Hepatic adenomas with synchronous or metachronous fibrolamellar carcinomas: both are characterized by LFABP loss

Abstract

Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-α inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n = 19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-α inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-α inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-α inactivation is an important event in fibrolamellar carcinoma pathogenesis.

Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1‐PRKACA fusion

“…The slides from the hepatocellular adenoma (case 2) and cardiac myxoma (case 3) were both reviewed. Aspects of both lesions have been described . The hepatocellular adenoma showed a myxoid pattern, a rare and recently described morphology for hepatic adenomas .…”

Intracranial metastasis in fibrolamellar hepatocellular carcinoma

“…The transcriptomic and proteomic changes in FLHCC are consistent from patient to patient and distinct from HCC . Molecular assays detecting the DNAJB1–PRKACA fusion have improved diagnostic accuracy for FLHCC …”

Environmental exposures as a risk factor for fibrolamellar carcinoma

“…9 Finally, laser capture microdissection and mass spectrometry-based proteomic analysis were performed on formalin-fixed, paraffin-embedded tissue sections as previously described. 8 …”

“…Fibrolamellar carcinomas can rarely co-occur with type 1 hepatocellular adenomas (HNF1α-inactivated), but they clearly do not develop out of hepatic adenomas. 8 Similarly, old notions of possible malignant transformation of focal nodular hyperplasia 34 have been disproven. Fibrolamellar carcinomas are well known for their propensity to occur in younger individuals, with 80% of all cases presenting between ages 10 and 35.…”

“…6) and ornithine aminotransferase, 7 while showing reduced or absent LFABP staining. 8 At the molecular level, fibrolamellar carcinomas show a specific DNAJB1-PRKACA fusion transcript in almost all bona fide cases. 7,9 The etiological risk factors for fibrolamellar carcinomas are unknown, as they arise in livers without underlying liver disease and without fibrosis.…”