While cross-sectional imaging can strongly suggest FLC, confirmation of the diagnosis can only be achieved with the use of a biopsy. While a needle biopsy is often obtained, a definitive diagnosis can be difficult to confirm by fineneedle biopsy, and occasionally, additional tissue (eg, core biopsy) is required for accurate diagnosis.

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It is important to note, however, that biopsy is typically not necessary – nor recommended – if the lesion is highly suspicious for FLC on cross-sectional imaging and resection is feasible. Under these circumstances, rather than biopsy, surgery should be recommended.

Rather, biopsy should more commonly be reserved for those circumstances of true diagnostic uncertainty or when the lesion is not amenable to resection and the tissue is required to direct other nonsurgical therapy. On pathology, FLC tumors tend to be large, yellow/tan, hypervascular, well-circumscribed masses with areas of necrosis in otherwise normal liver parenchyma.

Up to 75% of tumors may have a central stellate scar and prominent fibrous tissue.55 Microscopically, FLC is characterized by large polygonal or spindle-shaped tumor cells with deeply eosinophilic cytoplasm due to abundant mitochondria and prominent nuclei arranged in cords surrounded by lamellated collagen fibers (Figure 2).3,7,56

In fact, the average size of FLC tumors cells is roughly three times larger than normal hepatocytes and 1.6 times larger than HCC tumor cells.57

Round- to oval-shaped cytoplasmic pale bodies lacking a nucleus and intracytoplasmic hyaline droplets are also seen on microscopy but are not required for diagnosis.58 Generally, there is no cirrhosis in the surrounding liver parenchyma; however, there may be nonspecific inflammation suggested by the presence of mononuclear cells and lymphocytes.56

Electron microscopy often demonstrates an increase in the number of mitochondria – a pathological feature specific to FLC.3 Immunohistochemical staining of FLC has some similarities to HCC, including staining positive for hepatocyte paraffin 1.

However, unlike HCC, FLC often stains strongly for CK7 and epithelial membrane antigen, which are characteristic of biliary differentiation as well as markers of hepatic differentiation (CK19 and EpCAM).51,59

In addition, unlike most HCC, FLC stains negative for alpha fetoprotein.51,59 Furthermore, FLC tends to express CD133 and CD44 markers that are associated with stem cells.60 FLC also stains more often and more diffusely for epithelial growth factor receptor and transforming growth factor beta than classic HCC.59,61

Transforming growth factor beta has been shown to be a profibrotic factor that may account for the lamellar pattern characteristic of FLC tumors on pathology.59,61

In addition to pathologic evaluation and immunohistochemical staining, there are genetic differences discovered recently which distinguish FLC from normal liver parenchyma and HCC. A 400 kb deletion in chromosome 19 seen in 100% of the FLC tumors tested by Honeyman et al results in a functional DNAJB1-PRKACA chimeric transcript, which further defines FLC as a unique entity.62,63