Fibrolamellar hepatocellular carcinoma: current clinical perspectives

Introduction

Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) that comprises ∼1%–9% of all HCCs according to the SEER database.¹

FLC was first described by Edmondson in 1956 as an adult type of liver tumor in a 14-year-old female with no underlying liver disease.²

The term FLC was not suggested, however, until 1980 when Craig et al described a set of patients with a unique histologic variant of HCC.³ The World Health Organization (WHO) Classification of Tumors subsequently recognized FLC as having a unique histological pattern; however, it took until 2010 for the WHO to designate this clinical entity with its own WHO classification number.⁴

Although FLC is a variant of HCC, it is distinct from HCC in that FLC most often affects younger patients (10–35 years of age) with no underlying liver disease.^5,6 On pathological analysis, FLC is characterized by large tumor cells with deeply eosinophilic cytoplasm due to abundant mitochondria and prominent nuclei arranged in cords surrounded by lamellated collagen fibers.^3,7

The tumor cells can demonstrate hepatocellular features; however, FLC tumors also can display both biliary and neuroendocrine differentiation. While the etiology of FLC tumors remains still unclear, FLC is thought to have an overall better prognosis than other primary liver tumors (eg, HCC, intrahepatic cholangiocarcinoma). We herein review the epidemiology, diagnosis, treatment, and prognosis of patients with FLC.

Epidemiology

FLC accounts for between 1% and 9% of all HCCs depending on the population studied.^8–15 From an epidemiologic viewpoint, one feature that often distinguishes FLC from HCC is the age at diagnosis.

FLC typically occurs in young adults, with most patients being 10–35 years of age at presentation compared with an average age of 65 years at presentation among patients with HCC.⁵

Compared with HCC, some studies note that FLC patients are more likely to be female, while others have noted no specific sex predilection.^5,10,13

Regarding race, one study that utilized SEER data noted a higher incidence of FLC versus HCC among patients of Caucasian ethnicity; however, the association of race with HCC subtype did not remain significant after adjustment for age.⁵

In addition, FLC has been reported with similar prevalence in countries across the globe including the United States, Mexico, Sweden, Saudi Arabia, Thailand, France, Canada, South Africa, Japan, Korea, India, Taiwan, and United Kingdom.

As such, the data would suggest that there is no strong association of race or ethnicity with the risk of FLC.^5,8–26

Presentation

FLC often presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss.³

While the physical examination is often within normal limits, when present, common physical findings include a palpable abdominal mass or hepatomegaly with or without pain in the right upper quadrant.

Other reported rare presentations include jaundice due to biliary obstruction,^27–29 gynecomastia in males,³⁰ fulminant liver failure,^6,31–33 recurrent deep vein thrombosis,34 encephalopathy,³⁵ thrombophlebitis of the lower extremity,³⁶ anemia,³⁷ ascites,³⁸ and hypoglycemia.³⁹ On serum analysis, beta human chorionic gonadotropin can sometimes be elevated.⁴⁰

Typically, liver function markers such as aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels are normal or mildly elevated.^3,10,41 Elevated alkaline phosphatase levels in the setting of FLC are likely due to the growth of the tumor into the biliary tree or biliary obstruction.⁴² Alpha fetoprotein levels are predominately normal in patients with FLC unlike in traditional HCC.⁴³ While uncommon, other serum proteins may be elevated with FLC.

For example, transcobalamin I (also known as haptocortin), which normally protects vitamin B12 from degradation in the digestive tract, may be elevated.^44–46

Transcobalamin II, a vitamin B12-binding protein induced by vitamin K absence/antagonist-II levels, may also be high.^13,22,47 Less frequently, elevations in serum proteins including fibrinogen and neurotensin can be noted.^33,48 No large study has determined, however, the diagnostic accuracy of these serum proteins as tumor markers.