INTRODUCTION Fibrolamellar carcinoma (FLC) is a rare primary liver cancer with distinctive histology, molecular biology, and clinical presentation that predominantly affects adolescents and young adults. Its characteristic histology was first described by Edmondson in 1956 following resection of a liver carcinoma from a 14-year-old patient.1 It was subsequently described as a distinct clinical and histological subtype of conventional hepatocellular carcinoma (HCC) in 1980 by Craig et al.2 based upon the presence of abundant eosinophilic cytoplasm and lamellar bands of intratumor fibrosis on histology and diagnosis in adolescents and young adults with noncirrhotic livers and a normal alpha-fetoprotein (AFP). Before the 2014 discovery of a recurrent molecular driver absent from conventional HCC, FLC was considered a subset of HCC defined primarily by its distinctive pathology and epidemiology.3–5 Pediatric and adult oncologists’ therapeutic approaches to FLC evolved separately, with systemic therapy regimens derived from those used in hepatoblastoma and conventional HCC, respectively, even in the absence of FLC-specific rationale.3,4 However, the response of FLC to these regimens has been poor, and the use of these therapies has not improved long-term survival rates.3,6,7 As a result, patients with FLC have often been excluded from trials designated specifically for hepatoblastoma or conventional HCC.3,8–10 NEW UNDERSTANDING OF FLC BIOLOGY: DISCOVERY OF THE DNAJB1::PRKACA FUSION In 2014, the discovery of a novel chimeric fusion transcript, DNAJB1::PRKACA, found in nearly all FLC tumors transformed understanding of the disease, as the fusion protein is believed to be the driver of FLC oncogenesis and persistence.4,11–18 This fusion results from a heterozygous deletion of ~400 kb in chromosome 19 that links exon 1 of the heat shock protein DNAJB1 to exons 2–10 of PRKACA, the catalytic subunit of protein kinase A (PKA; Figure 1A).11 The deletion’s relatively small size had previously prevented it from being discovered with conventional cytogenic techniques, requiring the use of RNA sequencing for detection.4,11 Induction of this deletion and expression of the DNAJB1::PRKACA transcript in mouse liver and human hepatocytes have resulted in the production of tumors resembling FLC histologically and cytologically.15,19 FLC has been shown to be oncogenically addicted to the fusion protein, as its inhibition results in tumor cell death in vitro and inhibition of tumor growth in patient-derived xenograft (PDX) models.15,20 While the fusion has predominantly been detected in FLC tumors, it has also been shown to occur in intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct, which share some histopathologic and cytologic similarities to FLC.21,22 While the biochemical mechanisms by which the DNAJB1–PRKACA fusion protein (DNAJ–PKAc) drives FLC are still under investigation, work to date suggests that increased expression/activity, mislocalization, and altered physical interactions may play roles.3 As detailed below, downstream transcriptional, metabolic, and signaling phenotypes driven by DNAJ–PKAc have been defined in FLC cell models and tumors, confirming the distinctions between FLC and conventional liver cancers. The fusion gene has demonstrated the ability to suppress differentiation of liver progenitor organoids into hepatocytes, and FLC tumors have been shown to co-express biliary, hepatocellular, and hepatic progenitor/stem cell markers, suggesting the tumor cells may be arrested at a specific stage of differentiation.23–26FIGURE 1: Molecular and histological features of fibrolamellar carcinoma. (A) The DNAJ–PKAc fusion results from an intrachromosomal deletion linking the J domain of DNAJB1 and the majority of the catalytic domain of PKAc. The direct site of linkage is shown and is the basis of the 24-amino acid peptide vaccine used in NCT04248569. Image adapted from Vyas et al.21 Inset shows the crystal structure of the DNAJ–PKAc fusion, which preserves most components of the PKAc structure but includes a portion of DNAJB1 on the kinase N-lobe. (B) Depiction of a gross image of an FLC tumor, including the commonly seen central scar. The microscopic image shows common FLC histological features, including pleomorphic tumor cells arranged in lamellar sheets and palisading fibrosis.The dependency of FLC on the DNAJB1::PRKACA driver is underscored by the infrequency of other somatic genetic alterations. FLC has a low tumor mutational burden, with infrequent mutations in genes reported to be implicated in other liver carcinomas.3,13 Genomic alterations besides the fusion detected in FLC specimens include activating mutations in the TERT promoter (found in the tumors of 7 of 31 patients studied) and mutations in MUC4 (found in tumors of 4 of 10 patients studied).13,27 Of note, mucin 4 can complex with HER2 to promote cell proliferation and migration.28 FLC has also been shown to overexpress ERBB2, translating to HER2 cell surface expression, neurotensin, and and shows of conventional HCC and FLC mutations in and However, has been shown to be and its is in the at This mutational is distinct from those of other hepatocellular FLC also has distinct and RNA RNA and that may be to histology and other including and clinical of in young and of of and with those seen in conventional HCC to be with FLC and and of suggests that the of the fusion and to these to the of in FLC in a from liver in rare to the complex has also been reported to in histology, and clinical presentation to those driven by the DNAJB1::PRKACA In between the catalytic of and have also of the pancreas and bile with some histopathologic to FLC that also share and response In HCC with mutations a or in The of these tumors from with but of of DNAJB1::PRKACA, or with all in human hepatocytes those seen in suggesting that in and the DNAJB1 domain may the FLC In discovery of the DNAJB1::PRKACA fusion has not the understanding of but also to and novel to and the in understanding have to an increased understanding of the FLC is to be a rare cancer adolescents and young but the in Before the discovery of the DNAJB1::PRKACA fusion, as conventional HCC and and the of a may to to in an of from The of of tumors from adolescents and young adults with the fusion and FLC histology as conventional a with pathology of tumors histologically as that of tumors of histology had the fusion, tumors histologically to be FLC and the fusion, and of tumors with FLC histology the the tumors found to be histologically to be FLC from patients with a of with an of for histologically The with histologically FLC had a of the as has been reported to and histologically but FLC in rare of and from to to and to suggests an of in the the first that FLC of primary liver cancer and of primary liver in patients However, other of FLC an as as of primary liver but may be by of conventional HCC or A of and has that FLC is the While FLC has been reported with relatively the its has not been the and its and a of the Fibrolamellar based on patients from to found of diagnosis to be with of patients The Fibrolamellar is a which may in reported based on and with in an While some the discovery of the fusion a at diagnosis and a in in of from and not this which may a of patients from have been of liver in with histological features of FLC and tumors have been shown to be and distinct from with presentation and resembling conventional 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with as a and as as from from expression or to As the of is often conventional in conventional HCC and is but may be and has been in a tumors abundant eosinophilic cytoplasm and lamellar bands of intratumor and of and have tumors for the of HER2 and of have not been tumors are believed to The primary tumor as a often a central on FLC may be commonly in the of the in the in Craig et in which the liver the 1 are described to with tumor on with on and as to the and seen in that FLC has a to to and other common of include the and While believed to a is to be with some patients for as in an and some patients to While resection or recurrent resection is with FLC a and long-term survival is to the and of most as as young and FLC often as disease, with and in and of to this of disease, resection is not for patients with FLC at the of While believed to have a conventional HCC, FLC has been found to have a to conventional HCC and adult HCC in noncirrhotic for resection have the with reported survival from to a reported of tumors and most patients of While a small has that most have been reported to occur 4 of has been reported as as patients with at reported are poor, with survival of and survival at disease, and the presence of 10 or tumors in the liver have all been with disease, and have been with A reported in an expression reported to in but this has not been in a a of and and the of and for the and the results from results from to trials and the use of in defined as of therapies clinical of or in a with in the of FLC including 4 4 1 1 1 and 1 clinical on diagnosis and of on the results of these a direct of therapies was and to regimens reported in to the of clinical of or in a with these a of regimens reported in the to clinical in FLC and the of which regimens for the of FLC in The of was also on which approaches for the of patients with FLC in specific This the of A was as it from at 7 and as it from A was as it from at and as it from had the of a as the or was not 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stage or in these be in as and by the primary and young adults with cancer cancer may have some from cancer in and and patients with cancer have not seen the in survival as patients in other patients can to in the young adults are to be patients of other and cancer can a at this stage of clinical trials this and are and not being at a are to be in a clinical diagnosis and can and for including in and in to and in patients with cancer also in and with and with and patients often and may to of FLC has also been which can a of In to of are at for and which long-term While and biology, the has the of novel therapies and therapies to While therapy has upon the use of and clinical trials have been to the of the DNAJ–PKAc fusion protein as a to FLC trials of peptide DNAJ–PKAc are In the a a peptide vaccine DNAJ–PKAc with inhibition for patients with or patients in the first of the of 4 therapy the first most often for clinical the patients at of and the detected in of patients and 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liver to be to is A of the with the in and young adult patients with cancer is also and of patients with FLC are to for FLC by the driven by the DNAJB1::PRKACA to PKAc to the of However, in mouse models demonstrated a therapeutic for DNAJ–PKAc inhibition with This the of in normal as to its in and of genetic that can an FLC and is for FLC tumor and a of for the use of a to to and of the the of DNAJ–PKAc has on the of downstream in FLC models and FLC have and as of with some phenotypes and to FLC the DNAJ–PKAc The of patients with FLC has improved the to and the that diagnosis is by biology, and the of novel in the as a driver of clinical as and therapeutic a to the of that can on a that the the for kinase and therapy include the sequencing of and and the and of is in the that a of to these be the use of or that the of of a can be As these are the of or the of that can therapeutic and be an the of clinical and improved to clinical are that in the to not therapies for patients with FLC but also the of therapies in use for patients with FLC of fibrolamellar carcinoma (FLC) systemic A of systemic therapies are in use or under for are based on mechanisms of and with FLC
O’Neill et al. (2026) studied this question.