Fibrolamellar hepatocellular carcinoma – Prolonged survival with multimodality therapy
Introduction
Fibrolamellar hepatocellular carcinoma (FLH) was first described in 1956 by Edmondson as a rare distinctive form of hepatocellular carcinoma (HCC)1 and is histologically characterized by eosinophilic neoplastic hepatocytes separated into cords by lamellar fibrous strands.2, 3 In addition FLH is distinguished from HCC by being associated with few chromosomal changes, genomic heterogeneity, absence of mutations in key genes such as p53 and low levels of promoter methylation.4, 5, 6, 7 In the western population FLH represents only 0.85% of all cases of primary liver cancer with an age-adjusted incidence rate 0.02 per 100,000 compared to 1.99 per 100,000 for HCC.8 In contrast to HCC, FLH occurs with equal frequency in men and women, is typically diagnosed in a younger age group, with a mean age of 25 years, and is not associated with viral hepatitis nor cirrhosis.8 Raised levels of alpha fetoprotein (AFP) are uncommon in FLH9 but elevations in neurotensin and vitamin B12 binding proteins have been reported.10, 11 The clinical symptoms are usually non-specific and often comprise abdominal pain, weight loss and malaise. The most common physical finding is an abdominal mass or hepatomegaly.12 Surgical resectability is associated with prolonged survival but a high relapse rate13, 14, 15 and there is currently no proven effective adjuvant systemic therapy. Moreover the optimal follow-up and approach to recurrent disease is not clearly defined.
We report a series of ten cases treated at our institution with multimodality therapy, including surgery, chemotherapy and radiotherapy. Follow-up included CT scan and B12 binding proteins measurements, with FDG-PET scan in selected patients allowing early detection of recurrence and an aggressive surgical and medical approach.
Section snippets
Patients and methods
Patients referred to the Royal Free Hospital between 1982 and 2004 with a histologically confirmed diagnosis of FLH were identified via medical records and the case notes and imaging were reviewed. Clinical and pathological features including age, gender, stage, tumour size, HBV status, levels of AFP and B12 binding proteins, treatment, site of relapses and survival data were recorded.
Patients and tumour characteristics
The median age at diagnosis was 24 years (range 16–50) (Table 1). Presenting symptoms were non-specific abdominal pain or discomfort, nausea and fatigue. Two patients were diagnosed having presented with an acute abdomen one of whom had a spontaneous rupture of the tumour. There were six males and four females. None had underlying hepatitis or cirrhosis. B12 binding proteins were elevated at diagnosis in eight cases and unknown in two. The mean levels were: Unsaturated vitamin B12 binding
Relapse rate and survival
After a median follow-up of 78 months, seven patients died of the disease and three were alive. Two patients were alive with disease while one remained free of relapse for eight years following resection of recurrent disease. The median overall survival for the ten patients was 9.3 years (95% CI 3.0–18.5) and the 5-year survival rate was 60% (CI 30–90%). All ten patients relapsed following initial surgery with median time to recurrence of 2.2 years (95% CI 0.9–2.7). Following relapse after
High relapse rate for resected FLH
FLH is a rare histological variant of HCC occurring in young patients in the absence of underlying cirrhosis.16 The perception that this tumour has an indolent clinical course, and that there is little proven alternative effective therapy, has encouraged an aggressive surgical approach including both resection and transplantation. However in all reported series relapse rates are high, ranging from 36 to 100% and the median time to relapse is relatively short at between 10 and 33 months.9, 13, 14
Conflict of interest
None declared.
Acknowledgments
This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.
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Cited by (71)
Tumours and Tumour-Like Lesions
2023, MacSween's Pathology of the Liver, Eighth EditionLiquid–liquid phase separation: a principal organizer of the cell's biochemical activity architecture
2021, Trends in Pharmacological SciencesCitation Excerpt :In breast cancer tissues, increased TAZ expression and more nuclear TAZ condensates compared with healthy breast tissue may serve as a potential biomarker [79]. In another example, the fusion of DnaJB1 exon 1 with the last nine exons of PKAcat (DnaJB1-PKAcat) is exclusively detected in patients with fibrolamellar carcinoma (FLC) [80], a rare liver cancer that has little similarity with other liver cancers [81]. While it is clear that this chimeric fusion enzyme drives FLC, as it is sufficient to induce FLC-like tumors in mice [82], biochemical and structural studies show little difference between DnaJB1-PKAcat and wild-type PKAcat in terms of either activity or regulation [83–85].
Fibrolamellar carcinoma: An entity all its own
2021, Current Problems in CancerSystemic therapy of liver cancer
2021, Advances in Cancer ResearchCitation Excerpt :There is no consensus opinion on systemic therapy as therapeutic options are not based on randomized studies. FLHCC is known as a chemotherapy-refractory tumor (Lafaro & Pawlik, 2015), yet successful results have been reported using chemotherapy plus interferon-α2b (IFN-α2b) (Bower, Newlands, & Habib, 1996; Maniaci et al., 2009). The combination of 5-fluorouracil plus IFN-α2b was found to be safe and effective in a phase 2 trial (n = 8 patients).
Hotspots of Aberrant Enhancer Activity in Fibrolamellar Carcinoma Reveal Candidate Oncogenic Pathways and Therapeutic Vulnerabilities
2020, Cell ReportsCitation Excerpt :We selected eight of these genes (CA12, FAM19A5, HSPA1B, LINC00473, OAT, SLC16A14, TESC, and VCAN) for further investigation. We chose SLC16A14 and LINC00473 because they have high densities of FLC-specific enhancers with FOSL2/JUN (Figure 3D) and CREB motifs (Figure 3E), respectively; FAM19A5 because it has the greatest number of significantly correlated enhancers (Figure 4G); TESC and VCAN because they have previously been strongly implicated in drug resistance (Lee et al., 2018; Li et al., 2017; Man et al., 2014), a salient feature of FLC (Maniaci et al., 2009; Torbenson, 2012); CA12 and OAT because we have previously identified them as candidate markers of FLC (Dinh et al., 2017) and because CA12 is a prominent mediator of drug resistance in other cancer types (Boyd et al., 2017; Doyen et al., 2013; Kopecka et al., 2016; Yoo et al., 2010); and HSPA1B because it encodes a member of the heat shock protein 70 (HSP70) family, which interacts with the DNAJB1-PRKACA fusion found in FLC (Turnham et al., 2019). We also selected one gene that only appears in the FLC-specific enhancer hotspot analysis (RPS6KA2) and another from the gene-enhancer correlation (FZD10) analysis for further investigation (Figure 6A).