It has become widely accepted that NASH is a hepatic manifestation of the metabolic syndrome. The heavy prevalence of DM, HTN, obesity, and hyperlipidemia in our series gives further clinical support to this concept. Moreover, our study demonstrates the sclerotic spectrum of NASH, with varying degrees of fibrosis seen originating from the centrilobular zone.
Our study consisted of patients with a large mean tumor size of 7.0
cm. The finding of more advanced tumors in our series is related to the modes of presentation; all cases were either discovered incidentally or because of mass-related symptoms. None of the patients had been enrolled in radiographic surveillance programs for HCC. Similarly, Giannini et al. found that CC-associated HCCs were more likely to be discovered at an advanced stage and less likely to be amenable to treatment when compared to HCV-associated HCCs; this was also attributed to less surveillance among the former group [25
]. It follows that of our 8 patients that survived the postoperative period 6 recurred within two years of resection, a clear sequella of the advanced nature of their initial tumors. Despite this high early recurrence rate, we were able to achieve a 5-year survival of 44%, likely attributable to the aggressive multimodality approach to treating those recurrences.
4.1. Fibrosis: A Necessary Precursor?
NASH is felt to progress to cirrhosis in 3–15% of cases [7
], and it has been suggested that the development of cirrhosis is a necessary intermediate step in a progression to HCC [6
]. This has been a difficult theory to prove, in part due to the disappearance of the histopathological features of NASH once cirrhosis is established [15
]. Nevertheless, “cryptogenic cirrhosis” has been shown to likely represent end-stage NASH based on clinical parameters [3
], with a risk of HCC development that rivals HCV-associated cirrhosis [7
]. In a large case-control study, Hashimoto et al. showed that the strongest independent predictor for HCC development in NASH patients was severe hepatic fibrosis [14
Despite this evidence, 44% of our patients showed only mild fibrosis in the nonneoplastic liver parenchyma. Similar findings have been echoed in other surgical series. Hashizume et al. found that 3 of 8 patients undergoing curative treatments (6 resections, 2 RFAs) of NASH-associated HCC had noncirrhotic livers [15
]. Kawada et al. found that 5 of 8 patients receiving resection of NASH-associated HCC showed only mild fibrosis (F2) in their background livers [16
]. Paradis et al. analyzed a group of 31 patients receiving resection of HCC that complicated only metabolic syndrome (81% with some form of NAFLD) and found nonfibrotic or mildly fibrotic livers in 20 (65.5%) of the cases [28
It is important to point out the natural selection bias for noncirrhotics that exists in a surgical resection series such as ours. Further supporting data, however, exists in nonsurgical studies [1
]. Guzman et al. found from a cohort of 50 HCC patients submitted to a wide spectrum of treatments 3 of 5 NAFLD-associated cases that were noncirrhotic [30
]. In a larger series, Ertle et al. showed that in a group of 36 NASH-associated HCC patients of which only a minority received resection, the prevalence of noncirrhotic background liver was 47.2% [1
We chose not to include cases of cryptogenic cirrhosis (CC) in our study group and instead included only patients with histologically-active NASH. Accepting the premise that the 18 CC cases in our entire population represented “burnt-out” NASH, the actual proportion of NASH-associated HCC cases that developed in the absence of cirrhosis becomes 14.8%. This is similar to the rate of noncirrhotic HCV-associated HCCs in our overall cohort (21/178, 11.8%, P = 0.751 by Fisher's exact test); it is less but also statistically similar to our rate of noncirrhotic HBV-associated HCCs (68/255, 26.7%, P = 0.246 by Fisher's exact test). Indeed, based on our experience and that of other investigators, the relevance of this entity should not be underestimated.
If the carcinogenic milieu of a cirrhotic liver represents only part of the story, the additional mechanisms underlying HCC development in the NASH liver have yet to be fully elucidated. Recent investigation has centered on the oncogenic effects of hyperinsulinemia, a key component of the metabolic syndrome [31
]. Additional research has focused on the oxidative stress present in the microenvironment of the steatotic liver. Specifically, lipid peroxidation, an important component of disease progression in NASH, has been implicated in the generation of reactive oxygen species that may possess mutagenic qualities sufficient to initiate malignant transformation [6
]. An additional effect of this oxidative stress has been shown to include clonal expansion of premalignant oval cells in both mouse and human forms of fatty liver [35
]. Further proliferation of these neoplastic cells may be driven by disturbances in cytokines and growth factors [6
]. Whether HCC development in NASH is an effect of factors directly derived from the underlying metabolic diseases or a result of biochemical derangements in the steatotic liver lesions is a question which remains to be answered.
“While the potential mutagenicity of the noncirrhotic NASH parenchyma is intriguing, we must acknowledge that alternate etiological agents might have been at play in these patients. One possibility is occult HBV infection, as evidenced by the presence of HBV DNA by PCR analysis in the context of a negative serological panel. Unfortunately, only 1 of the 4 noncirrhotic patients in our series received this PCR analysis (negative), and this scenario cannot be ruled out in the other three. Environmental exposure to a hepatocarcinogen such as aflatoxin A, nitrosamine, or benzopyrene serves as an additional plausible, albeit unlikely, etiology. Finally, advanced age (one noncirrhotic over 70) and male gender (all 4 noncirrhotics) placed these patients at slightly increased risk of primary hepatic malignancy.”
In conclusion, HCC may arise in a liver affected by NASH, often in association with multiple metabolic comorbidities. Although cirrhosis increases the risk of malignant transformation, it does not appear to be a necessary precursor to such an event. NASH-HCC often presents at a late stage leading to increased local failure following resection; nevertheless, with an aggressive approach to recurrence, long-term survival may still be achieved. With the increasing prevalence of obesity and diabetes mellitus in Western populations, investigation into the utility of HCC surveillance for patients with established NASH seems warranted.