Nodular regenerative hyperplasia (NRH) is an uncommon liver disease associated with noncirrhotic portal hypertension. Several risk factors for NRH have been identified including X-linked agammaglobulinemia (XLA).1,2 NRH is diagnosed histologically by noting alternating regions of hypertrophic and atrophic liver cell plates without fibrosis, particularly seen on reticulin staining (Figure 1). Portal venopathy causing variance in blood flow is believed to cause differential cellular growth leading to NRH.2,3 NRH is not considered to be premalignant. We present a case of hepatic angiosarcoma (HAS) in a patient with long-standing NRH. HAS is an aggressive tumor accounting for 2% of primary liver malignancies.4 Identification of angiosarcoma arising from vascular endothelium, in underlying NRH, with postulated vascular etiology, emphasizes a possible link between the 2.
We present a 29-year-old North-Korean man with a history of XLA-related NRH complicated by noncirrhotic portal hypertension and later diagnosed with HAS. He was diagnosed with XLA at the age of 9 years after a workup for pneumococcal sepsis. He was maintained on intravenous immunoglobulin since then and followed at the National Institute of Allergy and Infectious Diseases. Over time, he was found to have a steady decline in platelet count along with pancytopenia. His course was complicated by ascites, and workup revealed serum markers and imaging changes supporting a diagnosis of cirrhosis. He underwent transjugular liver biopsy and portal pressure measurements at the age of 18 years, and pathology showed NRH with mild lobular inflammation and sinusoidal fibrosis (Figure 1). Hepatic venous pressure gradient at the time was 7 mm Hg. Physical examination was remarkable for chronic nontender hepatomegaly. Serum studies during the time revealed a white blood cell count of 2.9 K/μL, platelets of 114 K/μL, serum alanine aminotransferase of 56 IU/L, serum aspartate aminotransferase of 49 IU/L, alkaline phosphatase of 179 IU/L, gamma-glutamyl transferase of 208 U/L, albumin of 2.6 g/dL, and normal international normalized ratio. He underwent screening endoscopy 1 year later and was found to have portal hypertensive gastropathy. He was followed at the National Institutes of Health annually with serum studies, abdominal imaging, and endoscopy. Surveillance imaging with magnetic resonance imaging (MRI) showed ill-defined T2 signal in the right hepatic lobe believed to be hemangioma, and it was stable for 5 years. He was then lost to follow-up for 3 years (Figure 2).
Care was re-established after 39 months. He continued to be functional with minimal symptoms and mild elevation in serum studies, as mentioned above. MRI of the abdomen showed innumerable hepatic lesions of T2 hyperintensity, with arterial enhancement and no wash out (Figure 2). Viral markers for hepatitis B and C were negative, and tumor markers including alpha fetoprotein, carcinoembryonic antigen, cancer antigen 125, and carbohydrate antigen 19-9 were normal. Because the etiology was unclear, he had liver biopsy from a segment V lesion, and pathology report was indicative of atypical vascular proliferation, suggesting angiosarcoma but not diagnostic (Figure 1). Liver biopsy was repeated from a segment VI lesion 2 months later and was diagnostic of angiosarcoma. CD34 staining of the tumor was positive. He did not have any known exposure to chemicals that might increase his risk of HAS.
He was not a candidate for any medical or surgical intervention because of extensive disease. Over the next 8 months, he had MRI examinations every 2 months and the lesions remained stable. During the follow-up period, he remained asymptomatic and had excellent quality of life. He was then lost to follow-up for 9 months. On return, he continued to be asymptomatic and had nontender hepatomegaly on physical examination. Serum studies did not show significant change in transaminases, but alkaline phosphatase and gamma glutamyl transferase had increased to 480 IU/L and 620 U/L, respectively, with a direct bilirubin of 2.3 mg/dL. MRI showed an increase in size of multiple arterially enhanced liver lesions with no evidence of intrahepatic or extrahepatic biliary duct dilatation (Figure 2). Two months later, he died from sepsis causing disseminated intravascular coagulation and intracerebral bleed. Histology of the liver at autopsy showed many infiltrating foci of angiosarcoma (Figure 1).
This case report emphasizes the development of HAS in a patient with NRH. Our patient was believed to have developed NRH secondary to XLA. The prevalence of NRH in patients with XLA is reported to be 29%.1 NRH is not considered to be premalignant, although there have been reports of hepatocellular carcinoma and cholangiocarcinoma in patients with NRH.5 It is unclear whether this patient's HAS is due to underlying NRH. However, disruption of Notch1 signaling has been reported to cause NRH and HAS in mice.3,6 Notch signaling pathway is believed to have a significant role in bile duct equilibrium.6 However, Notch1 knockout after birth in mice showed nodular transition of the liver within a week, with no disruption of bile duct homeostasis.6 However, another study analyzing the significance of Notch 1 signaling in liver sinusoidal endothelial cells concluded that dysregulation of Notch 1 signaling results in spontaneous angiosarcoma.3 Genetic analysis in our patient did not reveal any pathologic mutations in the Notch pathway. Further studies exploring the role of Notch signaling pathway in NRH and HAS will help clarify this proposed mechanism.
Angiosarcomas are aggressive tumors with poor outcomes secondary to high rate of recurrence and lack of response to radiotherapy and chemotherapy.7 Seventy-five percent of cases have unknown etiology.8 There are no set guidelines for treatment, and partial liver resection remains the treatment option.9 The median survival is 6 months with treatment.10 Our patient died 19 months after diagnosis.
NRH is believed to have a vascular etiology, and angiosarcoma is a tumor arising from the endothelium of vascular structures; the co-occurrence of the two in this patient is of particular interest. This report extends the literature on a link between malignancy and NRH. As NRH is increasingly identified and patients followed closely, it is likely that further associations with malignancy, particularly HAS, will be identified.
Author contributions: NA Majeed wrote the manuscript. G. Uzel, C. Koh, and DE Kleiner revised the manuscript. NA Majeed and T. Heller reviewed the literature. T. Heller edited the manuscript and is the article guarantor.
Financial disclosures: None to report.
Informed consent was obtained for this case report.
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