Fibrolamellar carcinoma: 2012 update

Abstract

Fibrolamellar carcinomas are a unique type of primary liver cancer. They occur most commonly in children and young adults. Their etiology remains a mystery, as they are not associated with chronic liver disease. Fibrolamellar carcinomas are not indolent tumors, but have an overall better prognosis than typical hepatocellular carcinomas, in part because of the younger age at presentation and the lack of cirrhosis. The most important prognostic feature is whether the tumor is resectable. Histologically, the tumor is made up of large cells that contain abundant mitochondria. The nuclei of the tumor cells have prominent nucleoli. The tumor cells induce the formation of extensive intratumoral fibrosis, which often grows in parallel, or lamellar bands. The tumor cells clearly show hepatocellular features but are also unique in showing both biliary and neuroendocrine differentiation. The uniqueness of fibrolamellar carcinoma extends to their molecular findings. While the genetic abnormalities that lead to fibrolamellar carcinomas are not yet known, studies have shown that they lack mutations in the genes most commonly mutated in typical hepatocellular carcinoma (TP53 and CTNNB1). In this paper, the clinical, pathological, and basic science literature on fibrolamellar carcinoma is comprehensively reviewed. Key areas of needed research are also discussed.

Figure 1

(a) Original magnification 160X. Fibrolamellar carcinomas are composed of large eosinophilic tumor cells with large vesiculated nuclei and large red nucleoli. (b) Original magnification 100X. Intratumoral fibrosis is a typical finding in fibrolamellar carcinoma. (c) Original magnification 160X. When FLC tumors grow in cell culture, they retain their large nucleoli and abundant cytoplasm. The nucleolus is often split into several larger subunits. (d) Original magnification 160X. Pale bodies are seen as large cytoplasmic inclusions with distinct borders and typically a “pale” grey color.

Figure 2

Original magnification 64X. A low power image demonstrates the characteristic lamellar fibrosis.

Figure 3

Original magnification 64X. An area of glandular-type differentiation with mucin production is shown.

Figure 4

(a) Original magnification 100X. Fibrolamellar carcinomas express CD68 with a characteristic granular cytoplasmic staining pattern. CD68 stains lysosomes within the cytoplasm of the tumor cells. (b) Original magnification 160X. Fibrolamellar carcinomas strongly express cytokeratin 7.

Figure 5

Original magnification 64X. This patient had a typical fibrolamellar carcinoma. Adjacent but clearly separate was a separate nodule of well-differentiated hepatocellular neoplasm with fatty change that lacked the features of fibrolamellar carcinoma.

Figure 6

Original magnification 64X. A patient with a typical fibrolamellar carcinoma had a subsequent lymph node metastasis. The metastatic carcinoma had a distinctive glandular growth pattern that mimicked a cholangiocarcinoma. However, the metastatic tumor was still HepPar positive ((b), original magnification 64X), CD68 positive ((c), original magnification 64X). Cytokeratin 7 was also strongly positive (not shown), while cytokeratin AE1/3 was weakly positive ((d), original magnification 64X).

Figure 7

(Original magnification 100X). Fibrolamellar carcinomas are strongly AGR2 positive.