Fibrolamellar Carcinoma

Updated: Jan 18, 2019
  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Overview

Practice Essentials

Fibrolamellar carcinoma (FLC) is a primary liver cancer that occurs in adolescents and young adults without underlying liver disease. Although FLC was historically considered to be a histologic variant of hepatocellular carcinoma (HCC), it is currently recognized as a distinct clinical entity with respect to its epidemiology, etiology, and prognosis. 

In 2014, Honeyman and colleagues discovered a novel, chimeric transcript that is present in all studied samples of FLC, DNAJB1-PRKACA. [1] Multiple studies have confirmed that this mutation is unique to FLC, and support the role of DNAJB1-PRACA as a major driver of this tumor and as a key diagnostic and therapeutic target. [2, 3, 4, 5, 6, 7]

A variant of FLC, known as mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) and characterized by the presence of both FLC and conventional HCC components within the same tumors, has also been reported. In these rare tumors, the DNAJB1-PRKACA fusion transcript is expressed at high levels. [5]

Because of the lack of defining symptoms or a specific diagnostic test, FLC is often detected after it has metastasized, at which point the disease is frequently progressive and fatal. Currently there are no effective treatments for inoperable or metastatic disease.  Locally invasive or disseminated disease is not reponsive to chemotherapy, and unless the tumor can be resected with clear margins, recurrence is common and outcomes are poor. Studies of FLC have reached conflicting conclusions regarding overall survival after complete resection, compared with HCC. [8, 9, 10]

 

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Background

Fibrolamellar carcinoma is a rare primary hepatic malignancy that was first described as a pathological variant of hepatocellular carcinoma by Edmondson in 1956. [11]  In his review of liver tumors and tumorlike liver lesions, Edmondson included a report of a 14-year-old girl with an unusually long survival following hepatic resection for liver cancer. Fibrolamellar carcinoma was more widely recognized as a clinical entity distinct from conventional hepatocellular carcinoma after 2 simultaneous reports in 1980 by Craig et al [12]  and Berman et al, [13]  both of which again highlighted the young age of onset and the relatively good prognosis that continue to distinguish fibrolamellar carcinoma from conventional hepatocellular carcinoma.

In the literature, fibrolamellar carcinoma has been referred to by several names, based on its histological characteristics, as follows:

  • Eosinophilic hepatocellular carcinoma with lamellar fibrosis [14]
  • Polygonal cell hepatocellular carcinoma with fibrous stroma [13]
  • Hepatocellular carcinoma with increased stromal fibrosis [15]
  • Eosinophilic glassy cell hepatoma [14]
  • Fibrolamellar oncocytic hepatoma [14]
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Pathophysiology

The more typical form of hepatocellular carcinoma is often associated with active hepatic inflammation, hepatitis B or C viral infection, alcohol-related liver disease, nonalcoholic fatty liver disease (NAFLD), cirrhosis from any other cause, or dietary aflatoxin B1. In contrast, the etiology of fibrolamellar carcinoma remains unclear. Underlying liver inflammation or fibrosis is typically absent, [16] and no histological precursor lesion to fibrolamellar carcinoma has been identified. [17]

In 2014, Honeyman et al reported FLC tumor samples from11 patients were shown to express a novel fusion transcript, DNAJB1-PRKACA. Whole-genome sequencing revealed that the fusion resulted from a ∼400-kilobase (kb) deletion on chromosome 19 (chr19). The fusion transcript encodes a chimeric protein that couples a segment of the heat shock protein, DNAJB1, with the catalytic domain of protein kinase A (PKA) and exhibits full retention of PKA activity. Notably, the DNAJB1-PRKACA fusion was not detected in any of the matched nontumor liver tissue samples. [1]  

Multiple independent studies confirmed the findings of Honeyman et al by demonstrating the presence of the fusion gene in FLCs. [2, 4, 18]  In one of the studies, whole-genome sequencing of 10 FLC tumors showed no recurrent structural variations that contribute significantly to the tumor genotype, aside from the deletion of chromosome 19 determining the DNAJB1-PRKACA fusion protein. [18]  The apparent lack of a second-hit mutation in the genome of FLCs supports the role of DNAJB1-PRACA fusion protein as a major driver of this tumor and as a key diagnostic and therapeutic target.

Another study found that the DNAJB1-PRKACA transcript was expressed 10-fold higher than the wild type PRKACA transcript, resulting in clear overexpression of the mutant protein in tumors. Consequently, FLCs exhibited elevated cyclic adenosine monophosphate (cAMP)–stimulated PKA activity, compared with normal liver tissue, thus suggesting that aberrant PKA signaling contributes to liver tumorigenesis [6]  The analysis of RNA-sequencing data from The Cancer Genome Atlas (TCGA) for more than 9000 tumors across about 30 cancer types showed that the DNAJB1-PRKACA fusion is specific for FLCs. In addition, both the messenger RNA and long intergenic noncoding RNA signatures support a major role for PKA signaling in shaping the FLC gene expression landscape. [7]

A variant of FLC, known as mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) and characterized by the presence of both FLC and conventional HCC components within the same tumors, has also been reported. In these rare tumors, the DNAJB1-PRKACA fusion transcript is expressed at high levels. [5]  

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Etiology

Specific risk factors for fibrolamellar carcinoma remain unidentified. Unlike typical hepatocellular carcinoma (HCC), fibrolamellar carcinoma is not associated with hepatotoxins, cirrhosis, α1-antitrypsin deficiency, or hemochromatosis.

Less than 10-20% of cases of fibrolamellar carcinoma are associated with hepatitis B viral infection, and even this association may simply reflect the high worldwide prevalence of hepatitis B infection. [17]  Fibrolamellar carcinoma is rarely associated with hepatitis C viral infection.

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Epidemiology

Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rate of fibrolamellar carcinoma in the United States is 0.02 per 100,000 per year, which is 100-fold lower than the 1.99 per 100,000 annual incidence rate of typical hepatocellular carcinoma (HCC). [19]  Fibrolamellar carcinoma has been reported all over the world, [20] but worldwide incidence data are not available.

In the United States, patients with fibrolamellar carcinoma are overwhelmingly (> 85%) non-Hispanic whites, with smaller numbers of cases seen among Chinese Americans (6%), blacks (4%), and white Hispanic persons (4%). [19] In contrast, typical HCC occurs in non-Hispanic white patients 57% of the time, with significant numbers of cases diagnosed in blacks (13%), Chinese Americans (8%), white Hispanics (7%), and other ethnic groups. [19]

The average age at presentation is 25 years, but there is a second smaller peak in incidence between 70 and 79 years. [8]  HCC in general is typically diagnosed in adults between 40 and 70 years of age, and is more common in males, while FLC does not have a gender bias. [19, 8]

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Prognosis

Prognosis after surgical therapy is superior to that with any medical management alone. Patients with unresectable metastatic fibrolamellar carcinoma have a median survival of 14 months. [21]

The population-based relative survival of patients with fibrolamellar carcinoma in the United States is 73% at 1 year and 32% at 5 years. [19]  In contrast, hepatocellular carcinoma relative survival is 26% at 1 year and 7% at 5 years. [19]  However, these figures include death from all causes. For example, because hepatocellular carcinoma patients tend to be older than those with fibrolamellar carcinoma, they may be at higher risk of death related to medical comorbidities (eg, heart disease or stroke). Nevertheless, even when only patients younger than 40 years are analyzed, fibrolamellar carcinoma still appears to portend a better prognosis than typical hepatocellular carcinoma. [19]

More importantly, fibrolamellar carcinoma usually occurs in the setting of a normal liver parenchyma (see the image below), while 80% of typical hepatocellular carcinoma occurs in the setting of a cirrhotic liver. Because cirrhosis is an independent risk factor for mortality, the observed difference in survival between fibrolamellar carcinoma and typical hepatocellular carcinoma may not in fact reflect differences in tumor biology or cancer-specific mortality. [17]

Two studies have found that fibrolamellar carcinoma and hepatocellular carcinoma in children have similar prognoses and responses to therapy. [22, 23]  Two studies in adults have found that fibrolamellar carcinoma and typical hepatocellular carcinoma in noncirrhotics have similar prognoses after resection, [24, 8]  supporting the viewpoint that the survival differences seen in older groups may be confounded by competing causes of death.

Fibrolamellar carcinoma: Note the large tumor size Fibrolamellar carcinoma: Note the large tumor size in the background of a noncirrhotic liver.

Using data from the Surveillance, Epidemiology, and End Results (SEER) program, Mayo et al studied surgical treatment and prognosis in patients with fibrolamellar carcinoma or hepatocellular carcinoma; 7,135 (99%) had hepatocellular carcinoma and 90 (1%) had fibrolamellar carcinoma. Patients with fibrolamellar carcinoma were younger (25 years vs 59 years) and more were women (44% vs 27%). Regional disease was nearly twice as common in patients with fibrolamellar carcinoma (42.2%) than in those with hepatocellular carcinoma (22.1%). [9]

Patients with fibrolamellar carcinoma were more often treated with a hemihepatectomy compared with patients with hepatocellular carcinoma, who were more often managed with a liver transplant. However, despite a higher likelihood of advanced disease at the time of diagnosis, surgically treated fibrolamellar carcinoma patients had better long-term outcomes than patients with conventional hepatocellular carcinoma, surviving a median of 75 months vs 43 months, respectively. [9]

A multi-institutional study that included 35 patients (13 female; median age, 32 years) with fibrolamellar carcinoma who underwent hepatectomy found that for curative-intent surgery (n=30), overall and recurrence-free survivals at 5 years were 62% and 45%, respectively. None of the patients who achieved a 4-year disease-free interval developed recurrence, suggesting possible freedom from disease thereafter. These authors concluded that in patients with recurrent resectable disease, repeat surgery should be strongly considered. [25]

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