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  • In a study highlighted the

    2024-02-20

    In 2010, a study highlighted the usefulness of arginase-1 as a sensitive and specific marker of hepatocytic differentiation for diagnostic pathology [9]. Subsequent studies have validated the high sensitivity and specificity of arginase-1, in particular its added value in evaluating poorly differentiated hepatocellular carcinomas [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Despite the sensitivity for poorly differentiated hepatocellular carcinoma, we have encountered in our routine consult practice a subset of well-differentiated hepatocellular carcinomas that are arginase-1 negative but HepPar1 positive, leading to diagnostic confusion amongst referring pathologists because of the reported higher sensitivity and specificity of arginase-1 over HepPar-1 [9], [15], [22]. To further clarify this NESS 0327 observation and determine clinicopathological correlates, we performed a retrospective study of well-differentiated hepatocellular carcinoma biopsy specimens. Biopsy specimens were chosen as the focus of the study, as most specimens raising diagnostic challenges in surgical pathology practice are biopsies and not resections.
    Materials and methods
    Results
    Discussion Arginase-1, HepPar-1, and glypican-3 are the most commonly used immunohistochemical markers for hepatocytic differentiation in routine surgical pathology practice [13], [15], [24]. Albumin ISH is less routinely available, but is also a robust marker of hepatocytic differentiation [19]. However, none of these markers are entirely specific or sensitive for hepatocellular carcinoma. In general, studies have found that sensitivity for these stains decreases with higher tumor grade. A detailed review of the literature on arginase-1 staining in hepatocellular carcinoma shows that the stain is robust and useful, a finding observed in essentially all studies [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Reinforcing the usefulness of arginase-1, these studies used a variety of antibodies, at different dilutions, on a variety of specimen types (full tumor sections, tissue microarrays and fine needle aspirate cell blocks). Overall, 951 of 1036 cases of hepatocellular carcinomas were positive for arginase-1, giving an overall sensitivity of 92% [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. To date, published data on hepatocellular carcinomas that are negative for arginase-1 have emphasized negative staining in poorly differentiated tumors [9], [12], [15], [19]. All the 166 well-differentiated hepatocellular carcinomas reported in the English literature have been positive for arginase-1 [9], [11], [12], [15], [16], [19], [20] (Table 2). However, the majority of these studies [9], [11], [12], [15], [16], [20] have used a polyclonal antibody to arginase-1, while in our study we used a monoclonal antibody. Hence, it is possible that use of polyclonal antibody may have detected weaker expression of the protein when compared to the monoclonal antibody that was used in our study. The results of the current study are important because they highlight a group of well-differentiated hepatocellular carcinomas (10%) that are arginase-1 negative. In our study, the background non-neoplastic liver parenchyma (present in 6 of the 7 cases) was positive in all cases in which the hepatocellular carcinomas were negative, demonstrating that negative staining is an intrinsic feature of these tumors and unlikely to be related to tissue fixation or technical issues. The biological explanation for this finding is not clear, but suggests that some hepatocellular carcinomas do not express this enzyme, either due to mutations or gene promoter methylation. It may be worthwhile to perform future studies examining arginase-1–negative cases for arginase-1 mutation or promotor methylation of the arginase-1 gene. Another possibility is that mutations could lead to alteration of the enzyme epitope (the N-terminal portion of the enzyme) that is targeted by the antibody. Basic science studies have shown reduced expression of arginase-1 in most hepatocellular carcinomas compared to paired normal tissues [25]. In addition, sequencing studies of hepatocellular carcinoma from the Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov/) found that 5/236 (2%) grade 1–2 hepatocellular carcinomas had bi-allelic mutations in ARG1, while no mutations were found in 137 grade 3–4 hepatocellular carcinomas (data accessed through http://www.cbioportal.org/) [26], [27]. These molecular data provide an explanation for the lack of arginase-1 expression in a subset of well-differentiated hepatocellular carcinomas, as observed in the current study. It is also interesting to note that the HepG2 cell line is arginase-1 negative [28].