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Am J Gastroenterol. 1996 May;91(5):879-84.

Hepatocellular carcinoma and nodular regenerative hyperplasia: possible pathogenetic relationship.

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Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington D.C., USA.



In a recent review of hepatocellular carcinoma (HCC) in North American residents, we were surprised to learn that 42.6% of these tumors in the 1980-1993 consultation files of the Armed Forces Institute of Pathology had arisen in noncirrhotic livers. We subsequently noted that the nonneoplastic livers of a number of these had nodular regenerative hyperplasia (NRH), a condition that has been associated with liver cell dysplasia, a putative premalignant lesion. To investigate the possibility that NRH might be a precursor of HCC, we studied those cases in which there was an association of HCC and NRH and examined the possible role of portal vein obstruction in NRH occurring in livers with HCC.


Subjects were selected based on study criteria and histological slides, clinical/autopsy records were reviewed, and features of neoplastic and nonneoplastic liver were noted. Simple statistical comparisons were made between the groups with and without NRH with respect to defined variables.


Of 804 patients suitable for study, 342 were noncirrhotic, and 23 of these had NRH. Mean age of patients with NRH was 65 +/- 13.6 (SD) yr. Seventeen of these (73.9%) had liver cell dysplasia, and 16 (69.6%) had portal venous invasion. Liver cell dysplasia occurred in a significantly greater proportion of those with NRH than those without (p < 0.01), but there was no significant difference between both groups with regard to portal venous invasion. Three patients (13%) had received chemotherapy and/or radiotherapy before diagnosis of NRH.


These findings may be due to the development of HCC within the dysplastic foci that occur in livers with NRH, but the findings do not exclude the converse possibility that NRH may also develop in a noncirrhotic liver with HCC, secondary to portal venous invasion with portal vein occlusion. The temporal relationship between HCC and NRH is probably determined in each case by the particular interaction of multiple pathogenetic factors. Among patients with HCC, factors other than the portal vein obstruction by tumor invasion may play a role in the pathogenesis of NRH.

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