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Primary hepatocellular carcinoma in a patient with neurofibromatosis type I

Neurofibromatosis type I (NF1) is a widely known genetic disorder caused by a loss of function of the NF1 gene (1). Although, the overall risk of malignancy in NF1 is higher than that in the general population, hepatocellular carcinoma (HCC) in NF1 is very rare (2, 3). We report the clinical outcome of HCC manifesting in a Japanese 40-year-old man with NF1. The patient had multiple caf e au lait spots, cutaneous neurofibromas (Fig. S1), and scoliosis, but possessed no history of drinking and hepatitis B/C. Computed tomography disclosed a 43-mm mass in the right hepatic lobe (Fig. 1a). A right lobectomy was performed, and histopathological findings confirmed that moderately differentiated HCC (Fig. S2) had manifested in the liver parenchyma without inflammation, fibrosis or bile duct abnormalities (Fig. S3). It was recently reported that selective suppression of guanosine triphosphatase activating proteins, including NF1, resulted in unregulated activation of Ras signalling in human hepatocarcinogenesis (4). Accordingly, we examined the expression of neurofibromin, a product of the NF1 gene, and p21-RAS by immunohistochemistry. Neurofibromin expression was negative in the HCC region (Fig. 1b) but positive in the surrounding non-HCC region (Fig. 1c). High expression of p21-RAS was detected in several tumour cells (Fig. 1d). As it has been shown that neurofibromin serves as a tumour suppressor by regulating the activity of RAS and that RAS overexpression leads to acceleration of cell division, we consider that a disruption in neurofibromin function and ensuing overactivation of RAS may be associated with hepatocarcinogenesis in this case.