuhiro Sano
- Department of Radiology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akio Saiura
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Juntendo University Hospital, 3-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan.
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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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Depauw L, De Weerdt G, Gys B, Demeulenaere S, Mebis W, Ysebaert D. Pediatric fibrolamellar hepatocellular carcinoma: case report and review of the literature. Acta Chir Belg 2021; 121:204-210. [PMID: 34082642 DOI: 10.1080/00015458.2019.1660060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND A 13-year-old boy presented with acute abdominal pain in the right upper quadrant without previous trauma. Abdominal ultrasound (US) revealed a mass in the right liver lobe with free intraperitoneal fluid, suggestive for hemoperitoneum. Magnetic resonance imaging confirmed a subcapsular lesion (5.7 × 4.6 × 4.1 cm), suggestive for fibrolamellar hepatocellular carcinoma (FL-HCC). Positron emission tomography-computed tomography revealed mild to moderate fluorodeoxyglucose (FDG) avidity, with no other FDG avid lesions. Hepatic tumor markers were negative. CASE REPORT An elective right hepatectomy with cholecystectomy and hilar lymph node resection was performed. RESULTS Histology showed a central fibrous scar and confirmed a FL-HCC (pT1bN0M0). The resected lymph nodes were tumor-free. Treatment of FL-HCC should consist of complete tumor resection with concurrent lymph node resection +/- orthotopic liver transplantation. Long-term follow-up is advised. A follow-up interval of 3-4 months in the first 2 years after surgical resection can be justified as FL-HCC have a high recurrence rate of more than 50% within 10-33 months. CONCLUSIONS Malignancy can be a rare cause of abdominal pain in pediatric patients. An abdominal US is essential to prevent misdiagnosis. Treatment of FL-HCC should consist of R0 tumor resection with concurrent lymphadenectomy +/- orthotopic liver transplantation.
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Affiliation(s)
- Laura Depauw
- Department of Hepatobiliairy Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Glenn De Weerdt
- Department of Hepatobiliairy Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Ben Gys
- Department of Hepatobiliairy Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Sofie Demeulenaere
- Department of Hepatobiliairy Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Wouter Mebis
- Department of Hepatobiliairy Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Dirk Ysebaert
- Department of Hepatobiliairy Surgery, Antwerp University Hospital, Antwerp, Belgium
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Samdanci ET, Akatli AN, Soylu NK. Clinicopathological Features of Two Extremely Rare Hepatocellular Carcinoma Variants: a Brief Review of Fibrolamellar and Scirrhous Hepatocellular Carcinoma. J Gastrointest Cancer 2021; 51:1187-1192. [PMID: 32860202 DOI: 10.1007/s12029-020-00500-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE We aimed to distinguish between fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma histopathologically. METHODS AND RESULTS In this review, fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma two specific and rare variants of hepatocellular carcinoma, which are difficult to diagnose histopathologically are discussed. CONCLUSION The clinical, radiological, gross, histopathological, immunohistochemical, and molecular features of these two tumors, which are defined by the World Health Organization (WHO), are mentioned.
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Affiliation(s)
- Emine Turkmen Samdanci
- Liver Institute, Pathology Department, Inonu University, School of Medicine, Malatya, Turkey.
| | - Ayse Nur Akatli
- Liver Institute, Pathology Department, Inonu University, School of Medicine, Malatya, Turkey
| | - Nese Karadag Soylu
- Liver Institute, Pathology Department, Inonu University, School of Medicine, Malatya, Turkey
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Tan N, Apostolov R, Au M, Vasudevan A, Nicoll A. Investigating Liver Masses in Young Adults. Am J Med 2021; 134:596-598. [PMID: 33245924 DOI: 10.1016/j.amjmed.2020.10.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 11/18/2022]
Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia.
| | - Ross Apostolov
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia
| | - Minnie Au
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia
| | - Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia; Eastern Health Clinical School, Monash University, Victoria, Australia
| | - Amanda Nicoll
- Department of Gastroenterology and Hepatology, Eastern Health, Box Hill, Victoria, Australia; Eastern Health Clinical School, Monash University, Victoria, Australia
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Vij M, Calderaro J. Pathologic and molecular features of hepatocellular carcinoma: An update. World J Hepatol 2021; 13:393-410. [PMID: 33959223 PMCID: PMC8080551 DOI: 10.4254/wjh.v13.i4.393] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/27/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Morphological diversity and several new distinct pathologic subtypes of hepatocellular carcinoma (HCC) are now well-recognized. Recent advances in tumor genomics and transcriptomics have identified several recurrent somatic/genetic alterations that are closely related with histomorphological subtypes and have therefore, greatly improved our understanding of HCC pathogenesis. Pathologic subtyping allows for a diagnosis which is clinically helpful and can have important implication in patient prognostication as some of these subtypes are extremely aggressive with vascular invasion, early recurrence, and worst outcomes. Several targeted treatments are now being considered in HCC, and the reporting of subtypes may be quite useful for personalized therapeutic purpose. This manuscript reviews the recently identified histomorphological subtypes and molecular alterations in HCC.
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Affiliation(s)
- Mukul Vij
- Department ofPathology, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India.
| | - Julien Calderaro
- Department of Pathology, Groupe Hospitalier Henri Mondor, Creteil F-94010, France
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Fu T, Ding H, Xu C, Zhu Y, Xue L, Lin F. Imaging findings of fibrolamellar hepatocellular carcinomas on ultrasonography: A comparison with conventional hepatocellular carcinomas. Clin Hemorheol Microcirc 2021; 77:49-60. [PMID: 32924993 DOI: 10.3233/ch-200896] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Fibrolamellar hepatocellular carcinoma (FLHCC) is an unusual variant of hepatocellular carcinoma (HCC). Revealing the imaging features is important to the diagnosis of FLHCC. OBJECTIVE The aim of this study was to investigate the imaging characteristics of FLHCCs. METHODS This retrospective study included 29 patients with histopathologically proved FLHCC and 96 patients proved HCC. All patients underwent an ultrasound examination pre-operation. RESULTS The average maximum diameters of the FLHCC and HCC lesions were 7.4±4.1 cm and 4.1±3.0 cm, respectively. On the ultrasound, 79.3% of the FLHCCs and 12.3% of the HCCs showed the internal hyperechoic area; 48.3% of the FLHCCs and 3.3% of the HCCs displayed a strip-like attenuation. Calcification was noted in 20.7% of the FLHCCs, while none in HCCs. On the contrast-enhanced ultrasound (CEUS), all FLHCC lesions and 87.7% of the HCCs displayed hyperenhancement in the arterial phase. An internal, unenhanced central scar appeared in all FLHCCs, while none in HCCs. CONCLUSIONS The ultrasonographic features of FLHCC lesions indicate that they are relatively large masses showing the internal hyperechoic area or strip-like attenuation or calcification on the US and hypervascularity with an unenhanced central scar on the CEUS as compared with conventional HCC lesions.
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Affiliation(s)
- Tiantian Fu
- Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hong Ding
- Department of Ultrasound, Huashan Hospital, Fudan University, Shanghai, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuli Zhu
- Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liyun Xue
- Department of Ultrasound, Shanghai Institute of Medical Imaging, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Feng Lin
- School of Computer Science and Engineering, Nanyang Technological University, Singapore, Singapore
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Olivieri C, Walker C, Karamafrooz A, Wang Y, Manu VS, Porcelli F, Blumenthal DK, Thomas DD, Bernlohr DA, Simon SM, Taylor SS, Veglia G. Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A. Commun Biol 2021; 4:321. [PMID: 33692454 PMCID: PMC7946884 DOI: 10.1038/s42003-021-01819-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 01/29/2021] [Indexed: 02/08/2023] Open
Abstract
An aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-CDNAJB1) in which the J-domain of the heat shock protein 40 is fused to the catalytic α subunit of cAMP-dependent protein kinase A (PKA-C). Deceivingly, this chimeric construct appears to be fully functional, as it phosphorylates canonical substrates, forms holoenzymes, responds to cAMP activation, and recognizes the endogenous inhibitor PKI. Nonetheless, PKA-CDNAJB1 has been recognized as the primary driver of fibrolamellar hepatocellular carcinoma and is implicated in other neoplasms for which the molecular mechanisms remain elusive. Here we determined the chimera's allosteric response to nucleotide and pseudo-substrate binding. We found that the fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing dramatic attenuation of the nucleotide/PKI binding cooperativity. Our findings suggest that the reduced allosteric cooperativity exhibited by PKA-CDNAJB1 alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.
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Affiliation(s)
- Cristina Olivieri
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Caitlin Walker
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Adak Karamafrooz
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Yingjie Wang
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
- Chemistry, University of Minnesota, Minneapolis, MN, USA
- Shenzhen Bay Laboratory, Shenzhen, China
| | - V S Manu
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Fernando Porcelli
- DIBAF - University of Tuscia - Largo dell' Università, Viterbo, Italy
| | - Donald K Blumenthal
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
| | - David D Thomas
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - David A Bernlohr
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Sanford M Simon
- Laboratory of Cellular Biophysics, Rockefeller University, New York, NY, USA
| | - Susan S Taylor
- Department of Chemistry and Biochemistry and Pharmacology, University of California at San Diego, La Jolla, CA, USA
| | - Gianluigi Veglia
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
- Chemistry, University of Minnesota, Minneapolis, MN, USA.
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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: 13] [Impact Index Per Article: 3.3] [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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Bello HR, Mahdi ZK, Lui SK, Nandwana SB, Harri PA, Davarpanah AH. Hepatocellular Carcinoma With Atypical Imaging Features: Review of the Morphologic Hepatocellular Carcinoma Subtypes With Radiology-Pathology Correlation. J Magn Reson Imaging 2021; 55:681-697. [PMID: 33682266 DOI: 10.1002/jmri.27553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States with the incidence rate more than doubling in 20 years. HCC is unique since a noninvasive diagnosis can be achieved with imaging alone when specific clinical criteria and imaging characteristics are met, obviating the need for tissue sampling. However, HCC is a highly heterogeneous neoplasm. Atypical HCC subtypes vary significantly in their morphology, which can be attributed to specific histologic and molecular features, and can cause deviations from the classic imaging characteristics. The different morphologic subtypes of HCC frequently present a diagnostic challenge for radiologists and pathologists since their imaging and pathologic features can overlap with those of non-HCC malignancies. Identifying an atypical subtype can have important clinical implications. Liver transplant, albeit a scarce and limited resource, is the optimal treatment for conventional HCC, potentially curing both the tumor and the underlying pre-malignant condition. Some HCC subtypes as well as mimickers are associated with unacceptably high recurrence and poor outcome after transplant, and there remains limited data on the role and prognosis of liver transplantation for treatment of rare HCC subtypes. Other subtypes tend to recur later than classic HCC, potentially requiring a different follow-up scheme. This review will discuss the appearance of different HCC subtypes in relation to their histopathologic features. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.
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Affiliation(s)
- Hernan R Bello
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Zaid K Mahdi
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Shu K Lui
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Sadhna B Nandwana
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Peter A Harri
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Amir H Davarpanah
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
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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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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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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: 29] [Impact Index Per Article: 7.3] [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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Shah PA, Cho J, Albitar HAH, Pajot G, Liu M, Ravi K. Hyperammonemic Encephalopathy Exacerbated by Parenteral Nutrition in Fibrolamellar Hepatocellular Carcinoma. Am J Med 2020; 133:e745-e746. [PMID: 32739410 DOI: 10.1016/j.amjmed.2020.06.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 06/09/2020] [Accepted: 06/09/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Pir Ahmad Shah
- Liver Research Center, Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.
| | - Janice Cho
- Mayo Clinic, Gastroenterology, Rochester, Minn
| | | | | | - Mengfei Liu
- Mayo Clinic, Gastroenterology, Rochester, Minn
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Razik A, Malla S, Goyal A, Gamanagatti S, Kandasamy D, Das CJ, Sharma R, Gupta AK. Unusual Primary Neoplasms of the Adult Liver: Review of Imaging Appearances and Differential Diagnosis. Curr Probl Diagn Radiol 2020; 51:73-85. [PMID: 33199074 DOI: 10.1067/j.cpradiol.2020.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 10/16/2020] [Indexed: 12/24/2022]
Abstract
The radiological appearance of common primary hepatic tumors such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is widely recognized. Hepatic masses with unusual histology are occasionally encountered, but seldom suspected on imaging. However, many possess characteristic imaging findings, which when assessed along with the clinical and demographic background and serum tumor markers, may enable a prospective diagnosis. This review attempts to familiarize the reader with the clinicopathological characteristics, imaging manifestations, and differential diagnosis of these unusual liver tumors in adults. Biphenotypic primary liver carcinoma is suspected in masses showing distinct areas of HCC and CCA-type enhancement pattern in cirrhotic livers. Fibrolamellar carcinoma occurs in young individuals without underlying chronic liver disease and shows a characteristic T2-hypointense scar frequently showing calcification. Perivascular epithelioid cell tumors are differentials for any arterial hyperenhancing mass in the noncirrhotic liver, particularly in patients with tuberous sclerosis. Multifocal subcapsular tumors showing target-like morphology, capsular retraction and "lollipop" sign are suspicious for epithelioid hemangioendothelioma. On the other hand, multiple hemorrhagic lesions showing patchy areas of bizarre-shaped arterial phase hyperenhancement are suspicious for angiosarcoma. Primary hepatic lymphoma (PHL) is suspected when patients with immunosuppression present with solitary or multifocal masses that insinuate around vessels and bile ducts without causing luminal narrowing. Intense diffusion restriction and low-level homogeneous or target-like enhancement are also ancillary features of PHL. Primary hepatic neuroendocrine tumor shows uptake on Ga-68 DOTANOC PET/CT. Although a straightforward diagnosis may be difficult in these cases, awareness of the characteristic imaging appearances is helpful in suspecting the diagnosis.
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Affiliation(s)
- Abdul Razik
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India
| | - Sundeep Malla
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India
| | - Ankur Goyal
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India
| | - Shivanand Gamanagatti
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India
| | | | - Chandan Jyoti Das
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India
| | - Raju Sharma
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India.
| | - Arun Kumar Gupta
- Department of Radiodiagnosis, All India Institute of Medical Sciences (A.I.I.M.S), New Delhi, India
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El Dika I, Mayer RJ, Venook AP, Capanu M, LaQuaglia MP, Kobos R, O'Neill AF, Chou JF, Ly M, Ang C, O'Reilly EM, Gordan JD, Abou‐Alfa GK. A Multicenter Randomized Three-Arm Phase II Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) with Leuprolide + Letrozole, and (3) Everolimus + EDT in Patients with Unresectable Fibrolamellar Carcinoma. Oncologist 2020; 25:925-e1603. [PMID: 32400000 PMCID: PMC7648371 DOI: 10.1634/theoncologist.2020-0367] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Indexed: 12/11/2022] Open
Abstract
LESSONS LEARNED FLC is a complex cancer with many implicated oncogenic pathways. Single or dual targeting does not appear to alter the natural history of the cancer, and novel therapeutics are needed. Estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. The study drugs were well tolerated when administered as single agents or in combination in this patient population. This study demonstrates that, despite the rarity of FLC, multicenter therapeutic clinical trials are feasible and support the value of this consortium. BACKGROUND Fibrolamellar carcinoma (FLC) is an uncommon malignancy in young people and is sometimes associated with pregnancy and oral contraceptive use. Immunohistochemical staining and genetic profiling of FLC tumor specimens have revealed aromatase overexpression. The overexpression of mTOR and S6 kinase has been noted in 25% of FLC. On the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, we hypothesized that suppression of estrogen and mTOR signaling could have antineoplastic activity in FLC. METHODS Patients were randomized to arm A (everolimus), arm B (letrozole/leuprolide; estrogen deprivation therapy [EDT]), or arm C (everolimus/letrozole/leuprolide). Upon disease progression, patients in arm A or B could proceed to part 2 (everolimus/letrozole/leuprolide). The primary endpoint was progression-free survival (PFS) at 6 months (PFS6) assessed using a Simon's minimax two-stage design, hypothesizing an improvement in PFS6 from 40% to 64% with the study regimen. RESULTS Twenty-eight patients were enrolled. An unplanned analysis was performed because of perceived concern for lack of efficacy. Stable disease was observed in 9 of 26 evaluable patients (35%). PFS6 was 0%. Median overall survival (OS) was 12.4 months (95% confidence interval [CI], 7.4-20.9) for the whole study cohort. Grade 3 adverse events in ≥10% of patients were nausea (11%), vomiting (11%), anemia (11%), elevated aspartate transaminase (AST; 32%), alanine transaminase (ALT; 36%), and alkaline phosphatase (14%). All 28 patients experienced an event for PFS outcome, and four deaths were due to disease progression. CONCLUSION Neither EDT nor mTOR inhibition improved outcomes in FLC. Other treatment strategies are needed.
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Affiliation(s)
- Imane El Dika
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Weill Cornell College of MedicineNew YorkNew YorkUSA
| | - Robert J. Mayer
- Dana‐Farber Cancer Institute, Harvard Medical SchoolBostonMassachusettsUSA
| | - Alan P. Venook
- University of California San FranciscoSan FranciscoCaliforniaUSA
| | | | - Michael P. LaQuaglia
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Weill Cornell College of MedicineNew YorkNew YorkUSA
| | - Rachel Kobos
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Weill Cornell College of MedicineNew YorkNew YorkUSA
| | - Allison F. O'Neill
- Dana‐Farber Cancer Institute, Harvard Medical SchoolBostonMassachusettsUSA
| | - Joanne F. Chou
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Michele Ly
- Sidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Celina Ang
- Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Eileen M. O'Reilly
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Weill Cornell College of MedicineNew YorkNew YorkUSA
| | - John D. Gordan
- University of California San FranciscoSan FranciscoCaliforniaUSA
| | - Ghassan K. Abou‐Alfa
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
- Weill Cornell College of MedicineNew YorkNew YorkUSA
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50
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El Dika I, Bowman AS, Berger MF, Capanu M, Chou JF, Benayed R, Zehir A, Shia J, O'Reilly EM, Klimstra DS, Solit DB, Abou-Alfa GK. Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver. Cancer 2020; 126:4126-4135. [PMID: 32663328 DOI: 10.1002/cncr.32960] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/23/2020] [Accepted: 04/13/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. METHODS Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. RESULTS A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%). CONCLUSIONS The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.
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Affiliation(s)
- Imane El Dika
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
| | - Anita S Bowman
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Michael F Berger
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
| | - Marinela Capanu
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Joanne F Chou
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ryma Benayed
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ahmet Zehir
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jinru Shia
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
| | - Eileen M O'Reilly
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
| | - David S Klimstra
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
| | - David B Solit
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Weill Cornell College of Medicine, New York, New York, USA
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