Toxicol Pathol. 2015 Aug;43(6):852-64.

Hepatic Lesions Caused by Large Granular Lymphocyte Leukemia in Fischer 344 Rats: Similar Morphologic Features and Morphogenesis to Those of Nodular Regenerative Hyperplasia (NRH) in the Human Liver.

Shiga A1, Narama I2.
  • 1Public Interest Incorporated Foundation, Biosafety Research Center (BSRC), Shizuoka, Japan
  • 2Public Interest Incorporated Foundation, Biosafety Research Center (BSRC), Shizuoka, Japan.



To characterize the hepatic lesions in Fischer 344 (F344) rats afflicted with large granular lymphocyte (LGL) leukemia, the livers of rats with LGL leukemia at various stages were examined histopathologically and immunohistochemically. The morphologic features in the livers of rats afflicted with LGL leukemia were diffuse, uniform-sized, granular, or micronodular lesions consisting of hepatocytes showing centrilobular atrophy and perilobular hypertrophy (CAPH) without fibrosis. With progression in the stage of the LGL leukemia, the severity of the CAPH of hepatocytes increased resulting in fatty change and/or single-cell necrosis, along with compensatory hyperplasia of the hepatocytes, finally resulting in lesions similar to those seen in nodular regenerative hyperplasia (NRH) in the human liver. The CAPH of hepatocytes was a nonspecific tissue adaptation against ischemia or hypoxemia and/or imbalance in blood supply due to disturbance in the portal circulation and hemolytic anemia induced by the leukemia cells. In addition, direct and/or indirect hepatocellular injuries by leukemia cells were considered to be necessary for the formation of human NRH-like lesions. Morphogenetic investigation of the livers of rats afflicted with LGL leukemia may be helpful to clarify the pathogenesis of NRH in the human liver.

KEYWORDS: F344 rat; LGL leukemia; hyperplasia; liver

PMID: 25903270



Large granular lymphocyte (LGL) leukemia is a fetal neoplastic disorder that develops spontaneously with high incidence in aged Fischer 344 (F344) rats more than 1 year old. Although this disease is referred to leukemia, the primary site is considered not to be bone marrow but spleen because of prominent reduction of incidence by splenectomy. F344 rats are used as a popular strain in 2-year carcinogenicity studies in USA and Japan, in which regulatory agency requires for the purpose of registration and application of medical drugs, pesticides, and food additives etc. In F344 rats bearing LGL leukemia, hemolytic anemia, thrombocytopenia, and the effects to the liver and bone has been noted as paraneoplastic syndrome.


Fig 1.


As a paraneoplastic effect of LGL leukemia, liver enlargement with micronodular appearance (Fig. 1, above) has been described in text book or papers and it looks like liver cirrhosis macroscopically, especially at advanced stage. However, there are no associated fibrosis histologically. This hepatic lesion is similar to nodular regenerative hyperplasia (NRH) in the human liver at the point of diffuse hepatocellular proliferative lesions like cirrhosis without fibrosis (Figs. 2 and 3, below). NRH in the human liver has been reported in relation to a bewildering arrays of diseases, that is no clear cut disease associations, and the cause still remains unknown. The relationships between the intrahepatic vascular anomaly or portal hypertension and the pathogenesis of NRH in the human liver has been discussed. So, we examined NRH-like lesion in the LGL leukemia rat liver histopathologically, focusing intrahepatic and extrahepatic vessels in rats bearing LGL leukemia at various stages to obtain the clue on the pathogenesis of NRH in the human liver.


Fig 2.


As the results, vascular lesions in the rat liver with LGL leukemia localized in intrahepatic portal veins and hepatic arteries and extrahepatic portal vein were intact, differently from presence of morphological abnormalities in both portal veins and arteries in NRH in the human liver. Centrilobular atrophy and periportal hypertrophy (CAPH) of hepatocytes are characteristic representative histological finding on NRH-like lesion and indicates the presence of hypoxic condition in the liver. What is the cause of this hypoxic condition? Hemolytic anemia due to autoimmune mechanism or erythrophagia of leukemia cells and marked occupancy of leukemia cells in blood are serious factors. Also, CAPH of hepatocytes is observed in the liver of rats with enlarged spleen more than 30 mm in length and severe extramedullary hematopoiesis. However, systemic hypoxic condition such as anemia cannot independently induce NRH-like lesion which is composed of the anisokaryosis and single cell or focal necrosis of hepatocytes and thickening of hepatic cords in addition to CAPH of hepatocytes. That is, factors except blood component are considered to participate in the pathogenesis of NRH-like lesion.




In LGL leukemia, splenic congestion is evident as a characteristic finding even in the early stage. Moreover, NRH-like lesion distributes diffusely throughout the liver. Therefore, we suspected that the vessels to be the cause of this lesion exists near the hilus of the liver. At first, the presence of portal hypertension in the LGL leukemia rat liver was suspected, because the major cause of splenic congestion is portal hypertension in general. However, there were no morphological abnormalities in the extrahepatic portal vein. Next, functional portal hypertension was suspected, but it could not be clarified. In the liver from advanced cases of LGL leukemia, factor VIII-related antigen (FVIII-RAg) expression was demonstrated in sinusoidal endothelial cells. FVIII-RAg expression in sinusoidal endothelial cells suggests sinusoidal capillarization and dominance of arterial blood flow in the hepatic circulation. Primary proliferation of leukemia cells in the spleen has some roles in the imbalance of the hepatic blood flow. Also, injuries to the endothelial cells of intrahepatic portal veins demonstrating by the presence of thrombus formation and thickening of intima of intrahepatic portal veins modifies intrahepatic circulation.

Heterogeneity in the hepatic blood supply, resulting from focal obliteration of the portal vein branches and compensatory augmentation of the arterial blood supply, has been suspected as being involved in the pathogenesis of NRH in the human liver 1). The concept that NRH in the human liver is a secondary and nonspecific tissue adaptation to heterogeneous distribution of the blood flow 2) is likely because experimental portacaval anastomosis induces NRH in the rat liver 3). Important point is whether the proliferative activities in hepatocytes of NRH in the human liver is high or not. NRH-like lesion in LGL rat liver is demonstrated to be proliferative lesions. In selenium-induced rat NRH model, injuries to sinusoidal endothelial cells seem to have an important role in its pathogenesis 4). Injuries to the sinusoidal endothelial cells is also observed in NRH-like lesion in the LGL leukemia rat liver. To know the similarities and differences on the mechanism of injuries in sinusoidal endothelial cells between selenium-induced rat liver model and LGL leukemia rat liver is considered to be significant.

Investigation of the LGL leukemia rat liver may be helpful to clarify the pathogenesis of NRH in the human liver. To investigate the presence or absence of the portal hypertension in LGL leukemia rats and the meaning of existence of the injuries to sinusoidal endothelial cells may lead to obtain a clue of the pathogenesis.



1)    Wanless, I.R. (2002). Benign liver tumor. Clin Liver Dis 6, 513-26,

2)    Wanless,I.R., Godwin, T.A., Allen, F., and Feder, A. (1980). Nodular regenerative hyperplasia of the liver in hematologic disoeders: A possible response to obliterative portal venopathy, a morphometric study of nine cases with a hypothesis on the pathogens. Medicine 59, 367-79.

3)    Weinbren, K., and Washington, S.L.A. (1976). Hyperplastic nodules after portacaval anastomosis in rats. Nature 264, 440-42.

4)    Dubuisson, L., Boussarie, L., Bedin, C.-A., Balabaud, C., Biolac-Sage, P. (1995). Transformation of sinusoids into capillaries in rat model of selenium-induced nodular regenerative hyperplasia: An immunolight and immunoelectron microscopic study. Hepatology 21, 805-14.



Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann