Hence it is important to perform additional markers to prevent false negatives

Hence it is important to perform additional markers to prevent false negatives. such as HepPar-1 and polyclonal carcinoembryonic antigen (pCEA). Of the four tumors, only one recurred at 28 months. All patients are currently stable with a mean survival of 43 months. Conclusions Arg-1 negative well differentiated HCC can be a clinical dilemma which can lead to misdiagnosis. Confirmation with other hepatocellular markers such as HepPar1 and pCEA is essential in making the correct diagnosis. The clinicopathologic outcomes of arginase negative well differentiated HCC has been poorly characterized, thus our findings are of utmost importance in understanding the clinical behavior of these tumors. This may have a potential role in understanding the mechanism of the use of targeted therapy in HCC tumors. (25) demonstrated high serum arginase activity in patients with HCC, which decreased drastically following curative surgery; thus suggesting a role for arginase in monitoring patients with HCC following hepatectomy. Therefore, it is possible that Arg-1 is involved in the tumorigenesis of HCC and Kcnmb1 may require other factors, such as having a higher histologic grade or 42-(2-Tetrazolyl)rapamycin TNM stage, which will result in the progression of HCC. Molecular studies to examine the gene is required to determine if certain mutations or methylation are present which may better serve as predictive markers. Limitations of our study is the small study size of arginase negative tumors due to the rare nature of the entity, hence further studies to fully characterize the implications of arginase negative well differentiated HCC is warranted. Furthermore, it is important to determine that arginase negative well differentiated HCC are indeed of 42-(2-Tetrazolyl)rapamycin hepatic origin. Although morphology still remains a major key factor to diagnosis, some cases of cholangiocarcinoma ( em Figure 1A /em ) or metastatic carcinomas to the liver can have a well differentiated hepatoid morphology. Our cases of arginase negative well differentiated HCC were all positive for other hepatocellular markers which include, HepPar-1 and pCEA. This correlates with other reports of arginase negative well differentiated HCC which were all positive for HepPar-1 (13,14). Hence it is important to perform additional markers to prevent false negatives. HepPar-1, which recognizes carbamoyl synthetase, an enzyme in the urea cycle and pCEA are among those commonly used (1). Sensitivities of 100% and 92% has been reported respectively with HepPar-1 and pCEA in well differentiated HCC (26). Glypican 3, a heparin sulfate proteoglycan can also be used in the detection of well differentiated HCC (26), however limitations include lower sensitivity (62%) and expression in other tumors such as lung squamous cell carcinoma and yolk sac tumor (5). Other hepatic immunohistochemical markers include CD10, which yields a canalicular pattern and AFP. Similarly, they are affected by the same limitations that is observed with Glypican 3. Although Arg-1 is the most sensitive marker for the detection of HCC, it is important to use at least 2 hepatic markers to prevent misdiagnosis in Arg-1 negative HCC. Conclusions In conclusion, we have demonstrated that well differentiated HCC can be negative for arginase expression. Although, only 8 arginase negative well differentiated HCC tumors have been described, the clinicopathologic outcomes have been poorly described. This entity has been rarely demonstrated possibly due to the use of polyclonal antibodies which has led to false positives in prior studies. Future studies are necessary to fully understand the clinical behavior of arginase negative well differentiated HCC. Acknowledgments 42-(2-Tetrazolyl)rapamycin None. Notes em Ethical Statement /em : The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Georgetown University Institutional board review (IRB #2018-1025) and written informed consent was waived. Footnotes em Conflicts of Interest /em : The authors have no conflicts of interest to declare..