Pigmented hepatocellular adenomas have a high risk of atypia and malignancy

Abstract

Pigment deposition is occasionally seen in hepatocellular adenomas. Several reports suggest that pigmented hepatocellular adenomas have increased risk of malignancy, but these tumors remain incompletely understood. To determine the frequency of pigment deposition, we evaluated and classified 109 well-differentiated hepatocellular neoplasms that were originally diagnosed or submitted in consultation as hepatocellular adenomas and found 27 (25%) pigmented tumors. All were negative on iron stain and in three cases electron microscopy confirmed the pigment was lipofuscin. The lipofuscin intensely stained with glypican-3 in most cases (89%). Of the 27 pigmented tumors, 11 cases (41%) were classified as hepatocellular adenomas, 7 cases (27%) were classified as atypical hepatocellular adenomas/hepatocellular neoplasms of uncertain malignant potential, and 9 cases (33%) were reclassified as well-differentiated hepatocellular carcinomas. Four (of 9) hepatocellular carcinomas arose in pigmented hepatocellular adenomas, giving a rate of malignant transformation in pigmented hepatocellular adenomas of 27%. Of the total 27 pigmented tumors, 78% were in women and 22% in men, but interestingly only men had tumors classified as hepatocellular carcinoma or hepatocellular neoplasm of uncertain malignant potential. Also of note, a total of 10 individuals (37%) had multiple hepatocellular neoplasms but in 9 of these cases the other adenomas were non-pigmented. Importantly, in cases with multiple hepatocellular neoplasms, only the pigmented hepatocellular neoplasms had atypia or malignancy. Genotype-phenotype classification of the pigmented tumors showed different subtypes: HNF1α inactivated (48%), β-catenin activated (26%), inflammatory (15%), concurrently β-catenin activated and inflammatory in 1 hepatocellular adenoma, concurrently HNF-1α inactivated and β-catenin activated in 1 hepatocellular adenoma, and unclassified in 1 hepatocellular carcinoma. In conclusion, hepatocellular adenomas with lipofuscin pigment are a heterogeneous group of adenomas, with HNF-1α inactivation being the commonest genotype. They have an increased risk of atypia and malignancy, especially in males.

Immunostains Used to Subtype Hepatic Adenomas Do Not Distinguish Hepatic Adenomas From Hepatocellular Carcinomas

“…17 Glypican-3 is also less useful with pigmented tumors, as lipofuschin cross reacts with glypican-3. 18 Although in most cases a diagnosis can be comfortably rendered with the available tools, a subset of cases remain very challenging and would benefit from additional diagnostic tools. In this regard, some pathologists have attempted to apply the panel of immunostains designed to subtype adenomas to the problem of distinguishing hepatic adenomas from HCCs.…”

Hepatocellular Adenoma and Focal Nodular Hyperplasia

“…13 Other variants include pigmented HCAs, characterized by prominent lipofuscin pigment deposition; this variant has an increased risk (27%) for a malignancy, especially in males. 14 Finally, rare HCAs show abundant sinusoidal accumulation of myxoid material. 15 These adenomas can be seen in men and women and are often multiple.…”

Giant hepatocellular carcinoma with bone metastasis in a young adult, emerged from pigmented adenoma with beta-Catenin activation: A case report

“…An interesting histological finding was a pigmentation of the HCA. It is suggested that these pigments constitute lipofuscin deposits and several reports indicate an increased risk of malignancy in pigmented HCAs [10], [11]. The pigments were also found in the HCC cells, but, unexpectedly, the nuclear β-Catenin activation of the HCA was not preserved in the HCC cells.…”