Fibrolamellar Hepatocellular Carcinoma (FLC/FL-HCC): Comprehensive Research Report

1. Disease Information

Overview. Fibrolamellar hepatocellular carcinoma (FLC, also FL-HCC or FLHCC) is a rare, histologically and molecularly distinct primary liver malignancy that predominantly arises in adolescents and young adults without underlying cirrhosis, viral hepatitis, or other chronic liver disease — a striking contrast to conventional hepatocellular carcinoma (HCC), which is overwhelmingly a cirrhosis-associated cancer of older adults. FLC is defined pathologically by large polygonal eosinophilic tumor cells embedded in parallel lamellae of collagenous stroma, and molecularly by a near-universal somatic DNAJB1-PRKACA gene fusion arising from a ~400 kb heterozygous deletion on chromosome 19p13.12 (Medscape; PMC8448801; PMC10787162).

Key identifiers: - MONDO: MONDO:0006210 - Orphanet: ORPHA:401920 (also cross-referenced under ORPHA:33402, Pediatric hepatocellular carcinoma) (Orphanet) - ICD-O-3: 8171/3 (fibrolamellar carcinoma morphology code) - ICD-10: C22.0 (liver cell carcinoma, as a subtype) - MeSH: D049688 (Carcinoma, Hepatocellular is D006528; fibrolamellar variant indexed under related HCC headings)

Synonyms: Fibrolamellar carcinoma; fibrolamellar hepatocellular carcinoma; fibrolamellar liver cancer; polygonal cell type hepatocellular carcinoma with fibrous stroma (older WHO terminology).

Information source. Most quantitative data below derive from aggregated disease-level resources — the SEER registry, the National Cancer Database (NCDB), and pooled case-series/systematic reviews — supplemented by individual case reports for rare presentations (e.g., paraneoplastic syndromes). Because FLC is rare, single-institution and multi-institution retrospective cohorts (rather than prospective trials) are the dominant human evidence base.

2. Etiology

Disease Causal Factors

The molecular driver of FLC is a somatic ~400 kb heterozygous deletion on chromosome 19p13.12 that fuses the first exon of DNAJB1 (encoding a heat-shock protein 40/Hsp40 co-chaperone) in-frame to exons 2–10 of PRKACA (the catalytic alpha subunit of protein kinase A, PKA) (PubMed:29162699; PNAS:1716483114). This fusion is found in >80–100% of morphologically classic FLC cases across independent series and is considered the pathognomonic, essentially disease-defining lesion (PMC5758901).

There is no established environmental, infectious, or lifestyle cause. Unlike conventional HCC, FLC arises in the absence of viral hepatitis (HBV/HCV), alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease, hemochromatosis, or cirrhosis of any etiology (NORD; PMC9750232 "Fibrolamellar Hepatocellular Carcinoma in the Absence of Risk Factors").

Risk Factors

Genetic risk factors: - The defining lesion is somatic, not germline — occurring de novo in tumor tissue and not inherited or transmissible to offspring (Fibrolamellar Cancer Foundation). - Whole-genome sequencing of 10 patient tumor/normal pairs found FLC has a remarkably low somatic coding-mutation burden, among the lowest of any solid tumor sequenced, with the DNAJB1-PRKACA fusion as essentially the only recurrent structural event and no consistent "second hit" (PMC4359253/Oncotarget:2712). - A single case report describes a 14-year-old girl with FLC carrying both a germline and somatic TP53 mutation, raising the possibility that FLC could rarely fall within the Li-Fraumeni tumor spectrum, though this is not an established recurrent association (Familial Cancer, 10.1007/s10689-017-9998-5). - No confirmed susceptibility loci, modifier genes, or GWAS-defined risk alleles have been established for FLC given its rarity.

Environmental/demographic risk factors: - Age: Bimodal incidence peaks at 15–19 years and 70–74 years, but the disease is classically associated with adolescents and young adults (typical reported range 14–33 years), with rare cases from age 2 to 74 (npj Precision Oncology, 10.1038/s41698-023-00371-2). - Race/ethnicity: In the U.S., >85% of patients are non-Hispanic white, with smaller proportions among Chinese Americans (~6%), Black patients (~4%), and white Hispanic patients (~4%) — a markedly different demographic distribution than conventional HCC (PubMed:32052215). - Sex: No strong sex predominance is consistently reported across series (unlike conventional HCC's male predominance), though some cohorts report a slight male-favoring trend as a prognostic (not necessarily risk) factor. - No family history association has been established (sporadic disease).

Protective Factors

No genetic or environmental protective factors have been identified in the literature; this reflects both disease rarity and lack of dedicated case-control epidemiological studies.

Gene-Environment Interactions

None established. Given the essentially monogenic somatic driver (DNAJB1-PRKACA) and absence of implicated environmental exposures, there is no described gene-environment interaction model for FLC, unlike conventional HCC (where HBV/HCV × alcohol × metabolic risk interactions are well characterized).

3. Phenotypes

FLC's clinical phenotype is notable for vague, insidious presentation and, critically, absence of the stigmata of chronic liver disease seen in conventional HCC.

(Source: Chinese Clinical Oncology review, cco.amegroups.org/article/view/21275; PMC12576631; PMC6304646; PMC11002470)

Phenotype characteristics: - Onset: Typically adolescent/young adult onset, though the true age range spans 2–74 years with a secondary elderly peak in registry data. - Progression: Often insidious for months before diagnosis due to nonspecific symptoms; disease is frequently locally advanced or has nodal/metastatic spread at presentation because of this diagnostic delay. - Severity/frequency: Symptom severity is variable; a subset of patients are diagnosed incidentally. - Quality of life impact: Not systematically measured with validated instruments (EQ-5D/SF-36) in FLC-specific studies; QoL burden is inferred from the aggressive natural history, high recurrence rate, and the young age of patients (loss of years of life, fertility/oncofertility concerns, and psychosocial burden of a rare cancer diagnosis in adolescence).

Hyperammonemic Encephalopathy — Mechanistic Detail

This is a distinctive, often under-recognized FLC paraneoplastic phenotype: tumor cells show upregulation of glutaminase (GLS), which generates ammonia from glutamine, coupled with downregulation of ornithine transcarbamylase and glutamine synthetase (GS) — the ammonia-detoxifying enzymes. Net tumor ammoniagenesis overwhelms the (non-cirrhotic) residual liver's clearance capacity, producing severe hyperammonemic encephalopathy disproportionate to tumor burden or synthetic liver failure (PMC9922532; PMC4828114). Immunohistochemistry shows weak/diffuse GS expression in tumor cells.

4. Genetic/Molecular Information

Causal Gene Fusion

DNAJB1-PRKACA is the signature and essentially universal driver: - DNAJB1 (HGNC:14887; DnaJ heat shock protein family member B1) exon 1 fused in-frame to - PRKACA (HGNC:9380; protein kinase cAMP-activated catalytic subunit alpha) exons 2–10 - Resulting from a ~400 kb heterozygous deletion on chromosome 19p13.12 (PubMed:29162699). - The fusion transcript is expressed at ~10-fold higher levels than wild-type PRKACA, and confers elevated cAMP-stimulated PKA catalytic activity relative to normal liver (ScienceDirect:S2772572322001911). - Detected in 99–102/103 (99%) of morphologically classic FLC cases in the largest multicenter FISH validation series (PubMed:35777788), and by RT-PCR in 92% (24/26) of tested cases, with the fusion transcript essentially specific to FLC among primary liver tumors tested (though see the diagnostic caveat below) (PMC5758901).

Variant Classification and Functional Consequence

• Somatic, not germline (essentially always) — arises in the tumor only.
• Functional impact: Gain-of-function/neomorphic — the fusion is not merely PRKACA overexpression; ectopic overexpression of wild-type PRKACA alone fails to recapitulate FLC's oncogenic phenotype, indicating the DNAJB1 moiety confers a qualitatively distinct, "acquired scaffolding function" (PMC6533061) that (a) recruits Hsp70 into an altered PKA holoenzyme complex, and (b) via the upregulated scaffold protein AKAP-Lbc, clusters DNAJ-PKAc/Hsp70 with a RAF-MEK-ERK signaling module.
• Structural biology studies of the PKA RIIβ holoenzyme containing the DNAJB1-PKAc fusion reveal protomer asymmetry and fusion-induced allosteric perturbations relative to wild-type PKA holoenzyme (PMC7793292).

Modifier/Cooperating Pathways

• Wnt/β-catenin (CTNNB1) pathway: DNAJB1-PRKACA interacts with β-catenin, and tumorigenesis is significantly enhanced by concurrent β-catenin activation in mouse models; this is consistent with recurrent Wnt-pathway mutations observed in human FLC series (PubMed:29162699; PNAS:1716483114). (Note: dedicated large-cohort CTNNB1 mutation-frequency data were not retrievable in this search pass and should be verified against primary genomic-landscape papers before citing a specific percentage.)
• SIK/CRTC2/p300 axis (2024 mechanistic advance): A 2024 Cancer Discovery study (10.1158/2159-8290.CD-24-0634) showed DNAJB1-PRKACA phosphorylates and inactivates salt-inducible kinases (SIKs), deregulating the CRTC2 transcriptional coactivator and p300 acetyltransferase, producing global histone hyperacetylation and transcriptional reprogramming that drives malignant growth — nominating CRTC2/p300 as a therapeutic target.
• RAS/MAPK and AURKA/GSK3-MYC networks: Two downstream signaling branches have been mapped: (1) RAS/MAPK pathway components, and (2) an Aurora Kinase A (AURKA)/GSK3 sub-network with activity toward MYC — oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms (PMC9925115).
• Oncogenic addiction: FLC tumor cells show dependency ("oncogenic addiction") specifically on the fusion kinase, supporting the fusion as the primary therapeutic vulnerability (PubMed:36302174).

Mutational Burden

Whole-genome sequencing of paired tumor/normal samples from 10 patients found relatively few coding somatic mutations — among the lowest mutation burdens described for any sequenced solid tumor — with no consistent recurrent "second-hit" mutation beyond the founding fusion event (PMC4359253).

Epigenetic Information

• Single-nucleus multi-omic profiling (snATAC-seq + snRNA-seq, 2024–2025) has revealed cell-type-specific chromatin accessibility, transcription factor networks (notably CREB3L1), microRNA regulatory elements, and super-enhancers, including super-enhancers near FLC-enriched genes such as CDH11 and SLC16A14 (Nature Scientific Reports 10.1038/s41598-026-44899-2; bioRxiv 10.1101/2024.12.11.627911).
• Global histone hyperacetylation downstream of CRTC2/p300 deregulation is a key epigenetic consequence of the fusion kinase (Cancer Discovery 2024).

Chromosomal Abnormalities

The defining lesion is itself the ~400 kb interstitial deletion at 19p13.12 producing the DNAJB1-PRKACA fusion; beyond this, FLC genomes are notably stable/quiet, without the widespread aneuploidy or chromothripsis seen in many other cancers (PMC4359253).

Diagnostic Caveat on Fusion Specificity

Although historically considered pathognomonic, DNAJB1-PRKACA fusions have also been reported in oncocytic pancreatic and biliary neoplasms, meaning the fusion is not absolutely exclusive to FLC and must be interpreted alongside morphology and clinical context (Modern Pathology 10.1038/s41379-019-0398-2).

Suggested ontology bindings: HGNC:9380 (PRKACA), HGNC:14887 (DNAJB1), HGNC:11986 (TP53, for the rare germline-mutation case), GO:0004691 (cAMP-dependent protein kinase activity), GO:0007190 (activation of adenylate cyclase activity), GO:0016575 (histone deacetylation, inverse direction relevant), NCIT for fusion gene concept.

5. Environmental Information

• Environmental factors: None established. FLC is not associated with aflatoxin exposure, industrial toxins, or occupational carcinogens the way conventional HCC or angiosarcoma can be.
• Lifestyle factors: No association with alcohol use, smoking, obesity/metabolic syndrome, or diet has been demonstrated; this is a key point of contrast with conventional HCC risk-factor profiles.
• Infectious agents: No association with HBV, HCV, or other hepatotropic pathogens. This absence is itself diagnostically informative — FLC is essentially defined in part by exclusion of viral/infectious hepatocarcinogenesis (NORD; Liver Foundation Australia).

6. Mechanism / Pathophysiology

Ordered Causal Chain (Proposed Sequence)

1. A somatic ~400 kb heterozygous deletion at chromosome 19p13.12 occurs in a hepatocyte (or hepatic progenitor/biliary-hepatocyte intermediate cell), fusing DNAJB1 exon 1 in-frame to PRKACA exons 2–10 — leads to formation of the chimeric DNAJB1-PRKACA transcript and protein (demonstrated; PubMed:29162699).
2. The fusion transcript is overexpressed (~10-fold over wild-type PRKACA) — results in markedly elevated, and qualitatively altered, cAMP-stimulated PKA catalytic activity, because the DNAJB1 moiety confers Hsp70-recruiting scaffold properties absent from wild-type PKA (demonstrated in vitro/structural studies; PMC6533061, PMC7793292).
3. The altered PKA holoenzyme, via upregulated AKAP-Lbc, clusters DNAJ-PKAc/Hsp70 subcomplexes with a RAF-MEK-ERK kinase module — leads to aberrant, spatially organized MAPK pathway activation (demonstrated; PMC6533061).
4. In parallel, DNAJB1-PRKACA phosphorylates and inactivates salt-inducible kinases (SIKs) — results in deregulation of the CRTC2 coactivator and p300 acetyltransferase, driving global histone hyperacetylation and a pro-tumorigenic transcriptional program (demonstrated 2024; Cancer Discovery 10.1158/2159-8290.CD-24-0634).
5. Downstream, an AURKA/GSK3 sub-network stabilizes MYC oncoprotein — leads to enhanced proliferative and cell-cycle-driving transcriptional output (demonstrated; PMC9925115).
6. The fusion kinase also interacts directly with β-catenin, and concurrent Wnt/β-catenin pathway activation significantly enhances tumorigenesis in mouse models, consistent with recurrent Wnt pathway alterations noted in human tumors — leads to cooperative oncogenic transformation of hepatocytes (demonstrated in mouse models; inferred as cooperating rather than sole driver in humans; PNAS:1716483114).
7. Neoplastic hepatocytes proliferate as large, eosinophilic, mitochondria-rich polygonal cells; concurrently, tumor cells (via TGF-β overexpression) induce stromal fibroblasts/myofibroblasts to deposit parallel lamellar collagen bands around cell nests — results in the pathognomonic fibrolamellar histologic architecture (mechanistically inferred from TGF-β overexpression data; direct causal proof in humans is largely histological/correlative).
8. Metabolically, tumor cells upregulate glutaminase (GLS) and downregulate ornithine transcarbamylase and glutamine synthetase (GS) — leads to a net ammoniagenic phenotype that, in a subset of patients (often with high tumor burden), overwhelms residual (non-cirrhotic) hepatic ammonia clearance — resulting in the paraneoplastic hyperammonemic encephalopathy phenotype (demonstrated mechanistically at the tumor tissue level; PMC9922532).
9. Neuroendocrine-gene overexpression, including neurotensin, provides an additional autocrine/paracrine source of cAMP and co-mitogenic signaling that may reinforce the PKA-driven proliferative loop (demonstrated in vitro; PMC6707953) — though neurotensin has not proven sufficiently sensitive/specific as a stand-alone clinical biomarker.
10. Clinically, unchecked local growth leads to a large, well-circumscribed hepatic mass (often 5–20 cm) with a central fibrous scar, and given the typically late, nonspecific symptom presentation, a substantial fraction of patients progress to regional lymph-node and distant (lung, peritoneal, osseous) metastatic spread by diagnosis or shortly after resection (documented in surgical/SEER series; e-jlc.org, cco.amegroups.org).

Molecular Pathways

• cAMP-PKA signaling (central driver pathway; KEGG hsa04024)
• RAS/MAPK (RAF-MEK-ERK) cascade, aberrantly scaffolded by AKAP-Lbc
• SIK-CRTC2-CREB/p300 transcriptional coactivation axis
• Wnt/β-catenin signaling (cooperating pathway)
• AURKA-GSK3-MYC proliferative axis

Suggested GO terms: GO:0007188 (adenylate-cyclase-activating G protein-coupled receptor signaling pathway), GO:0004691 (cAMP-dependent protein kinase activity), GO:0060070 (canonical Wnt signaling pathway), GO:0000165 (MAPK cascade), GO:0016575 (histone deacetylation — inverse relevant to acetylation increase), GO:0006541 (glutamine metabolic process, for the hyperammonemia axis).

Cellular Processes

• Sustained hepatocyte proliferation and impaired terminal differentiation
• TGF-β–driven activation of hepatic stellate cells/portal fibroblasts producing the lamellar fibrotic stroma
• Altered mitochondrial biogenesis (tumor cells are notably mitochondria-rich, contributing to the granular eosinophilic cytoplasm seen histologically)
• Neuroendocrine transdifferentiation/gene expression program (neurotensin and related genes)

Protein Dysfunction

The DNAJB1-PRKACA fusion protein represents a gain-of-function, neomorphic chimeric kinase — not simple PKA overactivity but a structurally altered holoenzyme with novel scaffolding and allosteric properties (PMC7793292). This is best captured in dismech schema terms as functional_impact_category: NEOMORPHIC on the fusion's genetic_context.

Metabolic Changes

Dysregulated nitrogen/ammonia handling (GLS↑, OTC↓, GS↓) as detailed above; broader metabolomic characterization (lipidomic, amino-acid flux) is less well established in the literature retrieved here.

Immune System Involvement

FLC tumors and their microenvironment have been targeted by immunotherapy approaches (see Treatment), and rewired cell-to-cell communication signaling — including SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, and FGF7-FGFR axes — has been identified via single-cell multi-omic analysis, implicating altered tumor-immune and tumor-stromal crosstalk (bioRxiv 2024.12.11.627911).

Tissue Damage / Structural Formation Mechanisms

TGF-β overexpression is implicated in driving the characteristic lamellar fibrosis — parallel bands of collagen encircling tumor cell nests — a pattern distinct from cirrhotic fibrosis and specific to this tumor's stroma-tumor interaction (ScienceDirect S0740257016301162).

Molecular Profiling Summary

• Transcriptomics: Neuroendocrine gene overexpression (including neurotensin) among the most significantly overexpressed genes; single-nucleus RNA-seq has mapped cell-type-specific expression programs (2024–2025 studies).
• Epigenomics: snATAC-seq has resolved FLC-specific chromatin accessibility and super-enhancer landscapes (CDH11, SLC16A14 loci).
• Genomics: Low overall mutation burden; the founding 19p13.12 deletion/fusion is essentially the sole recurrent structural event (PMC4359253).
• Single-cell/spatial: 2024 multi-omic single-nucleus study is the most advanced published dataset, revealing rewired intercellular signaling (SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, FGF7-FGFR).
• Functional genomics: In vitro drug screens have nominated HDAC inhibitors, topoisomerase I inhibitors, and the STAT3 inhibitor napabucasin as active compounds, with synergy reported when combined with Bcl-xL inhibition (Molecular Therapy, cell.com S1525-0016(23)00664-0).

7. Anatomical Structures Affected

Organ level: - Primary organ: Liver (hepatic parenchyma), typically arising as a solitary large mass, often in the left lobe in a substantial proportion of cases (per multiple imaging series). - Secondary/metastatic involvement: Regional (hilar, celiac, mediastinal) and distant lymph nodes; lungs; peritoneum; bone; less commonly pancreas, ovary, and — rarely — cardiac/right atrial extension via IVC. - Body systems: Primarily hepatobiliary/digestive system; secondary lymphatic and, in metastatic disease, respiratory and skeletal systems.

Suggested UBERON terms: UBERON:0002107 (liver), UBERON:0002370 (thymus – n/a), UBERON:0000029 (lymph node), UBERON:0002048 (lung), UBERON:0001474 (bone element), UBERON:0000992 (ovary).

Tissue and cell level: - Tumor cells are large, polygonal, hepatocyte-derived (or hepatic-progenitor-derived) neoplastic epithelial cells (CL:0000182 hepatocyte, or a progenitor-like cell type given ongoing debate about cell-of-origin). - Stromal compartment: activated portal/stellate fibroblasts producing lamellar collagen (CL:0000057 fibroblast; CL:0000632 hepatic stellate cell as a candidate contributor). - CD68+ macrophage-lineage co-expression pattern is diagnostically notable in tumor cells themselves (aberrant marker expression rather than true macrophage infiltration is one interpretation; CL:0000235 macrophage marker used diagnostically).

Subcellular level: - Tumor cells are characteristically mitochondria-rich (GO:0005739 mitochondrion), contributing to granular eosinophilic cytoplasm. - Intracytoplasmic "pale bodies" (amphophilic, fibrinogen-containing inclusions) and "hyaline bodies" (smaller, intensely eosinophilic) are seen in roughly half of cases (AASLD Pathology Pearls; ScienceDirect S0740257016301162).

Localization: Typically a single large hepatic mass (5–20 cm); bilobar or multifocal presentation is less common. No established lateralization pattern beyond frequent left-lobe predominance noted in some imaging series.

8. Temporal Development

• Onset: Adolescent/young-adult onset is classic (peak ~15–19 years in registry data), with a smaller elderly-onset peak (~70–74 years); reported age range 2–74 years (npj Precision Oncology 2023).
• Onset pattern: Insidious — symptoms (abdominal pain, distension, malaise) typically develop gradually over weeks to months before diagnosis, contributing to advanced stage at presentation.
• Disease stages: No FLC-specific staging system exists; conventional HCC/AJCC liver staging or the Milan-type resectability framework is generally applied, alongside surgical categorization into resectable vs. unresectable/advanced disease.
• Progression rate: Variable but often aggressive once metastatic; recurrence after resection is common — reported in up to 86% of patients in some surgical series (Yamashita et al., cited in cco.amegroups.org review).
• Disease course pattern: Typically progressive with a high rate of locoregional and distant recurrence; not classically relapsing-remitting.
• Remission patterns: Surgical resection (with negative margins) offers the only realistic chance of durable remission; spontaneous remission is not described. Recurrence, when resectable again, can still yield meaningful survival benefit (median OS 122 months with repeat resection of recurrence vs. 37 months without, per the Yamashita series).
• Critical periods: Early surgical intervention while disease remains resectable is the single most important modifiable window; delayed diagnosis due to nonspecific symptoms is a major driver of poor outcomes.

9. Inheritance and Population

Epidemiology

• Incidence: Age-adjusted U.S. incidence is approximately 0.02 per 100,000 person-years, roughly 100-fold lower than the ~1.99 per 100,000 annual incidence of conventional HCC (npj Precision Oncology 2023).
• FLC represents ~1–2% of all hepatocellular carcinoma cases in the U.S. (PubMed:32052215; Fibrofoundation).
• A 2023 computational/tiered clinical-data analysis suggests true incidence may be 5- to 8-fold higher than prior registry-based estimates, implying substantial historical under-ascertainment (PMC10034241/npj Precision Oncology 2023).
• Bimodal age distribution: incidence peaks at ages 15–19 and 70–74.

Inheritance Pattern

FLC is essentially sporadic, driven by a somatic (non-inherited) DNAJB1-PRKACA fusion. No Mendelian inheritance pattern, penetrance, expressivity, anticipation, germline mosaicism, founder-effect, or carrier-frequency data apply in the conventional sense, since the causal lesion is not transmitted through the germline. A single case report of concurrent germline + somatic TP53 mutation raises a hypothesis-generating (not established) link to Li-Fraumeni-spectrum tumors in rare instances (Familial Cancer 2017), but this is not a recognized recurrent inheritance mechanism for FLC as a class.

Population Demographics

• Race/ethnicity: >85% non-Hispanic white in U.S. cohorts; ~6% Chinese American, ~4% Black, ~4% white Hispanic (PubMed:32052215).
• Geographic distribution: No clearly defined endemic regions; most epidemiological data derive from U.S. (SEER, NCDB) cohorts, with case series also reported from Europe and Asia, though comparative incidence data outside the U.S. are sparse.
• Sex ratio: No strong sex predominance is consistently reported in the largest series (contrasts with conventional HCC's male predominance), though some surgical-outcome cohorts note male sex as a favorable prognostic factor.
• Age distribution: Predominantly adolescents/young adults, with a smaller elderly subgroup.

10. Diagnostics

Laboratory Tests

• Alpha-fetoprotein (AFP): Characteristically normal — an important distinguishing feature from conventional HCC, where AFP is often elevated (emedicine.medscape.com/278354-workup).
• Vitamin B12-binding globulin (transcobalamin): Elevated in some series (classic but not universally sensitive/specific marker).
• Neurotensin: Elevated in a subset of patients but not sufficiently sensitive or specific for stand-alone diagnostic use (PMC search results synthesis).
• Procalcitonin: A newly proposed (2025) candidate tumor biomarker for diagnosis and follow-up, based on case reports and a literature review (medRxiv 2025.11.18.25340286; PMC12907347) — still investigational.
• Serum ammonia: Elevated in the rare hyperammonemic encephalopathy presentation.

Imaging Studies

• CT: Large (7–20 cm), heterogeneous, hypervascular, well-defined lobulated mass; central non-enhancing stellate scar in >80% of tumors at diagnosis; calcifications in 33–68% of cases, usually within the central scar (AJR 10.2214/AJR.13.11117; PMC4112400).
• MRI: Near-isointense to liver on T1, hyperintense on T2; central scar is hypointense on both T1 and T2 (a helpful distinguishing feature from focal nodular hyperplasia, whose central scar is typically T2-hyperintense and lacks calcification).
• Distinguishing FNH vs. FLC: Low T2 signal intensity and presence of calcification in the central scar favor FLC over FNH.

Biopsy/Pathology

• Histopathology: Large polygonal/spindled cells with abundant granular eosinophilic cytoplasm, vesicular nuclei, prominent macronucleoli; paucicellular fibrous stroma in parallel lamellae; pale bodies/hyaline bodies in ~50% of cases.
• Immunohistochemistry: CK7 and CD68 co-expression — when combined with compatible morphology, this combination is considered diagnostic of FLC (PMC search synthesis).

Molecular/Genetic Testing

• Break-apart FISH for PRKACA rearrangement: Positive in 99% (102/103) of classic FLC cases in the largest multicenter validation study; a clinically validated, high-sensitivity/specificity assay (PubMed:35777788).
• RT-PCR for DNAJB1-PRKACA fusion transcript: Successful detection in 92% (24/26) of tested cases; fusion transcript essentially specific to FLC among primary liver tumors tested, though shared with rare oncocytic pancreatobiliary neoplasms (PMC5758901; Modern Pathology 2019).
• Targeted NGS fusion panels (e.g., MSK-IMPACT/MSK-Fusion hybridization-capture assays) are used clinically to detect the fusion (search synthesis).
• Commercial clinical assay example: Mayo Clinic Laboratories' PRKAF test (FISH for PRKACA rearrangement, tissue-based).

Clinical Criteria / Differential Diagnosis

No DSM/ICD-based diagnostic criteria apply (this is a solid-organ malignancy); diagnosis rests on the combination of clinical context (young patient, no cirrhosis, normal AFP), imaging (central scar with calcification), histology, and CK7/CD68 IHC, confirmed by DNAJB1-PRKACA fusion testing (FISH, RT-PCR, or NGS). Key differentials: focal nodular hyperplasia (shares central scar but lacks fusion/calcification pattern), conventional HCC, hepatocellular adenoma, and other oncocytic hepatobiliary/pancreatic tumors that can rarely share the fusion.

Screening

No population or genetic screening program exists for FLC, consistent with its sporadic, non-heritable molecular basis and rarity.

11. Outcome/Prognosis

Survival Statistics (SEER/NCDB-based)

• Overall median survival: ~24.5 months in a recent SEER cohort analysis (JCO 2024.42.16_suppl.e16213); considerably better in surgically managed patients (median survival ~75 months) (Dove Medical Press IJGM).
• Age-stratified survival (SEER, n=225): Median survival 85 months for patients ≤19 years; 29 months for ages 20–59; 12 months for ages ≥60 — indicating younger age is strongly favorably prognostic (search synthesis of SEER analyses).
• Stage-dependent survival: 1-year OS 67–100%; 5-year OS 28–65% across series; 5-year OS ~80% for resectable disease vs. ~10% for advanced/unresectable disease (systematic review/meta-analysis, PMC10073062).
• Surgical outcome comparison: 3-year survival ~100% after liver resection vs. ~76% after liver transplantation in one comparative series (search synthesis).

Prognostic Factors

• Favorable: Male sex, younger age, white race, surgical resectability, combined liver + lymph node resection (vs. liver resection alone).
• Unfavorable: Vascular invasion, lymph node metastasis, advanced/unresectable disease at diagnosis, older age at diagnosis.

Recurrence

Recurrence after resection is common — reported in 86% of patients in one series (Yamashita et al.) — most frequently to intra-abdominal/intrathoracic lymph nodes, liver, lungs, and peritoneum. Notably, surgical resection of recurrent disease is associated with substantially improved median OS (122 months) compared to non-surgical management of recurrence (37 months), underscoring an aggressive surgical approach even at relapse.

Morbidity

Beyond mortality, morbidity includes recurrent surgical burden, paraneoplastic hyperammonemic encephalopathy (potentially severe/refractory), and — rarely — thromboembolic and cardiac complications from tumor extension. Systematic QoL outcome data (EQ-5D/PROMIS) specific to FLC were not identified in this search.

12. Treatment

Surgical/Interventional (Mainstay)

• Surgical resection remains the only potentially curative modality and the single most important determinant of outcome, with 5-year OS of 50–76% in resected cohorts (cco.amegroups.org). NCIT: NCIT:C15329 (Surgical Procedure); more specific NCIT:C158** hepatectomy-type terms as applicable.
• Orthotopic liver transplantation (OLT): Reserved for selected unresectable cases; outcomes are generally inferior to resection (3-year survival ~76% vs. ~100% for resection in comparative data), but transplantation (including living-donor transplant) has been reported even in cases with hilar lymph node metastasis (PubMed:29633928).
• Lymphadenectomy: Combined liver resection + lymph node dissection is associated with better survival than liver resection alone, reflecting the disease's propensity for nodal spread.
• Re-resection of recurrence: Associated with markedly improved survival versus non-operative management of relapse (see Outcome section).

Pharmacotherapy — No Established Standard of Care

There is no FDA-approved systemic therapy specific to FLC; conventional HCC systemic regimens (sorafenib, lenvatinib, other multikinase inhibitors) have shown limited/inconsistent efficacy, reflecting FLC's distinct molecular biology.

Immunotherapy

• Checkpoint inhibitor combinations: Case reports describe tumor control with atezolizumab + bevacizumab re-administration (PMC11659117).
• Nivolumab + fluorouracil + interferon alfa-2b: Active phase I/II trial at MD Anderson (NCT04380545) for unresectable FLC, estimated primary completion 2028 (NCIT:C2963 for immune checkpoint inhibitor class; therapeutic_agent CHEBI/NCIT terms for nivolumab, 5-FU, interferon alfa-2b).
• Therapeutic peptide vaccine (2025 landmark trial): A phase 1 trial of a DNAJB1-PRKACA fusion-neoantigen peptide vaccine, combined with nivolumab + ipilimumab, was reported safe with encouraging early efficacy — disease control rate 75% (9/12) in patients completing the priming phase, including 3 partial responses (25%) (Nature Medicine 2025, 10.1038/s41591-025-03995-y). This is the first therapy directly targeting the fusion neoantigen immunologically and represents the most significant recent (2025) treatment advance.

Targeted/Experimental Therapies

• ENMD-2076 (oral Aurora A kinase/VEGFR/FLT3/FGFR3 inhibitor): Phase 2 multicenter trial (NCT02234986) met its Stage 1 non-futility endpoint and advanced to Stage 2, but final results were modest — only 1/N (3%) partial response, 57% stable disease — insufficient to support further single-agent development (PubMed:32154962; CASI Pharmaceuticals press releases). Rationale was AURKA overexpression downstream of the fusion.
• DT2216 (Bcl-xL-targeting PROTAC/degrader) + irinotecan: Phase I/II trial (NCT06620302) for relapsed/refractory pediatric, adolescent, and young-adult solid tumors including FLC, building on preclinical synergy between Bcl-xL inhibition and HDAC/topoisomerase I inhibitors/napabucasin (Fibrofoundation; Molecular Therapy 2023).
• Napabucasin (STAT3/cancer-stemness inhibitor), HDAC inhibitors, and topoisomerase I inhibitors showed the most potent activity in a preclinical drug screen ("preclinical magic bullet" study), with synergy when combined with Bcl-xL inhibition — supporting the DT2216 combination trial rationale (Molecular Therapy 2023, S1525-0016(23)00664-0).
• CRTC2/p300 targeting: Nominated as a therapeutic strategy following the 2024 mechanistic discovery of SIK inactivation/CRTC2-p300 deregulation by the fusion kinase (Cancer Discovery 2024) — not yet in clinical testing per available search results.

Supportive Care

Management of paraneoplastic hyperammonemic encephalopathy (a proposed treatment algorithm exists in the literature — PMC4828114) typically involves ammonia-lowering strategies (e.g., lactulose, rifaximin, sometimes dialysis/CRRT) alongside tumor-directed therapy, since standard cirrhosis-based hyperammonemia treatments may be less effective given the tumor-intrinsic ammoniagenic mechanism.

Treatment Algorithm Summary

1. Assess resectability at diagnosis (imaging + multidisciplinary review).
2. If resectable: hepatic resection + regional lymphadenectomy — curative-intent, best survival outcomes.
3. If borderline/unresectable: consider liver transplantation in selected cases; consider clinical trial enrollment (peptide vaccine + checkpoint inhibitors, nivolumab-based regimens, DT2216 combinations).
4. At recurrence: re-resection where feasible, given demonstrated survival benefit; otherwise systemic/experimental therapy.
5. Manage paraneoplastic complications (notably hyperammonemic encephalopathy) proactively.

Suggested NCIT terms: NCIT:C15329 (Surgical Procedure), NCIT:C15289 (Organ Transplantation), NCIT:C1647 (Nivolumab), NCIT:C2039 (Ipilimumab — verify code), NCIT:C328 (Interferon alfa-2b — verify code), NCIT:C561 (Fluorouracil), NCIT:C15346 (Vaccination, for the peptide vaccine), NCIT:C15632 (Chemotherapy).

13. Prevention

• Primary prevention: None established, since there are no modifiable environmental/lifestyle risk factors and the driver mutation is a sporadic somatic event.
• Secondary prevention/screening: No population or genetic screening program exists; early recognition depends on clinical suspicion in young patients presenting with an incidental hepatic mass, especially with the CT/MRI central-scar-with-calcification pattern and normal AFP.
• Tertiary prevention: Post-resection surveillance imaging is standard practice to detect recurrence early, given the high (up to 86%) recurrence rate and the demonstrated survival benefit of re-resection.
• Genetic counseling: Not routinely indicated given the sporadic, somatic nature of the disease; would only be considered in the rare context of a suspected co-occurring germline cancer-predisposition syndrome (e.g., the isolated TP53/Li-Fraumeni-spectrum case report).
• Public health/environmental interventions: Not applicable, as no environmental driver has been identified.

14. Other Species / Natural Disease

The literature retrieved in this search did not identify well-characterized naturally occurring FLC in companion animals or wildlife (unlike some other cancers with recognized veterinary correlates via OMIA). FLC-like disease in other species has not been prominently reported in the sources found. Genetically engineered animal models (see below) are the primary cross-species research tool, rather than natural veterinary disease. (This is a gap that would benefit from a dedicated OMIA/veterinary-literature search if higher confidence is needed.)

15. Model Organisms

Genetically Engineered Mouse Models

• Transgenic/genetically engineered mouse models expressing DNAJB1-PKA(c) in the liver have been developed; initial adult-liver expression models produced FLC-resembling tumors but at low penetrance (bioRxiv 2023.12.06.569624; PMC11582006).
• Mouse models combining DNAJB1-PRKACA expression with β-catenin activation show significantly enhanced tumorigenesis, supporting a two-hit cooperative model relevant to human Wnt-pathway alterations (PNAS:1716483114; PubMed:29162699).

Zebrafish Models

A zebrafish model expressing the DNAJB1-PRKACA fusion has been used to study fusion-induced liver inflammation as an early step in FLC pathogenesis (bioRxiv 781583).

Patient-Derived Models

• Patient-derived xenografts (PDX) established from patient tumor tissue or ascites in immunocompromised mice, and PDX-derived organoids composed of FLC epithelial cells, endothelial progenitor cells, and stellate cells, have been developed by several research groups (PMC11582006).
• CRISPR/Cas9-engineered ex vivo hepatocyte models: Mature hepatocytes edited to express the fusion gene (and, in some models, additional FLC-associated mutations) to generate FLC-like cells for mechanistic and drug-screening studies.
• A commercial PDX model (Crown Bio's LI5132) is available for liver cancer/FLC-relevant preclinical drug testing.

Model Limitations

Current models — particularly the low-penetrance transgenic mouse — do not fully recapitulate the human disease's histology (lamellar fibrosis), long latency, and metastatic behavior; PDX/organoid models better preserve tumor-stroma heterogeneity but are lower-throughput and harder to scale for large drug screens. The Aurora kinase inhibitor ENMD-2076, effective in some preclinical models, translated to only modest clinical activity, illustrating a translational fidelity gap.

Research Applications

These models collectively support: (1) validation of the DNAJB1-PRKACA fusion as a necessary/sufficient driver, (2) testing of cooperating mutations (β-catenin), (3) mechanistic dissection of the SIK-CRTC2-p300 axis and AURKA/MYC network, and (4) preclinical drug screening (napabucasin, HDAC inhibitors, topoisomerase I inhibitors, Bcl-xL degraders such as DT2216).

Summary of Key Ontology Term Suggestions

Notable Evidence Gaps / Curation Cautions

1. CTNNB1 mutation frequency in human FLC — the mouse-model cooperation with β-catenin is well documented, but a precise human-cohort mutation frequency was not retrievable in this pass and should be verified against the primary genomic-landscape papers (Oncotarget 2015; subsequent cohort studies) before citing a specific percentage.
2. DNAJB1-PRKACA specificity — not absolutely exclusive to FLC (also found in oncocytic pancreatobiliary neoplasms); curation should qualify "pathognomonic" claims accordingly.
3. Natural veterinary disease — no strong evidence of naturally occurring FLC in other species was found; this section should be flagged as a gap rather than asserted as "none exists" without a dedicated OMIA search.
4. Quantitative QoL data (EQ-5D/SF-36/PROMIS) specific to FLC patients were not identified and likely do not exist in validated form.

Sources

• DNAJB1-PRKACA fusion peptide immunotherapy (Nat Commun 2022)
• DNAJB1-PRKACA interacts with β-catenin (PubMed 29162699)
• SIK/CRTC2/p300 mechanism (Cancer Discovery 2024)
• DNAJB1–PRKACA and β-catenin (PNAS)
• Zebrafish model liver inflammation
• Oncogenic addiction to DNAJB1-PRKACA (PubMed 36302174)
• Orphanet: Fibrolamellar hepatocellular carcinoma
• Population-based observational study (PubMed 32052215)
• Defining incidence via tiered computational analysis (npj Precision Oncology 2023)
• Fibrolamellar Cancer Foundation: What is Fibrolamellar?
• Peptide vaccine phase 1 trial (Nature Medicine 2025)
• NCT04380545 — Nivolumab/5-FU/IFN-α2b
• NCT02234986 — ENMD-2076 phase 2
• ENMD-2076 phase 2 results (PubMed 32154962)
• CASI Pharmaceuticals ENMD-2076 update
• DT2216 clinical trial (Fibrofoundation)
• Framework for FLC research and clinical trials (Nat Rev Gastro Hepatol)
• Molecular testing for clinical diagnosis (PMC5758901)
• Procalcitonin as tumor marker (PMC12907347)
• Treatment and prognosis national perspective (PMC4596238)
• SEER epidemiology and survival (JCO 2024)
• 5-year cancer survival SEER (PubMed 37307948)
• Survival factors (Dove Press IJGM)
• Treatment/prognosis systematic review meta-analysis (PMC10073062)
• PKA scaffolding function (PMC6533061)
• Road map for fibrolamellar carcinoma (Dove Press JHC)
• Oncogenic PKA increases MYC (PMC9925115)
• PRKACA as therapeutic target (ScienceDirect S2772572322001911)
• Neurotensin as cAMP/co-mitogen source (PMC6707953)
• PKA holoenzyme structure (PMC7793292)
• AASLD Pathology Pearls: FLC
• Imaging features (AJR)
• FLC histologically unique tumor (ScienceDirect S0740257016301162)
• Murine models development (bioRxiv 2023.12.06.569624)
• Models of FLC review (PMC11582006)
• Management of FLC (Chinese Clinical Oncology)
• Surgical outcomes single-center (World J Surg Oncol)
• Resection vs transplantation outcomes (PubMed 11112043)
• Living-donor transplant with nodal metastasis (PubMed 29633928)
• FLC absence of risk factors case report (PMC9750232)
• FLC advances/challenges/opportunities review (PMC12576631)
• Hyperammonemic encephalopathy (PMC6304646)
• Molecular basis of hyperammonemic encephalopathy (PMC9922532)
• Hyperammonemic encephalopathy treatment algorithm (PMC4828114)
• Single-cell multi-omic analysis (bioRxiv 2024.12.11.627911)
• snATAC-seq analysis (Nature Scientific Reports)
• Genomic landscape whole genome sequencing (PMC4359253)
• Preclinical magic bullet HDAC/napabucasin (Molecular Therapy)
• DNAJB1-PRKACA FISH specificity (ScienceDirect S089339522201417X)
• FISH validation study (PubMed 35777788)
• Fusion not fully specific — oncocytic neoplasms (Modern Pathology)
• TP53 germline/somatic case report (Familial Cancer)
• CT/MRI case series (PMC4112400)
• Medscape: FLC Practice Essentials
• NORD: Fibrolamellar Carcinoma
• Liver Foundation Australia: FLC

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0006210 (3 mentions) - the report calls it "if available", "Fibrolamellar hepatocellular carcinoma"; MONDO calls it fibrolamellar hepatocellular carcinoma
• HP:0033834 (1 mention) - the report calls it "Fatigue-related"; HP calls it Malaise
• GO:0016575 (2 mentions) - the report calls it "histone deacetylation, inverse direction relevant", "histone deacetylation — inverse relevant to acetylation increase"; GO calls it obsolete histone deacetylation

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

• NCIT:C158 (1 mention) - NCIT does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0016575 (obsolete histone deacetylation) (2 mentions)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• GO:0007188 (1 mention) - the report calls it "adenylate-cyclase-activating G protein-coupled receptor signaling pathway"; GO calls it adenylate cyclase-modulating G protein-coupled receptor signaling pathway
• GO:0006541 (2 mentions) - the report calls it "glutamine metabolic process, for the hyperammonemia axis"; GO calls it L-glutamine metabolic process
• UBERON:0002370 (1 mention) - the report calls it "thymus – n/a"; UBERON calls it thymus

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• MONDO:0006210 - called "if available", "Fibrolamellar hepatocellular carcinoma"
• GO:0016575 - called "histone deacetylation, inverse direction relevant", "histone deacetylation — inverse relevant to acetylation increase"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, PubMed, PNAS, Oncotarget.