Metastatic fibrolamellar hepatocellular carcinoma in the immune checkpoint and multikinase inhibitor era: A case report

Abstract

Fibrolamellar carcinoma (FLC) is a rare liver cancer that predominantly affects young adults without liver disease. Its typical symptoms include abdominal pain, palpable mass, and/or generalized signs such as weight loss and fatigue. Although patients with localized FLC frequently experience favorable outcomes after surgical resection, the recurrence rate is high. For patients with metastatic or unresectable FLC, alternative treatments such as chemotherapy and radiation are considered; however, standardized treatment protocols remain scarce. This case report describes a 24-year-old man with de novo metastatic FLC and peritoneal involvement. The patient was administered various therapies, including atezolizumab and bevacizumab combination therapy; lenvatinib, folinic acid, fluorouracil, oxaliplatin; and folinic acid, fluorouracil, irinotecan plus bevacizumab. The response to each regimen varied, ranging from initial response followed by disease progression to no response at all. Although metastatic FLC is an uncommon disease, it presents a substantial challenge to patients and healthcare professionals due to the absence of well-established guidelines. In addition to numerous published cases, this case report may offer clinicians valuable insights into the management of FLC.

Keywords

Fibrolamellar carcinoma / Hepatocellular carcinoma / Immune checkpoint inhibitors / Folinic acid / Fluorouracil / Oxaliplatin / Folinic acid / Fluorouracil / Irinotecan / Lenvatinib

References

[1] Edmondson HA. Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA J Dis Child. 1956; 91(2):168-186. doi: 10.1001/archpedi.1956.02060020170015

[2] Chaudhari VA, Khobragade K, Bhandare M, Shrikhande SV. Management of fibrolamellar hepatocellular carcinoma. Chin Clin Oncol. 2018; 7(5):51. doi: 10.21037/cco.2018.08.08

[3] Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: A tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer. 1980; 46(2):372-379. doi: 10.1002/1097-0142(19800715)46:2<372:aid-cncr2820460227>3.0.co;2-s

[4] Graham RP, Torbenson MS. Fibrolamellar carcinoma: A histologically unique tumor with unique molecular findings. Semin Diagn Pathol. 2017; 34:146-152. doi: 10.1053/j.semdp.2016.12.010

[5] O’Neill AF, Church AJ, Perez-Atayde AR, Shaikh R, Marcus KJ, Vakili K. Fibrolamellar carcinoma: An entity all its own. Curr Probl Cancer. 2021; 45(4):100770. doi: 10.1016/j.currproblcancer.2021.100770

[6] 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. doi: 10.1016/j.prp.2023.154655

[7] Alsadery HA, Almaiman H, Alibrah R, et al. Case report of fibrolamellar hepatocellular carcinoma in A 15-year-old male. Med Arch. 2022; 76(5):387-390. doi: 10.5455/medarh.2022.76.387-390

[8] Bacinschi X, Zgura AF, Mercan-Stanciu A, et al. Management of diagnosis and treatment in a case of fibrolamellar carcinoma. Cancer Diagn Progn. 2021; 1(1):23-28. doi: 10.21873/cdp.10004

[9] Berger R, Dinstag G, Tirosh O, et al. Fibrolamellar carcinoma transcriptomic-based treatment prediction: Complete response after nivolumab and ipilimumab. J Immunother Cancer. 2022; 10(12):e005620. doi: 10.1136/jitc-2022-005620

[10] Wu J, Liu W, Qiu X, et al. A Noninvasive approach to evaluate tumor immune microenvironment and predict outcomes in hepatocellular carcinoma. Phenomics. 2023; 3(6):549-564. doi: 10.1007/s43657-023-00136-8

[11] Tan J, Fan W, Liu T, et al. TREM2+ macrophages suppress CD8+ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma. J Hepatol. 2023; 79(1):126-140. doi: 10.1016/j.jhep.2023.02.032

[12] Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. New Engl J Med. 2020; 382(20):1894-1905. doi: 10.1056/nejmoa1915745

[13] Al Zahrani A, Alfakeeh A. Fibrolamellar hepatocellular carcinoma treated with atezolizumab and bevacizumab: Two case reports. J Med Case Rep. 2021; 15(1):132. doi: 10.1186/s13256-021-02695-8

[14] Matsuki R, Okano N, Hasui N, et al. Atezolizumab and bevacizumab combination therapy and sequential conversion hepatectomy for advanced fibrolamellar hepatocellular carcinoma presenting pseudoprogression. Liver Cancer. 2023; 12(2):180-183. doi: 10.1159/000527250

[15] Chen KY, Popovic A, Hsiehchen D, et al. Clinical outcomes in fibrolamellar hepatocellular carcinoma treated with immune checkpoint inhibitors. Cancers (Basel). 2022; 14(21):5347. doi: 10.3390/cancers14215347

[16] Bernon MM, Gandhi K, Allam H, Singh S, Kloppers J, Jonas E. Trans-arterial therapy for fibrolamellar carcinoma: A case report and literature review. Int J Surg Case Rep. 2022; 94:106980. doi: 10.1016/j.ijscr.2022.106980

[17] Zhang N, Yin Y, Xu SJ, Chen WS. 5-Fluorouracil: Mechanisms of resistance and reversal strategies. Molecules. 2008; 13(8):1551-1569. doi: 10.3390/molecules13081551

[18] Hundal J, Nagaraj A, Luke A, Vredenburgh J. A rare case of metastatic ectopic fibrolamellar hepatocellular carcinoma in a young healthy patient: A case report. Curr Probl Cancer Case Rep. 2021; 4:100099. doi: 10.1016/j.cpccr.2021.100099

[19] Thakral N, Simonetto DA. Hyperammonemic encephalopathy: An unusual presentation of fibrolamellar hepatocellular carcinoma. Clin Mol Hepatol. 2020; 26(1):74-77. doi: 10.3350/cmh.2018.0042

[20] Chai Y, Liu JL, Zhang S, et al. The effective combination therapies with irinotecan for colorectal cancer. Front Pharmacol. 2024; 15:1356708. doi: 10.3389/fphar.2024.1356708

[21] Kent P, Stockwell T, Tasse JC, et al. Lenvatinib, gemcitabine, and oxaliplatin for 67 patients with fibrolamellar carcinoma. J Clin Oncol. 2024; 42:e16151. doi: 10.1200/JCO.2024.42.16_suppl.e16151

[22] Kent P, Tasse JC, Schadde E, et al. Early experience with nivolumab, gemcitabine, and lenvatinib for fibrolamellar hepatocellular carcinoma. J Clin Oncol. 2023; 41:4076. doi: 10.1200/JCO.2023.41.16_suppl.4076

[23] Gottlieb S, Gliksberg A, Schadde E, Kent P. Novel Systemic Therapies in the Treatment of Fibrolamellar Carcinoma. United States: Wolters Kluwer Health; 2021.

[24] Chakrabarti S, Tella SH, Kommalapati A, et al. Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma. J Gastrointest Oncol. 2019; 10(3):554-561. doi: 10.21037/jgo.2019.01.35

[25] Smith M, Tomboc PJ, Markovich B. Fibrolamellar hepatocellular carcinoma. StatPearls. Sreasure Island, FL: StatPearls Publishing; 2024.

[26] Na SK. Fibrolamellar hepatocellular carcinoma that was successfully treated with surgical resection: A case report. J Liver Cancer. 2022; 22(2):178-182. doi: 10.17998/jlc.2022.06.10

[27] Tanaka H, Hijioka S, Iwaya H, et al. Fibrolamellar hepatocellular carcinoma with multiple lung metastases treated with multidisciplinary therapy. Intern Med. 2018; 57(24):3537-3543. doi: 10.2169/internalmedicine.1243-18

[28] Shebl B, Ng D, Lalazar G, et al. Targeting BCL-XL in fibrolamellar hepatocellular carcinoma. JCI Insight. 2022; 7(17):e161820. doi: 10.1172/jci.insight.161820

[29] Hagiwara S, Oda I, Ueshima K, et al. A case of fibrolamellar hepatocellular carcinoma in which tumor control was achieved by re-administering atezolizumab and bevacizumab. Cancer Rep (Hoboken). 2024; 7(12):e70090. doi: 10.1002/cnr2.70090

[30] Torbenson M. Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol. 2007; 14(3): 217-223. doi: 10.1097/PAP.0b013e3180504913

[31] Assi HA, Mukherjee S, Machiorlatti M, Vesely S, Pareek V, Hatoum H. Predictors of outcome in patients with fibrolamellar carcinoma: Analysis of the national cancer database. Anticancer Res. 2020; 40(2):847-855. doi: 10.21873/anticanres.14017

[32] Wahab MA, El Hanafy E, El Nakeeb A, Ali MA. Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma (experience with 22 patients over a 15-year period). World J Gastrointest Surg. 2017; 9(2):61-67. doi: 10.4240/wjgs.v9.i2.61

[33] Friedman AC, Lichtenstein JE, Goodman Z, Fishman EK, Siegelman SS, Dachman AH. Fibrolamellar hepatocellular carcinoma. Radiology. 1985; 157(3):583-587. doi: 10.1148/radiology.157.3.2997835

[34] Ganeshan D, Szklaruk J, Kundra V, Kaseb A, Rashid A, Elsayes KM. Imaging features of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol. 2014; 202(3): 544-552. doi: 10.2214/AJR.13.11117

[35] Lafaro KJ, Pawlik TM. Fibrolamellar hepatocellular carcinoma: Current clinical perspectives. J Hepatocell Carcinoma. 2015; 2:151-157. doi: 10.2147/jhc.S75153

[36] Abdelhamed W, El-Kassas M. Fibrolamellar hepatocellular carcinoma: A rare but unpleasant event. World J Gastrointest Oncol. 2022; 14(6):1103-1114. doi: 10.4251/wjgo.v14.i6.1103

[37] Di Bisceglie AM. Epidemiology and clinical presentation of hepatocellular carcinoma. J Vasc Interv Radiol. 2002; 13(9 Pt2):S169-S171. doi: 10.1016/s1051-0443(07)61783-7

[38] Bauer J, Köhler N, Maringer Y, et al. The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. Nat Commun. 2022; 13(1):6401. doi: 10.1038/s41467-022-33746-3

[39] Xu L, Hazard FK, Zmoos AF, et al. Genomic analysis of fibrolamellar hepatocellular carcinoma. Hum Mol Genet. 2015; 24(1):50-63. doi: 10.1093/hmg/ddu418

[40] Cieply B, Zeng G, Proverbs-Singh T, Geller DA, Monga SP. Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology. 2009; 49(3): 821-831. doi: 10.1002/hep.22695

[41] Neumayer C, Ng D, Jiang CS, et al. Oncogenic addiction of fibrolamellar hepatocellular carcinoma to the fusion kinase DNAJB1-PRKACA. Clin Cancer Res. 2023; 29(1): 271-278. doi: 10.1158/1078-0432.Ccr-22-1851

[42] Gritti I, Wan J, Weeresekara V, et al. DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming. Cancer Discov. 2025; 15(2):382-400. doi: 10.1158/2159-8290.Cd-24-0634

[43] Patt YZ, Hassan MM, Lozano RD, et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol. 2003; 21(3):421-427. doi: 10.1200/JCO.2003.10.103

[44] Ang CS, Kelley RK, Choti MA, et al. Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: Data from the fibrolamellar carcinoma consortium. Gastrointest Cancer Res. 2013; 6(1):3-9.

[45] Gummadi J, Wang X, Xie C. Current advances in the treatment of fibrolamellar carcinoma of liver. J Hepatocell Carcinoma. 2023; 10:745-752. doi: 10.2147/jhc.S406902

[46] Kang E, Martinez M, Moisander-Joyce H, et al. Stable liver graft post anti-PD1 therapy as a bridge to transplantation in an adolescent with hepatocellular carcinoma. Pediatr Transplant. 2022; 26(3):e14209. doi: 10.1111/petr.14209

[47] El Dika I, Bowman AS, Berger MF, et al. Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver. Cancer. 2020; 126(18):4126-4135. doi: 10.1002/cncr.32960

[48] Kang S, Magliocca J, Sellers M, et al. Successful liver transplantation of recurrent fibrolamellar carcinoma following clinical and pathologic complete response to triple immunochemotherapy: A case report. Oncol Res Treat. 2022; 45(7-8):430-437. doi: 10.1159/000524872

[49] Chung J, Ali SZ. Hepatocellular carcinoma- fibrolamellar variant: Cytopathology of an unusual case. Diagn Cytopathol. 2002; 26(4):257-261. doi: 10.1002/dc.10088

[50] Bawashkhah AS, Sindi GA, Almatrafi SB, Obaid EF, Bakhsh RI. Fibrolamellar hepatocellular carcinoma in the absence of risk factors: A case report. Cureus. 2022; 14:e32483. doi: 10.7759/cureus.32483