Large-Cell Change of Hepatocytes in Cirrhosis May Represent a Reaction to Prolonged Cholestasis

Abstract

Large-cell change of hepatocytes (LCC), also called liver cell dysplasia of large-cell type, is a set of cytologic changes comprising nuclear and cytoplasmic enlargement, nuclear pleomorphism, and multinucleation. This entity is encountered frequently on histologic or cytologic examination of specimens obtained from livers with a variety of chronic diseases and originally was thought to have a premalignant nature. Accumulating evidence, however, now suggests that LCC is merely a reactive change. Having often observed LCC in liver specimens with chronic biliary tract disease, that is, in livers where cholestasis preceded hepatocyte injury, we surmised that LCC may be a result of prolonged cholestasis. To determine whether there was any association between LCC and cholestasis, we examined microscopically a series of 400 nodules from 40 consecutive adult cirrhotic livers, resected on transplantation, and graded LCC and cholestasis semiquantitatively. LCC was present diffusely in cirrhotic nodules of 25 specimens (62.5%). Nine additional specimens (22.5%) had focal mild LCC. Usually, LCC and cholestasis occurred together, in the same cirrhotic nodules and in the same areas of nodules. There was a statistically significant association between the presence and grade of LCC and those of cholestasis (p < 0.0001; chi-square test). Within etiological categories of cirrhosis (chronic hepatitis; n = 28; alcoholic liver disease; n = 6; biliary disease: n = 6), the significance was maintained. We conclude that, in cirrhosis of different etiologies, LCC may represent a reactive change that results from prolonged cytoplasmic cholestasis.

Clonal analysis of macronodules in cirrhosis

“…28,29 Indeed, recent studies have accumulated evidence suggesting that LLCC in cirrhotic liver is merely a diffuse and degenerative change to prolonged cholestasis, rather than a neoplastic feature. 4,6,30,31,32 The question arises as to whether there exists several subsets of LLCC, with a benign form of scattered LLCC associated with prolonged cholestasis and a neoplastic subset consisting of clusters of large liver cells in cirrhotic macronodules. In our study, none of the cases with LLCC showed any association with bile or cholate stasis (Table 3).…”

Chromosomal Alterations in Hepatocellular Nodules by Comparative Genomic Hybridization: High-Grade Dysplastic Nodules Represent Early Stages of Hepatocellular Carcinoma

“…There is no precise correspondence between genetic and morphologic alteration (IWP, 1995), so that the concept itself of hepatic dysplasia is still controversial. The original description of Anthony et al (1973) referred to what is today called "large cell dysplasia" (enlarged hepatocytes with nuclear pleomorphism and prominent nucleoli), a morphologic change that has been considered a reactive change Su et al, 1997) or a sign of concurrent malignant neoplasia (Natarajan et al, 1997). On the other hand, a truly premalignant lesion seems to be represented by "small cell dysplasia" (Watanabe et al, 1983) (small hepatocytes with decreased, more basophilic cytoplasm and hyperchromatic nucleus), which shows phenotypic markers that are in favor of its precancerous nature (Su et al, 1997;Zhao et al, 1994aZhao et al, , 1994b.…”

Large Liver Cell Dysplasia in Hepatitis B Virus X Transgenic Mouse Liver and Human Chronic Hepatitis B Virus-Infected Liver

“…LCD has been regarded as a precancerous lesion, because LCD contains abnormal and increased DNA content or numerical chromosome aberrations [10][11][12][13] and its N/C ratio, measured by morphometry, is increased [8]. However, over the last 30 years, this proposal has been contested, and other researchers have concluded that LCD represents a regenerative or degenerative phenomenon, because LCD was reported to be a low proliferative and highly apoptotic lesion and to have no histological continuum to HCC [14][15][16]. Recently, LCD related to hepatitis virus was reported to be an independent risk factor for HCC [17][18][19][20].…”