Fibrolamellar carcinoma (FLC) is a rare form of liver cancer that primarily affects adolescents and young adults without underlying liver disease or cirrhosis. Unlike the more common hepatocellular carcinoma (HCC), which is strongly associated with chronic liver conditions such as hepatitis or alcohol abuse, FLC typically arises in individuals with otherwise healthy livers. Despite its rarity, FLC is an important topic in oncology due to its unique clinical, genetic, and pathological characteristics.
What is Fibrolamellar Carcinoma?
Fibrolamellar carcinoma is a subtype of primary liver cancer, accounting for less than 1% of all liver cancer cases. It is most commonly diagnosed in individuals aged 10 to 35 years, with no significant gender predilection. The absence of known risk factors such as liver cirrhosis or viral hepatitis further distinguishes FLC from other hepatic malignancies.
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| Liver cancer or liver tumor, Hepatocellular carcinoma (HCC), causes, symptoms, treatments, 3D illustration. Image credit: Istock- Mohammed Haneefa Nizamudeen |
Histologically, FLC is characterized by large polygonal cancer cells surrounded by dense bands of fibrous tissue, which give the tumor its name. This unique fibrotic structure can often be observed on imaging studies, aiding in diagnosis.
Causes and Genetic Insights
The exact cause of FLC remains unclear. However, recent research has identified a characteristic genetic mutation in most cases of FLC—a DNAJB1-PRKACA fusion. This mutation results from a chromosomal rearrangement, leading to the fusion of the DNAJB1 and PRKACA genes. The resulting hybrid protein is thought to play a critical role in tumor development by dysregulating cellular signaling pathways.2,3
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| Figure 1 Liver cancer disease progression. Fibrolamellar carcinoma mainly develops against a background of liver tissue, which appears to be normal without any kind of cirrhosis. Recently performed genetic research demonstrated the inclusion of a fusion gene, namely DNAJB1-PRKACA, in 79%-100% patients diagnosed with FLC. Although CCA and HCC and their pathologic subtypes, such as scirrhous HCC or mixed CCA-HCC, and the different genetic variants typically have a uniformly poor prognosis, patients diagnosed with FLC generally have a good prognosis. The complex molecular heterogeneity further demands a personalized approach to therapy and emphasizes the requirement for future genomic studies. FLC enrichment of known gene signatures falls into the "proliferation" and "inflammation" classes also found in HCC and CCA. The "unannotated" subgroup had enrichment in general cancer-related genes such as MAPK, PIK3, RAS, CTNNB1, and TGFb, not specific to liver cancers. |
Unlike other liver cancers, FLC is not linked to environmental or lifestyle factors. The discovery of the DNAJB1-PRKACA fusion has not only deepened our understanding of the disease but also opened new avenues for targeted therapies.4
Symptoms and Diagnosis
FLC often presents with non-specific symptoms, which can delay diagnosis. Common symptoms include:
• Abdominal pain or discomfort
• A palpable abdominal mass
• Unexplained weight loss
• Fatigue
• Jaundice (in advanced cases)
Due to these vague symptoms, FLC is often detected incidentally during imaging studies for unrelated conditions. Diagnostic tools include:
1. Imaging: CT scans and MRIs often reveal a well-demarcated mass with a characteristic central scar.5
2. Biopsy: Histological examination confirms the diagnosis, highlighting the fibrous bands and tumor cells.1
3. Biomarkers: Unlike HCC, FLC does not typically show elevated alpha-fetoprotein (AFP) levels, but other markers like neurotensin may be elevated.6
Treatment Options
The primary treatment for FLC is surgical resection. Complete removal of the tumor offers the best chance for long-term survival. Unfortunately, many patients present with advanced or metastatic disease, limiting surgical options.7
For unresectable or metastatic FLC, treatment options include:
• Systemic Therapy: Chemotherapy has shown limited success in FLC, but newer targeted therapies and immunotherapies are under investigation.8
• Liver Transplantation: In select cases, transplantation may be considered.9
• Clinical Trials: Ongoing studies are exploring novel agents, including drugs targeting the DNAJB1-PRKACA fusion protein.10
Prognosis and Future Directions
The prognosis of FLC varies depending on the stage at diagnosis and the extent of surgical resection. Patients with localized disease who undergo complete tumor removal generally have better outcomes, with a 5-year survival rate ranging from 40% to 60%. However, for those with advanced or metastatic disease, survival rates drop significantly.7
Advancements in genetic research and the development of targeted therapies offer hope for improved outcomes in FLC patients. The identification of the DNAJB1-PRKACA fusion has laid the groundwork for the development of precision medicine strategies, including therapies that specifically target the molecular drivers of this rare cancer.2,3
Conclusion
Fibrolamellar carcinoma, though rare, represents a distinct and challenging subset of liver cancer. Its unique genetic profile and occurrence in young individuals highlight the importance of tailored research and treatment approaches. Continued advancements in genetic and molecular biology are essential to unraveling the complexities of FLC and improving outcomes for those affected by this rare malignancy.
For patients and caregivers, awareness and early detection remain critical. As research progresses, the hope is that targeted therapies and novel treatment strategies will transform the management of fibrolamellar carcinoma, providing new opportunities for effective care and improved quality of life.
References
1. Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinicopathologic features. Cancer. 1980;46(2):372-379.
2. Honeyman JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174):1010-1014.
3. Graham RP, Pestova E, Bird I, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015;28(6):822-829.
4. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170(6):1062-1078.
5. Weeda VB, Murugan P, Ibrahim SM, et al. Imaging characteristics of fibrolamellar carcinoma. Radiographics. 2021;41(1):212-225.
6. Stipa F, Yoon SS, Liau KH, et al. Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer. 2006;106(6):1331-1338.
7. El-Gazzaz G, Wong C, Bonham CA, et al. Survival after liver transplantation for fibrolamellar hepatocellular carcinoma. Liver Transpl. 2009;15(2):135-142.
8. Abou-Alfa GK, Goff LW, Davidson T, et al. Phase II trial of 5-fluorouracil and interferon for fibrolamellar carcinoma. J Clin Oncol. 2006;24(10):1485-1488.
9. Meyers DE, Basha HI, Hameed S. An update on targeted therapy and immunotherapy for hepatocellular carcinoma. Can J Gastroenterol Hepatol. 2021;2021:6614464.
10. Strosberg J, Mizrahi J, Pishvaian MJ, et al. A phase I study of a DNAJB1-PRKACA fusion-targeted therapy in advanced fibrolamellar carcinoma. J Clin Oncol. 2022;40(4_suppl):366-366.
11. Fibrolamellar Hepatocellular Carcinoma: A Rare but Distinct Type of Liver Cancer. Andersen, Jesper B.
- Gastroenterology, Volume 148, Issue 4, 707 - 710
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