Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy

Abstract

Fibrolamellar hepatocellular carcinoma is a rare and unique subtype of primary liver cancer that predominantly affects adolescents and young adults who do not have underlying liver disease or cirrhosis. Representing less than five percent of all liver tumors, it poses significant diagnostic and therapeutic challenges due to its uncommon occurrence, vague clinical symptoms, and absence of standardized treatment protocols. This review summarizes the current understanding of the disease, covering its epidemiology, clinical presentation, imaging characteristics, histopathologic features, molecular biology, and treatment approaches. Patients often present with nonspecific abdominal symptoms, and typical tumor markers, such as alpha-fetoprotein, are usually absent. Imaging may show a central scar and calcifications, while histology reveals large eosinophilic tumor cells separated by fibrous bands. A defining molecular hallmark is the DNAJB1-PRKACA fusion gene, found in the majority of cases. Surgical resection remains the primary curative treatment for localized disease, although recurrence rates are high. Liver transplantation may be an option for selected patients with non-resectable, liver-confined tumors. Treatment options for advanced disease are limited, with some benefit observed from chemotherapy and targeted agents. Recent developments in molecular therapies and immunotherapy offer promise, but further research and clinical trial participation are essential to improve outcomes in this challenging malignancy.

Key Words: Hepatocellular carcinoma; Fibrolamellar carcinoma; Liver surgery; Systemic treatment; Oncologic outcomes

Core Tip: Fibrolamellar hepatocarcinoma is a rare subtype of primary liver cancer characterized by unique histological, clinical, and molecular features. Although surgical resection remains the cornerstone of curative treatment, advances in molecular biology and identifying specific genetic alterations hold promise for developing targeted therapies, potentially improving outcomes for patients with this rare disease.

INTRODUCTION

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare form of liver cancer, with particularities regarding epidemiology, clinical presentation, diagnosis, and therapeutic management. Data from the Surveillance, Epidemiology, and End Results (SEER), the program indicates an incidence rate of 0.2 new cases per million person-years, accounting for < 5% of the primary liver tumors[1]. While classical hepatocellular carcinoma (HCC) usually develops in the setting of cirrhosis and pre-existing liver conditions, FLHCC typically presents in otherwise healthy adolescents and young adults. This situation poses complexity in diagnostic and therapeutic approaches and in the development of new therapies based on biologic features. The first description of FLHCC was made in 1956 by Edmondson[2] in a 14-year-old female patient without previous liver disease. It was initially called eosinophilic hepatoma with lamellar fibrosis because of tumor cells with eosinophilic cytoplasm and parallel arrangement of the collagen in conspicuous fibrous septa. Several case reports, series, and cohorts have been reported in the following decades[3,4]. With this, a clearer picture of FLHCC has been drawn, leading to some advances in the field, such as the definition of genetic features, such as the DNAJB1-PRKACA fusion, firstly identified by Honeyman et al[5] in 2014. However, the rarity of the disease hampers advancements in many aspects. Some reports suggest that the real proportion of FLHCC among primary liver tumors might be slightly higher, due to underdiagnosis[1,3]. There is no specific designation for FLHCC in the International Classification of Diseases, and a poor representation of FLHCC in genomic studies. The management of FLHCC is primarily informed by the practices adopted in other liver tumors. For patients with the disease confined to the liver, surgical resection or transplantation are options. For patients with a limited burden of extrahepatic disease, a multidisciplinary approach including surgical resection can be considered. On the other hand, for patients with unresectable advanced disease, systemic treatment can be offered[6,7]. However, there is a lack of consensus and randomized trials to inform the most suitable regimens for use, as well as personalized and targeted therapies. Therefore, this review aimed to present a comprehensive review of data on the general aspects of FLHCC and recent advancements in treatment.

EPIDEMIOLOGY AND RISK FACTORS

The epidemiology of FLHCC differs from other primary liver tumors. Most of the patients are diagnosed under 40 years old, with a median age of 39.5 years[8]. In a study with 115 cases, 60% were diagnosed under the age of 40, 7% between 40-49 years, 33% older than 50 years old. An incidence analysis demonstrated two age-specific peaks, one among young patients between the ages of 10-30 years and a second among persons aged 60-69 years[8]. In a study with SEER database including 225 patients, there were 124 (55.1%) Whites, 52 (23.1%) Hispanics, 27 (12.0%) Blacks, and 22 (9.8%) Asian and Pacific islanders[9]. Mean ages were 35.9, 37.2, 33.6, and 49.5 years, respectively, suggesting that there might be a differential distribution of the age at diagnosis across different ethnicities. Patients ≤ 19-year-old had more advanced lymph nodes spread, but they received more surgical interventions. SEER registries contain population-based data on cancer incidence, characteristics, treatment, and mortality in select states of the United States since 1973[9]. Although survival appears to be better in younger ages, this observation needs validation and is potentially biased due to treatment tolerance. Data from a Mexican study analyzed FLHCC cases between 1987 and 2001, compared to literature reports from 1980 to 1990. Interestingly, FLHCC represented 5.8% of all primary liver tumors, which is high than what is reported in other regions[10]. In contrast to HCC, FLHCC affects both sexes at similar proportions[1]. A study showed that male gender was more prevalent in overall HCC (case male to female ratio of 3.6) vs FLHCC (case male to female ratio of 1.7)[7]. Nevertheless, some studies suggest a female preponderance, but in general, most of the studies indicates an equal distribution[1]. Another crucial particularity of FLHCC is the absence of known risk factors. Less than 10% of patients shows concomitant features of chronic liver disease, such as cirrhosis and viral infection. Tumor markers, such as alpha-fetoprotein are rarely elevated in FLHCC. Despite some incipient evidence of hepatitis B virus-DNA sequences in tumor and nontumor tissue in a patient with the fibrolamellar variant of HCC[11], there is no association between hepatitis B virus chronic infection and FLHCC and neither that benign liver lesions might transform into FLHCC[12]. Tumor-associated lymphatic vessel density could predict survival and recurrence after resection in patients with hepatic tumors, according to a meta-analysis of ten studies involving 761 patients[13]. However, its role in FLHCC is yet to be explored. The genomic evidence of chimeric protein formation derived from the DNAJB1-PRKACA fusion, along with the strikingly consistent transcriptomic and proteomic changes observed in FLHCC tumors compared to adjacent normal tissue, revealed several key insights into the disease. Notably, one major finding was that FLHCC is not a genetically inherited condition. This conclusion stems from the fact that the mutation was present only in the tumor tissue and absent in the surrounding normal tissue, indicating that the driver of FLHCC is a somatic mutation[5].

DIAGNOSIS AND CLINICAL PRESENTATION

Patients with FLHCC may present with a broad spectrum of clinical features, ranging from nonspecific symptoms to the incidental detection of a hepatic mass during imaging or evaluation for unrelated conditions. Unlike conventional HCC, the symptom profile in FLHCC is distinct, lacking many of the common clinical manifestations observed in typical HCC cases, such as those related to cirrhosis decompensation. Presenting symptoms are often vague and include nonspecific abdominal pain, nausea, abdominal distension or fullness, constitutional symptoms such as malaise, and unintentional weight loss. On physical examination, patients may exhibit hepatomegaly or a palpable abdominal mass, which may be associated with or without right upper quadrant tenderness and obstructive jaundice. Less frequent but notable clinical findings include gynecomastia in males, fulminant hepatic failure, recurrent episodes of deep vein thrombosis, hepatic encephalopathy, thrombophlebitis of the lower extremities, anemia, ascites, and hypoglycemia[14,15]. A rare manifestation is the occurrence of hyperammonemic encephalopathy. Proposed mechanisms of this symptom in FLHCC patients includes additional insult induced by therapy, resulting in increased cell breakdown and nitrogen load; an overwhelming urea cycle, as seen with congenital enzymatic deficiencies; and aggravation of pre-existing hyperammonemia. Also, decreased expression of ornithine transcarboxylase, the urea cycle enzyme, and inhibition its by cancer itself can play a role[16]. Biochemical profiles typically reveal hepatic transaminases and alkaline phosphatase levels within normal limits or only mildly elevated.

IMAGING FEATURES

Differently from HCC, that shows typical radiologic features, FLHCC reveals distinct characteristics across several modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound. On CT imaging, FLHCC typically appears as a large mass with heterogeneous enhancement following the administration of intravenous contrast. The tumor often has a central hypoattenuating region, which represents necrosis, surrounded by more hyperattenuating tissue that reflects its vascularity. In some cases, the lesion includes cystic components caused by internal hemorrhage or necrosis, giving the tumor a complex appearance. A characteristic feature is the presence of capsular enhancement on delayed-phase imaging, suggesting the presence of fibrous tissue encasing the mass. These tumors usually arise in the right lobe of the liver and are well defined with a lobulated outline, although some may appear ill-defined. On unenhanced CT, the tumors are predominantly hypoattenuating. A central stellate scar is present in approximately 65%-70% of cases, and calcifications - often located within this scar - are observed in 40%-68% of patients. While a central scar is not exclusive to FLHCC and can be seen in other hepatic lesions, its size (typically greater than 2 cm), radiating fibrotic bands, and associated calcifications favor the diagnosis of FLHCC[17,18]. Following intravenous contrast administration, FLHCC typically exhibits marked heterogeneous enhancement during the arterial phase. This pattern is due to the tumor’s architecture, with hypervascular tumor cells surrounding hypovascular fibrotic bands, along with areas of necrosis and cystic degeneration. The portal venous and delayed phase enhancement patterns are variable. Approximately half of FLCHCCs become isoattenuating to the surrounding liver in the portal venous phase, while others remain hyperattenuating or hypoattenuating. Delayed phase images can also show variable attenuation. Importantly, contrast enhancement within the central scar is not consistent; although previously believed to lack enhancement, more recent studies show that delayed enhancement of the scar occurs in 25%-65% of cases[17,19]. The delayed enhancement is thought to result from vascular and cellular elements within the scar, as opposed to avascular collagen seen in other lesions. Portal vein thrombosis and biliary obstruction are less common findings in FLHCC, occurring in only 5%-10% of cases[17,19]. On MRI, FLHCC demonstrates signal characteristics that align with its histologic structure. On T1-weighted images, the tumor appears hypointense, while on T2-weighted sequences, it typically appears hyperintense due to necrotic or cystic regions. The fibrous stroma within the tumor, particularly the central scar, is hypointense on both T1- and T2-weighted images - unlike in focal nodular hyperplasia, where the scar is usually hyperintense on T2. Calcifications, while often visible on CT, are less reliably detected on MRI. Gadolinium-enhanced MRI shows intense, heterogeneous arterial phase enhancement similar to CT, with washout in the portal venous and delayed phases. FLHCC generally does not retain hepatobiliary-specific contrast agents like gadoxetate disodium, which may help in differential diagnosis. Although diffusion-weighted imaging has not been thoroughly studied in FLHCC, limited data suggest the tumors may demonstrate restricted diffusion[19-21]. Ultrasound typically reveals a heterogeneously hypoechoic lesion, although echogenicity may vary depending on the amount of fibrosis, hemorrhage, or calcification. The tumor is often well-circumscribed, but extensive necrosis can make the borders appear irregular or poorly defined. Doppler ultrasound usually reveals increased internal vascularity, consistent with the hypervascular nature of FLHCC[19,22]. Metastatic spread is common in FLHCC. Regional lymph node metastases are found in 50%-65% of cases, most often involving the hepatic hilum and hepatoduodenal ligament. Distant lymphadenopathy may also be present in the retroperitoneum, pelvis, or mediastinum[23]. Lymph node involvement has significant prognostic implications; in one study, patients without nodal metastasis had a 100% five-year survival rate, compared to only 45% in those with nodal involvement[24]. Distant metastases occur in approximately 20%-30% of patients, with the lungs, peritoneum, and adrenal glands being the most common sites. Less frequently, metastases may also appear in bone, ovary, mediastinum, and skeletal muscle. Additional adverse prognostic features include satellite nodules within the liver, biliary obstruction, and vascular invasion (Table 1)[23,25].

Table 1 Main characteristic of fibrolamellar hepatocellular carcinoma in imaging modalities.

Modality	Characteristic findings	Diagnostic utility
Computed tomography	Large, lobulated mass with central scar, calcifications	Good for detecting mass, vascular involvement
Magnetic resonance image	T2 hyperintense mass, T1 hypointense, scar hypointense	Better for soft tissue contrast, evaluates central scar
Ultrasound	Hypoechoic, heterogeneous lesion	First-line, limited specificity
PET/CT	May be useful in recurrence or unclear imaging	Not standard, adjunct in certain scenarios

PET: Positron emission tomography; CT: Computed tomography.

HISTOLOGY

FLHCC differs significantly from conventional HCC in its histologic appearance on gross examination, FLHCC usually presents as a single, large, firm, and well-demarcated mass, which may be encapsulated. The surface of the tumoral lesion often displays thick, fibrous, gray-white bands that divide it into smaller nodules[26]. Microscopically, FLHCC is composed of large polygonal cells with abundant eosinophilic, granular cytoplasm, prominent nucleoli, and large vesicular nuclei. The granular cytoplasm is due to a high mitochondrial content. These tumor cells are arranged in clusters or nests separated by parallel lamellae of dense, hyaline fibrous stroma. Pseudoglandular structures can sometimes be seen and may contain bile or mucin-like substances, potentially mimicking combined hepatocellular-cholangiocarcinoma[27]. The immunohistochemical profile of FLHCC overlaps with that of conventional HCC, showing positivity for markers such as HepPar1, glypican-3, arginase-1, polyclonal carcinoembryonic antigen, and cluster of differentiation (CD) 10. However, FLHCC is distinguished by consistent positivity for cytokeratin 7 and epithelial membrane antigen, suggesting a dual lineage with features of both hepatocytes and cholangiocytes[27,28]. Additionally, CD68 is a useful marker for FLHCC; it highlights a lysosomal transmembrane glycoprotein and is associated with expression of the CD68 gene[29]. Fewer than 40% of cases express hepatic progenitor cell markers like cytokeratin 19 and EpCAM[14,17].

MOLECULAR DIAGNOSIS

The defining molecular hallmark of FLHCC is the DNAJB1-PRKACA fusion gene, caused by a 400 kb deletion on chromosome 19. While originally thought to be exclusive to FLHCC, this fusion has also been identified in rare oncocytic tumors of the pancreas and bile duct[30]. DNAJB1 encodes a heat shock protein, and PRKACA encodes the catalytic subunit of protein kinase A (PKA), with the fusion leading to aberrant PKA activation[31]. FLHCC typically shows low mutational burden, but mutations in genes like TERT, MUC4, LKB1, and TAFA5 have been reported. TP53 is rarely mutated, but its activity may be disrupted due to mislocalization and elevated nuclear murine double minute 4[31-33]. Some tumors exhibit mixed FLHCC-HCC features. While many of these lack the DNAJB1-PRKACA fusion, some show biallelic BAP1 mutations, even in tumors histologically resembling pure FLHCC[34]. These findings suggest molecular heterogeneity within FLHCC and may explain the variable age of onset. Tumors harboring the DNAJB1-PRKACA fusion or BAP1 mutations can show abnormal activation of PKA. In BAP1-mutated liver cancers, this is often accompanied by PRKACA gene amplification and/or PRKAR2A gene deletions, both of which can deregulate PKA, making its activity less reliant on cyclic adenosine monophosphate[33-35]. The DNAJB1-PRKACA fusion transcript produces a chimeric protein (46 kDa), called DNAJ-PKAc, which replaces part of the normal PKA catalytic subunit with the J-domain of heat shock protein 40. While preclinical studies using selective PKA inhibitors show promise, targeting this protein is challenging due to toxicity from inhibiting normal PKA in healthy tissues[30,32]. The presence of the DNAJB1-PRKACA fusion transcript is evaluated using RNA-based next generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). Graham et al[36] developed an RT-PCR assay for paraffin-embedded tissues and a FISH probe for detecting rearrangements of the PRKACA locus in a study involving 106 primary liver tumors, including 26 FLHCC cases. Both methods identified the fusion at the transcriptional and genomic levels. RT-PCR was successful in 92% of FLHCC cases tested, consistently detecting the DNAJB1-PRKACA fusion transcript in all FLHCC samples but not in other tumor types. FISH detected rearrangements of the PRKACA locus in all 19 FLHCC cases analyzed. Additionally, RNA in situ hybridization was positive in all 7 cases where hybridization was successful, demonstrating mRNA overexpression in each FLHCC sample. These findings collectively indicate that detection of the DNAJB1-PRKACA fusion is a highly sensitive and specific marker for diagnosing FLHCC[36].

STAGING

FLHCC is staged using the American Joint Committee on Cancer 8^th edition tumor-node-metastasis system, like other primary liver tumors. However, for practical purposes, the disease is classified according to disease extension in resectable or unresectable/advanced[37]. At diagnosis, about 20% of patients present with early-stage (I-II) disease, while 42%-50% present with stage IV, often with nodal or distant metastases[38,39]. Unlike HCC, nodal involvement in FLHCC does not usually preclude surgery. Prognosis is mainly determined by stage and resectability. Patients who undergo curative surgery may achieve 5-year survival rates of 40%-70%, whereas unresectable cases have a median survival under 12 months[23,39]. Factors associated with worse outcomes include nodal or extrahepatic spread, microvascular invasion, elevated alpha-fetoprotein, and possibly female sex, though findings are not consistent[37]. Recent data suggest that long-term survival in FLHCC is comparable to noncirrhotic HCC (Table 2)[40].

Table 2 Summary of differences between fibrolamellar and convention hepatocellular carcinoma.

Feature	FLHCC	Conventional HCC
Typical age group	Adolescents/young adults	Older adults with liver disease
Underlying liver disease	Absent	Often present
AFP elevation	Rare	Common
Histology	Large eosinophilic cells, fibrous lamellae	Variable, often trabecular
Genetic alterations	DNAJB1-PRKACA fusion	TP53, TERT, CTNNB1 mutations
Common metastasis sites	Lymph nodes, lungs, peritoneum	Lungs, bones

AFP: Alpha-fetoprotein; FLHCC: Fibrolamellar hepatocellular carcinoma; HCC: Hepatocellular carcinoma.

TREATMENT SURGERY

Surgical resection remains the cornerstone of treatment when feasible. Approximately 70% of patients present with potentially resectable disease, often requiring major hepatectomy due to size and location. Despite aggressive surgery, recurrence rates are high, with studies reporting recurrence in 33% to 100% of cases, and median recurrence-free survival ranging from 20 months to 48 months. This data comes from a retrospective cohort study involving patients identified from 1973 to 2009[41]. Achieving a complete (R0) resection is crucial for improved survival. Retrospective studies have shown that patients with R0 resection have significantly better overall survival (OS) compared to those with incomplete resection[41]. The presence of regional lymph node metastases is a negative prognostic factor. However, isolated nodal metastases may not significantly impact overall or recurrence-free survival. The absence of large vessel invasion is favorable for prognosis. Vascular invasion is associated with a higher risk of recurrence and poorer survival outcomes[1,8,40,42]. A series of ten patients with fibrolamellar hepatocellular treated with resection followed by close surveillance and aggressive management of relapse by Maniaci et al[43] found that all patients experienced recurrence after initial surgery, with a median time to recurrence of 2.2 years. For those who underwent re-resection, the median OS increased to 4.7 years, with a 5-year survival rate of 48%. Liver transplantation is considered for select patients with unresectable FLHCC without extrahepatic disease. A systematic review of 35 series involving 575 patients indicated a 5-year survival rate ranging from 29% to 55% for those undergoing liver transplantation[44,45]. Given the high recurrence rates, postoperative surveillance is essential. Recommended strategies include regular imaging studies such as CT scans every 3 months to 6 months for the first 2 years to 3 years postoperatively. In cases where imaging is inconclusive, but tumor markers are elevated, positron emission tomography/CT scans may be utilized. For patients experiencing recurrence, repeat surgical resection can be beneficial. Case series have demonstrated that re-resection of recurrent FLHCC lesions can lead to improved survival outcomes, with median OS extending up to 122 months in some cases[40].

OTHER LOCOREGIONAL TREATMENTS

Although limited, available data suggest that embolization may offer an alternative treatment for FLHCC in select patients. Hepatic artery chemoembolization has been used in cases without extrahepatic metastases when surgical resection or liver transplantation is not feasible, or when the disease fails to respond to systemic therapy. However, the precise role of embolization remains undefined. In some instances, embolization has been employed to reduce tumor burden and improve resectability. Additionally, portal vein embolization may be utilized preoperatively to enhance future liver remnant volume and ensure sufficient liver function following major resections[46]. Radiation therapy has been reported in several clinical contexts. It has been used to manage unresectable primary tumors, convert unresectable cases to operable ones, and treat relapses or metastases. In one case, internal radiation therapy using yttrium-90 resulted in a significant tumor response, enabling successful curative resection[47]. Another report documented an 85% reduction in metastatic tumor volume using external beam radiation therapy (40 Gy in 10 fractions over 13 days)[48]. Furthermore, an analysis of ten patients with nonresectable metastatic FLHCC treated with external beam radiation in combination with chemotherapy showed that three patients achieved partial responses, six had stable disease, and one experienced early progression[49,50]. While embolization and radiotherapy are not established standards of care in FLCHH, they may be beneficial in carefully selected cases, particularly when integrated into a multimodal approach aimed at downsizing tumors or controlling unresectable disease.

SYSTEMIC TREATMENT

Systemic therapy for FLHCC remains an area of active investigation, as no standard regimen has been established due to the rarity of the disease and its unique characteristics. Patients with locally advanced or metastatic disease who are not candidates for surgical resection often receive systemic treatment, though the effectiveness of these therapies varies. Due to the early onset and preserved liver function in patients, systemic therapies typically used for hepatoblastoma, conventional HCC and other gastrointestinal cancers have been explored. In a pooled analysis by Kaseb et al[37] involving 26 patients with FLHCC who received systemic therapy without surgery, the median OS was 20.6 months, with promising results observed using 5-fluorouracil (5-FU) combined with interferon. Another phase II trial, which included nine FLHCC patients treated with the same regimen, reported a response rate of 62.5% and a median OS of 23.1 months[51]. Similarly, Lamarca et al[52] found favorable outcomes with this combination, showing a median OS of 38.5 months among those who had received interferon and 5-FU at some point. In a study from our group, patients treated with interferon and capecitabine had a comparable median OS of 38 months[53]. Chemotherapy combinations have been one of the cornerstones in treating advanced FLHCC. Platinum-based regimens, such as cisplatin combined with epirubicin, and 5-FU, have shown some efficacy in case series[37,43]. Other combinations, including gemcitabine and oxaliplatin, have also been reported to yield partial responses. However, the OS benefit remains modest, with five-year survival rates for patients with advanced disease being less than 10% and median survival under 2 years[54]. Data from the fibrolamellar consortium, which includes three large institutions with cases from 1986 to 2011, published by Ang et al[55], described outcomes for 45 patients treated with various systemic agents such as fluoropyrimidines, cisplatin, oxaliplatin, irinotecan, gemcitabine, and doxorubicin, yielding mixed results. Sorafenib was administered to 10 patients, most of whom had progressive disease, with only one showing a mixed response[55]. In a separate study by Chakrabarti et al[56] involving 17 patients, 4 out of 9 treated with sorafenib achieved stable disease, lasting from 5 months up to 5 years. In our experience, sorafenib showed a disease control rate of 20% when used as first-line therapy and was linked to a longer median survival of 38.1 months compared to other regimens, suggesting its benefits may become apparent over time[53]. Recent efforts have focused on identifying therapeutic targets and precision treatments. The DNAJB1-PRKACA fusion gene, found in nearly all FLHCC cases, leads to increased aurora kinase A expression. A phase II trial of ENMD-2076, a selective aurora kinase A inhibitor, reported a median OS of 19 months, with one partial response and stable disease in 20 of the 35 patients treated[57,58]. Trials investigating everolimus and sunitinib were halted due to lack of efficacy. Whether DNAJB1-PRKACA is a viable therapeutic target remains an area of active research, with ongoing studies currently evaluating this possibility. Recent studies have investigated novel combination therapies[59]. In a multi-agent approach, patients were treated with combinations such as 5-FU/interferon/nivolumab, gemcitabine/oxaliplatin/Lenvatinib, and nivolumab/Lenvatinib/quercetin. The best objective response rates were 58% for the 5-FU/interferon/nivolumab regimen, 55% for gemcitabine/oxaliplatin/Lenvatinib, and 33% for nivolumab/Lenvatinib/quercetin. The median progression-free survival varied among the regimens, with the 5-FU/interferon/nivolumab combination showing the longest duration. These results indicate that while combination therapies may offer some benefit, and the overall response is variable[59]. Elevated expression of several immune checkpoints has been observed in FLHCC, supporting the rationale for exploring immune checkpoint inhibitors as a potential therapeutic approach[60]. However, clinical use of immunotherapy remains limited, and published outcomes have been inconsistent. The studies have shown no responses to either single-agent immunotherapies such as pembrolizumab or nivolumab, or to dual-agent regimens like atezolizumab combined with bevacizumab[61,62]. Despite this, a recent retrospective analysis reported encouraging results using a three-drug combination of nivolumab, pegylated-interferon alpha-2b, and a fluoropyrimidine[63]. Recently, the ‘study to understand the methods of prolonging remission in type 2 diabetes’ trial, a global, phase 2 open-label “basket” study that assessed the safety and effectiveness of neratinib - an irreversible inhibitor targeting the human epidermal growth factor receptor family of kinases - in various cancer types harboring activating human epidermal growth factor receptor 2 somatic mutations[64]. In this trial, fifteen individuals with FLHCC were treated with neratinib alone. The objective response rate was 5%, and the disease control rate reached 13.3%. Following disease progression, five of these patients went on to receive additional therapies involving immune checkpoint inhibitors, with or without the addition of everolimus or sunitinib. Outside of the ‘study to understand the methods of prolonging remission in type 2 diabetes’ study, two more patients were treated with neratinib-based combination therapies, bringing the total number of neratinib-treated patients to 17. Among these, one patient who received neratinib in combination with pembrolizumab achieved a confirmed partial response. Another patient who was treated with neratinib and everolimus maintained stable disease for six months, while a third patient, treated with a triple combination of neratinib, pembrolizumab, and sunitinib, experienced stable disease for 16 months[64]. Given the rarity of FLHCC and the variability in treatment responses, enrolling patients in clinical trials is strongly encouraged. Clinical trials offer access to emerging therapies and contribute to the understanding of effective treatment strategies for this rare malignancy.

CONCLUSION

FLHCC is a rare and distinct liver malignancy that primarily affects adolescents and young adults without underlying liver disease. Its unique clinical, radiologic, histologic, and molecular characteristics set it apart from conventional HCC, yet limited representation in large-scale studies continues to hinder the development of targeted treatment strategies. Although surgical resection remains the cornerstone of potentially curative treatment, high recurrence rates and the frequent presence of advanced or metastatic disease at diagnosis present significant clinical challenges. Systemic therapy options, including traditional chemotherapy regimens and targeted agents, have shown variable and generally modest efficacy, highlighting the urgent need for more effective therapies. Emerging molecular insights, such as the identification of the DNAJB1-PRKACA fusion and HER2 pathway alterations, have led to the exploration of targeted and immunomodulatory therapies. Trials with agents such as interferon, 5-FU, sorafenib, and neratinib - with or without immunotherapy - have shown occasional promising outcomes but lack consistent and durable responses. The role of immune checkpoint inhibitors remains unclear, with mixed results reported. As such, ongoing research into the molecular drivers of FLHCC is essential. Given the rarity and biological complexity, enrollment in clinical trials remains critical for advancing treatment options and improving outcomes for this underserved patient population.