Glutamine Synthetase (GS-6)

Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia in the mammalian liver. In normal liver, GS expression is seen in pericentral hepatocytes, but not in mid-zonal or periportal hepatocytes.1 Glutamine, the end product of GS activity, is the major energy source of tumor cells.1 Based on findings from experimental hepatocarcinogenesis, GS positive tumor cells are believed to be derived from GS positive hepatocytes.1 Thus, anti-GS has been suggested as a marker for hepatocellular carcinoma (HCC).1 GS immunoreactivity has been seen in a majority of HCC (37 of 53 cases, 70%), including 7 of 10 cases of early HCC (70%) and 12 of 22 (59%) for low grade HCC.1 In nonmalignant nodules, GS overexpression was only seen in 3 high grade dysplastic nodules (HGDN,13.6%). In these cases, GS overexpression was restricted to 11.5%-50% of hepatocytes, whereas in HCC the majority of cases (28 of 53, 53%), including early HCC (60%), showed diffuse immunostaining (>50% tumor cells). Overall, the sensitivity, specificity, and positive and negative predictive values of anti-GS for HCC detection were 69.8%, 94.2%, 92.5%, and 75.4%, respectively. A panel composed of antibodies against HSP70, GPC3, and GS has been proposed to be very useful in distinguishing between dysplastic and early malignant hepatocellular nodules arising in cirrhosis. The “all positive” phenotype is restricted to approximately half of early HCC to well-differentiated HCC but has never been reported in dysplastic lesions, whereas the reverse phenotype, “all negative”, has been shown to be a feature of the majority of HGDN and of all low grade dysplastic nodules.1 Staining of hepatocellular lesions with anti-GS antibody have been useful in the differential diagnosis of focal nodular hyperplasia (FNH), hepatic adenoma (HCA),2 and dysplastic nodules, and low grade hepatocellular carcinoma.3-6 In the case of FNH, GS stains in a characteristic “map-like” pattern, thus differentiating it from HCA, in which GS staining is usually absent, but may occasionally be present at the border of the lesion or around the veins inside the tumor.4,5