Does Argininosuccinate Synthase 1 (ASS1) Immunohistochemistry Predict an Increased Risk of Hemorrhage for Hepatocellular Adenomas?

Abstract

Hepatocellular adenomas (HCAs) often pursue an innocuous clinical course. Recent work has elucidated important subtypes of HCA and biomarkers to identify them, including HCA at an increased risk for malignant transformation. Another key complication of HCAs is the risk of spontaneous tumoral hemorrhage, which may be life-threatening. Identification of a predictive biomarker for this clinical complication would therefore be of clinical value. It has been suggested that Argininosuccinate Synthase 1 (ASS1) immunohistochemistry (IHC) identifies HCA with a high propensity for hemorrhage. The aim of our study was to validate ASS1 IHC as a predictive marker of hemorrhage. Eighty-nine HCAs were collected for ASS1 IHC and subtyped according to published criteria. Clinical records were examined for evidence of tumoral hemorrhage. Twenty-one (23.6%) HCAs were complicated by clinically detected hemorrhage and were more likely to be resected (P=0.0002). Hemorrhage complicated all WHO subtypes of HCA. There was no association between hemorrhage and HCA subtype (P=0.92). Neither the distribution of ASS1 expression nor the intensity of ASS1 expression compared to normal liver showed a significant association with hemorrhage (P=0.051 and 0.34). Interlaboratory comparison of 8 cases showed good agreement regarding the intensity (6/8 and 7/8) and distribution of staining (7/8 and 7/8) across 3 laboratories performing ASS1 IHC. In conclusion, all subtypes of HCA may be complicated by hemorrhage. ASS1 IHC expression did not correlate with hemorrhagic complications. Caution is prudent before routine implementation of ASS1 IHC in clinical practice.

Hepatocellular Adenoma and Focal Nodular Hyperplasia

“…Although some found immunohistochemical expression of Argininosuccinate Synthase 1 (ASS1) to identify in unclassified HCA a subgroup with a high risk for bleeding, others found no such correlation. 12 A more recently described subtype is sonic hedgehog (sh) activated HCA (5% of HCAs), which is frequently identified in obese patients and may…”

“…HCAs not demonstrating any of the specific earlier phenotypes are considered “unclassified.” These represent 5% to 10% of HCAs. Although some found immunohistochemical expression of Argininosuccinate Synthase 1 (ASS1) to identify in unclassified HCA a subgroup with a high risk for bleeding, others found no such correlation 12 . A more recently described subtype is sonic hedgehog (sh) activated HCA (5% of HCAs), which is frequently identified in obese patients and may be associated with increased risk for bleeding 13 .…”

ASS1 Overexpression: A Hallmark of Sonic Hedgehog Hepatocellular Adenomas; Recommendations for Clinical Practice

“…In a recent paper, ASS1 IHC positivity (without comparison to NT liver in 57% of cases) was not found to correlate with hemorrhage, whatever the HCA subtype. ( 21 ) It is quite obvious that all HCA subtypes can bleed. In this work, our purpose was to identify, using ASS1 overexpression, shHCA that are known to be at high risk of bleeding.…”

“…ASS1 positivity without overexpression in different HCA subgroups has been reported and has created confusion about the pertinence of ASS1 as an immunomarker. ( 19,21 )…”

Hepatocellular adenoma: Where are we now?

“…While there are no specific histopathologic features in this HCA subtype, it seems that prostaglandin D synthase and argininosuccinate synthase 1 (ASS1), particularly ASS1 positivity by immunohistochemistry is a hallmark of shHCA[ 2 , 33 ]. Although ASS1 may be expressed in other HCA subtypes with hemorrhage and thought to be a marker of hemorrhage[ 34 ], a recent study showed ASS1 expression did not correlate with HCA hemorrhagic complications[ 35 ]. Interestingly, higher risk of hemorrhage has been consistently observed both histologically and clinically in shHCA[ 2 , 31 ].…”