Managing Advanced Fibrolamellar Carcinoma at Stage IV: A Case Report.

Introduction
Fibrolamellar carcinoma (FLC) is a rare liver tumor, historically considered a variant of primary hepatocellular carcinoma (HCC), but with distinct characteristics. Unlike typical HCC, FLC predominantly affects young individuals, often in their teens to early adulthood, without pre-existing liver conditions [1]. It appears to be slightly more common in females [2]. There are no specific risk factors identified, and its etiology and pathogenesis remain largely unknown, presenting significant challenges in diagnosis and treatment [3, 4]. The clinical presentation of FLC is nonspecific, and diagnosis may take several years. Abdominal pain and a palpable mass are the most common symptoms. Other symptoms may include malaise, weight loss, encephalopathy, and liver failure, among others [4, 5]. Present in nearly all cases of FLC, the DNAJB1-PRKACA fusion kinase is typically identified directly with reverse transcription-polymerase chain reaction or RNA sequencing and indirectly with fluorescence in situ hybridization through visualization of genomic rearrangement [2, 3, 6, 7]. It is believed to act as an oncogenic driver in FLC. The DNAJB1 gene encodes the Hsp40 protein, while the PRKACA gene encodes a protein kinase A subunit, a key regulator of cell growth, differentiation, and programmed cell death [3, 8].
Recent evidence suggests that FLC does not share genetic signatures with mature hepatocytes but rather with subpopulations of biliary tree stem cells. These biliary tree stem cells are hepato-pancreatic stem/progenitor cells that reside within peribiliary glands of the biliary tree and contribute to the formation and postnatal regeneration of both the liver and pancreas [8]. This supports the hypothesis that FLC may originate from a stem-like progenitor cell population with multilineage potential, rather than from differentiated hepatic cells. The resemblance of FLC to fetal liver at the transcriptomic level further reinforces its developmental and progenitor-like phenotype [8]. The diagnosis of FLC can be challenging to establish and relies on a combination of clinical presentation, imaging studies, and pathology, with the latter serving as the gold standard. Imaging techniques such as computed tomography (CT) or magnetic resonance imaging are crucial for identifying the characteristic features of FLC [5, 9]. On imaging, FLC typically appears as a large solitary mass with a central fibrous scar. However, this feature is not pathognomonic [5, 9]. Lesion calcification is also commonly seen [9]. Other common radiologic findings include vascular invasion, biliary obstruction, regional lymphadenopathy, and distant metastases [9]. The primary differential diagnoses include benign liver lesions such as focal nodular hyperplasia, hepatic adenoma, and hemangioma, as well as primary hepatic malignancies, including conventional HCC and combined hepatocellular cholangiocarcinoma [5, 9]. Additionally, negative serum tumor markers, such as alpha-fetoprotein (AFP), may also support the diagnosis, as FLC is typically not associated with an elevation of AFP, unlike in HCC. A definitive diagnosis of FLC is established with pathological examination [4, 9]. Microscopic evaluation generally reveals well-differentiated, large, polygonal tumor cells with eosinophilic hyaline cytoplasmic bodies and abundant fibrous stroma arranged in thin, parallel lamellae around the tumor cells. Additionally, cytoplasmic pale bodies are frequently observed [4, 9]. The most important immunohistochemical markers for identifying tumor cells in FLC are cytokeratin 7 (CK7) and cluster of differentiation 68 (CD68), as they are particularly useful in distinguishing it from conventional HCC [5, 9]. Despite the distinct clinical, imaging, and pathological characteristics, FLC is often mistaken for HCC [5, 9]. Differentiating FLC from HCC and other liver masses is essential, as the treatment strategies and prognosis for FLC can differ significantly. The stage of disease and resectability are paramount prognostic factors in FLC. Approximately 20–30% of patients present with unresectable disease at diagnosis [5, 10]. Those with unresectable disease or extrahepatic involvement generally experience poorer outcomes [5, 10]. Among these patients, the median overall survival is reported to be approximately 12 months, with a 5-year survival rate of 0% [10]. In the context of advanced disease, effective systemic therapies for FLC are lacking, and no trials have established the superiority of any specific regimen. Several early phase trials have shown limited efficacy. As a result, treatment decisions are often based on evidence derived from case reports, retrospective studies, and database analyses [4].

Case Report
A 29-year-old female, ECOG performance status 1, with a history of left limb deep vein thrombosis diagnosed at the same age. Her medical history includes grade 3 obesity (body mass index 44 kg/m2), and Helicobacter pylori-positive gastritis treated 4 years earlier. The patient had no history of alcohol consumption, smoking, or other toxic habits, and her history of oral contraceptive use was unknown. Investigation began in May 2023 due to a 3-year history of diffuse abdominal pain with radiation to the back, diarrhea, and unintentional weight loss of 20.9% (∼24 kg). Abdominal ultrasound revealed a hepatic mass and multiple peritoneal nodules. A subsequent thoraco-abdominal-pelvic (TAP) CT scan showed an enlarged liver with a hypervascular mass (∼11.5 cm) in the left lobe without washout along with several similar nodules in the right lobe, the largest measuring 16 mm in segment 6 (shown in Fig. 1a–c, 2a, b). Additionally, an enlarged celiac lymph node (up to 5 cm short axis), numerous peritoneal nodules, and multiple bilateral small subpleural pulmonary nodules, the largest measuring 4 mm, were noted. AFP was slightly elevated (7.74 ng/mL [reference <7 ng/mL]), and liver function tests were mildly abnormal (shown in Table 1). Tests for hepatitis B surface antigen and hepatitis C virus antibody were negative. A percutaneous liver biopsy confirmed moderately differentiated FLC (shown in Fig. 3a, b). The case was discussed at the hepatobiliopancreatic multidisciplinary meeting, and systemic palliative treatment was recommended. The patient was treated with 6 cycles of GEMOX (gemcitabine 1,000 mg/m2 + oxaliplatin 100 mg/m2, both on day 1 and day 15, every 28 days) between September 2023 and February 2024. Notable treatment-related toxicities included CTCAE v5.0 grade 3 anemia and grade 2 nausea and vomiting, leading to a 25% dose reduction from the 4th cycle onward. After 4 cycles, treatment was interrupted for 2 weeks to manage antral gastritis due to recurrent H. pylori infection. The first control TAP CT scan was performed in November 2023 (after 3 cycles) and showed stable disease with the largest liver mass decreasing from 11.5 cm to 9 cm. After the 6th and last cycle, a TAP CT scan in March 2024 (Fig. 4a–c) showed a stable primary lesion but increased peri-celiac lymph nodes and peritoneal carcinomatosis, which did not meet progression criteria after multidisciplinary review. The patient was managed with active surveillance. After 3 months of surveillance, a follow-up TAP CT scan was performed, revealing a slight reduction in mean lesion size (now 8.4 cm on the largest axis, down from 11.5 cm), but significant progression of peritoneal carcinomatosis with large volume ascites (shown in Fig. 5a, b).
At that time, the patient’s performance status was progressively deteriorating to an ECOG performance status 3, accompanied by increasing asthenia, cachexia, and a frequent need for paracentesis. Ultimately, best supportive care was recommended. The patient died in September 2024.

Discussion
Due to the lack of robust studies evaluating the outcomes of various treatment modalities, standardized treatment protocols for FLC are not well established. As a result, treatment decisions are often based on empirical approaches [4].
Our patient received GEMOX due to the absence of established therapeutic guidelines, the exclusion of this histological subtype from trials assessing dual immunotherapy, the limited efficacy of sorafenib reported in retrospective studies, and the lack of robust evidence supporting immunotherapy in FLC. Additionally, case reports have documented responses to platinum-based chemotherapy in patients with metastatic FLC, further supporting this approach [10, 11].
In unresectable nonmetastatic FLC, treatment options include liver transplantation, embolization, and systemic therapy, with the role of liver transplantation being controversial and considered only for selected patients. Chemoembolization serves as an alternative treatment for patients who are ineligible for surgery or transplantation. Multimodality therapy, including neoadjuvant chemotherapy, presents potential alternatives with reported cases of downstaging to resectability [5, 10].
In the metastatic setting, treatment with chemotherapy, immunotherapy, and targeted therapy has been reported. Several chemotherapy regimens have been used for the treatment of FLC, including platinum-based regimens, fluoropyrimidine-based therapies, doxorubicin, and gemcitabine [11–13]. However, the effectiveness of these regimens varies, and no single treatment has emerged as a standard of care. Based on case reports, platinum-based regimens have demonstrated some efficacy [11, 12]. Notably, in the report by Gras et al. [12] GEMOX resulted in complete responses on 2 separate occasions, with sustained disease control and a complete remission lasting more than 5 years after treatment completion. In a case series of patients treated after relapse, among the 9 who received first-line chemotherapy, 3 achieved a partial response and 3 had stable disease with cisplatin-based regimens [13]. A phase II trial investigating systemic continuous fluorouracil in combination with subcutaneous recombinant interferon alfa-2b, administered three times weekly for HCC, included nine patients with FLC. Of these, 78% had metastatic disease, 1 patient achieved a complete response, and 4 had partial responses. The median overall survival for patients with FLC was 23.1 months [14]. Most existing studies include mixed populations of FLC and conventional HCC, making interpretation difficult due to fundamental biological differences between the two diseases. In addition, the inclusion of heterogeneous treatment settings, including curative and palliative approaches, limits the ability to evaluate chemotherapy outcomes specifically in the metastatic setting. Our patient was treated with the GEMOX chemotherapy regimen and survived for 12 months after initiating treatment, which is consistent with published data for stage IV FLC [15].
Retrospective analyses indicate that targeted therapies, such as sorafenib, have limited efficacy in FLC [16]. The available data are sparse and lack robust evidence; thus, the efficacy of these agents is not well established [16]. The DNAJB1-PRKACA gene fusion, identified in a significant number of FLC tumors and recognized as an oncogenic driver, has generated interest in its potential as a therapeutic target. However, current research has not yielded positive results, indicating a need for further research [17]. In a multicenter, phase II study evaluating the efficacy of ENMD-2076, an Aurora kinase A (AURKA) inhibitor, the primary endpoint of overall objective response was not met [17]. Retrospective analyses of immunotherapy in FLC have produced variable outcomes, reflecting inconsistency in the efficacy across different studies. In a case series of 3 patients treated with immunotherapy (1 with pembrolizumab and 2 with nivolumab) demonstrated limited efficacy, as all patients showed disease progression within 3 months of therapy [18]. Similarly, in another case series involving 2 patients treated with atezolizumab + bevacizumab, both individuals experienced disease progression shortly after treatment initiation [19]. The HIMALAYA and CheckMate-9DW clinical trials, which studied the use of immunotherapy in patients with unresectable HCC, did not include patients with FLC.
In recent years, retrospective data on multiagent combinations, including platinum-based chemotherapy and lenvatinib with or without nivolumab, have shown promising results in advanced disease [20–22]. Kent. et al. reported that GEMOX-lenvatinib in patients with advanced FLC achieved an overall response rate of 22%, a disease control rate of 98%, and an overall survival of 65% at 24 months [22]. In another study by the same authors, nivolumab combined with lenvatinib and gemcitabine achieved an objective response rate of 41%, a disease control rate of 100%, and a 12-month overall survival of 67% [21]. However, more detailed and peer-reviewed data are needed to validate these findings.

Conclusion
Disease stage and resectability are the two primary prognostic factors influencing outcomes in patients with FLC. In patients with unresectable disease, overall survival remains poor.
As in previously reported cases, our patient had no underlying liver disease. This case highlights the challenges of managing FLC, a rare and aggressive liver cancer with limited treatment options. Currently, no standard or consistently effective treatment exists for advanced or metastatic FLC.
Identifying novel therapeutic targets and the pursuit of effective treatments are central themes in current FLC research, with ongoing studies exploring targeted therapies, immunotherapy, and molecular profiling to improve patient outcomes. Future research should focus on large patient cohorts, clinical trials of combination therapies, novel immunotherapeutic approaches, and personalized medicine strategies to improve outcomes for patients with unresectable or metastatic FLC.

Acknowledgments
The authors would like to thank Dr. Leonor Fernandes (Medical Oncology Department, Hospital de Santo António dos Capuchos, Unidade Local de Saúde de São José) for her guidance in selecting the appropriate journal for submission. The authors also thank Dr. Ana Carvalho (Pathology Department, Hospital Curry Cabral, Unidade Local de Saúde de São José) and Dr. Tiago Bilhim (Radiology Department, Unidade Local de Saúde de São José) for their support and supervision as clinical tutors in the selection and preparation of the imaging included in this case report.

Statement of Ethics
Written informed consent for publication of the details of this medical case and any accompanying images was obtained from the patient’s mother, as the patient is deceased. This publication did not require ethical approval as per local laws. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550704).

Conflict of Interest Statement
The authors have no conflicts of interest to declare.

Funding Sources
This study was not supported by any sponsor or funder.

Author Contributions
Ivánia Furtado conceived the study, collected the clinical data, and drafted the manuscript. Nuno Gião provided histopathology images and critically revised the manuscript. Martim Urbano provided the radiology images and critically revised the manuscript. João Boavida Ferreira supervised the preparation of the report and critically revised the manuscript. All authors approved the final version for submission.