- Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS more...
Although fibrolamellar carcinoma (FLC) has conventionally been considered to be a histologic variant of hepatocellular carcinoma (HCC), it has more recently been recognized as a distinct clinical entity with respect to its epidemiology, etiology, and prognosis.
Fibrolamellar carcinoma is a rare primary hepatic malignancy that was first described as a pathological variant of hepatocellular carcinoma by Edmondson in 1956. 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 distinct clinical entity from conventional hepatocellular carcinoma after 2 simultaneous reports in 1980 by Craig et al and Berman et al, 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.
Due to the histological characteristics of fibrolamellar carcinoma, it has been referred to in the literature by several names: eosinophilic hepatocellular carcinoma with lamellar fibrosis, polygonal cell hepatocellular carcinoma with fibrous stroma, hepatocellular carcinoma with increased stromal fibrosis, eosinophilic glassy cell hepatoma, and fibrolamellar oncocytic hepatoma.
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. It typically occurs in the absence of underlying liver inflammation or fibrosis, and no histological precursor lesion to fibrolamellar carcinoma has been identified.
Little is known about the molecular pathogenesis of fibrolamellar carcinoma. Fibrolamellar carcinoma exhibits fewer chromosomal alterations than typical hepatocellular carcinoma, but frequent gains of chromosome 1q have been noted (as in typical hepatocellular carcinoma). Overexpression of genes in the RAS, MAPK, PIK3, and xenobiotic degradation pathways has been reported in fibrolamellar carcinoma. In contrast to viral-associated hepatocellular carcinoma, epigenetic instability is rare in fibrolamellar carcinoma.[9, 10]
Fibrolamellar carcinoma has been reported to occur in association with focal nodular hyperplasia (FNH),[11, 12, 13, 14] a type of benign liver lesion, and both diseases tend to present in younger patients and in the setting of normal liver parenchyma. Additionally, fibrolamellar carcinoma and focal nodular hyperplasia share several features, such as a stellate central scar on imaging studies and copper accumulation on histological examination, that have prompted some to suggest that focal nodular hyperplasia may be a benign precursor lesion to fibrolamellar carcinoma.[14, 15] However, an etiological relationship has yet to be demonstrated and is not widely accepted.
See the image below.
Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI), 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 incidence rate of typical hepatocellular carcinoma (1.99 per 100,000 per year).
Fibrolamellar carcinoma has been reported all over the world, but worldwide incidence data are not available.
The population-based relative survival of patients with fibrolamellar carcinoma in the United States is 73% at 1 year and 32% at 5 years. In contrast, hepatocellular carcinoma relative survival is 26% at 1 year and 7% at 5 years. 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 have a better prognosis than typical hepatocellular carcinoma.
More importantly, fibrolamellar carcinoma usually occurs in the setting of a normal liver parenchyma (see the image below), while typical hepatocellular carcinoma occurs in the setting of a cirrhotic liver 80% of the time. 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.
Two studies have found that fibrolamellar carcinoma and hepatocellular carcinoma in children have similar prognoses and responses to therapy.[18, 19] Two studies in adults have found that fibrolamellar carcinoma and typical hepatocellular carcinoma in noncirrhotics have similar prognoses after resection,[20, 21] supporting the viewpoint that the survival differences seen in older groups may be confounded by competing causes of death.
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%).
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.
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.
In the United States, patients with fibrolamellar carcinoma are overwhelmingly (>85%) non-Hispanic white people, with smaller numbers seen among Chinese-Americans (6%), blacks (4%), and white Hispanic persons (4%). In contrast, typical hepatocellular carcinoma 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.
While typical hepatocellular carcinoma demonstrates a 3:1 male-to-female ratio. Fibrolamellar carcinoma demonstrates no such sex disparity. It affects males and females equally.
The median age of diagnosis is 33 years for fibrolamellar carcinoma, with 63% of cases diagnosed in patients younger than 40 years. In contrast, the median age of diagnosis is 66 years for typical hepatocellular carcinoma, with only 4% of cases diagnosed in patients younger than 40 years. It is important to remember, however, that despite the younger age of onset of fibrolamellar carcinoma, the most common form of primary liver cancer (60-80%) in children and young adults is nevertheless typical hepatocellular carcinoma.
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