Volume 42, Issue 5, Pages 341-347 (May 2010)

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Hepatocellular carcinoma in non-cirrhotic liver: A reappraisal

Received 20 July 2009; accepted 11 September 2009. published online 15 October 2009.

Abstract

Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.

Keywords: Hepatocellular carcinoma, Chronic hepatitis, Fatty liver, Liver cirrhosis, Liver fibrosis

Article Outline

• Abstract

• 1. Introduction

• 2. Demographic characteristics

• 3. Etiological factors

• 3.1. Viral infections

• 3.2. Alcohol intake

• 3.3. Genotoxic substances

• 3.4. Inherited diseases

• 3.5. Sex hormones

• 3.6. Germ-line mutations

• 4. Hepatocarcinogenetic pathways

• 5. Pathologic findings of HCC and the surrounding non-cirrhotic liver

• 6. Diagnosis

• 7. Treatment and survival

• 8. Conclusions

• Conflict of interest

• Acknowledgment

• References

• Copyright

1. Introduction

Hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is the sixth most common solid tumour and the third cause of cancer mortality in world population [1].

Liver cirrhosis is the main risk factor for HCC, leading to chronic necroinflammation and hepatocellular regeneration. This is the background for genetic mutations to accumulate and cells to progress to overt malignancy. Nevertheless, a certain number of HCCs arise in non-cirrhotic livers. This kind of hepatic carcinogenesis occurs in a proportion of cases that ranges widely from 7% to 54% across the geographic areas and according to the aetiology of the liver disease [2], [3], [4], [5], [6], [7], [8], [9].

This review describes the epidemiological and clinical features, and the therapeutic management of non-cirrhotic HCCs, which are fairly distinct from those of the same tumour when it occurs in a cirrhotic background.

2. Demographic characteristics

Some series of non-cirrhotic HCCs reported a lower male preponderance (male/female ratio: 1.3–2:1) as compared with the cirrhotic counterpart, where this ratio ranges from 3.2 to 8:1 [6], [8], [10]. However, this feature was not confirmed by other studies, reporting similar ratios [5], [11], [12].

The mean age is generally less advanced in non-cirrhotic than in cirrhotic patients [6], [8], [12], although there is not full agreement about this feature either [5], [11], [13]. Namely, cirrhotic HCC shows an unimodal age distribution, peaking at the 7th decade, whereas non-cirrhotic HCC reveals a bimodal distribution, peaking at the 2nd and 7th decades (Fig. 1) [6], [10]. Interestingly, the first peak presents with a balanced male/female ratio, and includes the vast majority of fibrolamellar hepatocellular carcinomas (FL-HCC), a rare variant that occurs almost exclusively in patients without cirrhosis and frequently occurs earlier than 40 years of age [14], [15].

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Fig. 1. Age distribution of patients carrying hepatocellular carcinoma with and without underlying cirrhosis. Ref. [6], Copyright 1995 American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

3. Etiological factors

3.1. Viral infections

As for cirrhotic HCC, hepatitis B virus (HBV) or C virus (HCV) chronic infections are the main risk factors. However, current or occult/past HBV (testified by serum anti-core antibody [HBcAb]) and HCV infections were more commonly found in cirrhotic than non-cirrhotic patients in most series [6]. Table 1, Table 2 report the prevalence of HBV surface antigen (HBsAg) and anti-HCV antibody in these two categories of patients coming from different geographic areas.

Table 1.

Prevalence of HBsAg carriage in cirrhotic and non-cirrhotic patients with hepatocellular carcinoma.


Reference	HBsAg positive status
	Non-cirrhotic HCC patients (%)	Cirrhotic HCC patients (%)	p-Value
Okuda et al. [16]	4/43 (9.3)	128/314 (40.8)	0.0001a
Okuda et al. [2]	4/54 (7.4)	138/518 (26.6)	<0.001
Kalayci et al. [17]	7/137 (5.1)	n.r.
Trevisani et al. [6]	10/102 (9.8)	81/360 (22.5)	0.007
Nzeako et al. [8]	17/342 (5.0)	43/462 (9.3)	<0.05
Stroffolini et al. [5]	10/66 (15.1)	167/993 (16.8)	n.s.
Grando-Lemaire et al. [18]	2/30 (7.0)	n.r.
Bralet et al. [19]	11/80 (13.7)	79/250 (31.6)	0.003a, b
Shimada et al. [13]	7/65 (10.8)	102/450 (22.7)	0.034b
Chen et al. [20]	179/254 (70.5)	n.r.
Grazi et al. [11]	17/135 (12.6)	46/308 (14.9)	n.s.
Chang et al. [12]	142/221(64.3)	150/217 (69.1)	n.s.
Kumar et al. [21]	26/52 (50.0)	85/137 (62.0)	n.s.a
Taura et al. [22]	15/127 (12.0)	31/166 (19.0)	n.s.

HBsAg: hepatitis B surface antigen; HCC: hepatocellular carcinoma; n.r.: not reported; n.s.: not statistically significant.

Calculated by the authors of the present article.

In Refs. [13], [19] the non-cirrhotic group was composed of patients with a non-fibrotic liver parenchyma.

Table 2.

Prevalence of anti-HCV status in cirrhotic and non-cirrhotic patients with hepatocellular carcinoma.


Reference	Anti-HCV positive status
	Non-cirrhotic HCC patients (%)	Cirrhotic HCC patients (%)	p-Value
Trevisani et al. [6]	15/28 (53.6)	104/138 (75.4)	0.03a
Stroffolini et al. [5]	31/66 (47.0)	780/993 (78.5)	<0.0001b
Grando-Lemaire et al. [18]	4/30 (13.3)	n.r.
Bralet et al. [19]	2/80 (2.5)	68/250 (27.0)	0.0001a, b
Shimada et al. [13]	22/42 (52.4)	243/332 (73.2)	0.007b
Chen et al. [20]	39/139 (28.1)	n.r.
Grazi et al. [11]	33/135 (24.4)	182/308 (59)	<0.001
Chang et al. [12]	39/216 (18.1)	57/208 (27.4)	0.02
Kumar et al. [21]	1/52 (1.9)	22/137 (16.1)	0.016a
Taura et al. [22]	81/119 (68.0)	106/145 (73.0)	n.s.

HCV: hepatitis C virus; HCC: hepatocellular carcinoma; n.r.: not reported; n.s.: not statistically significant.

Calculated by the authors of the present article.

In Refs. [13], [19] the non-cirrhotic group was composed of patients with a non-fibrotic liver parenchyma.

HBV infection can trigger hepatic carcinogenesis independently of the development of cirrhosis [23]. In fact, HBV genome integration can lead to host DNA microdeletions, and HBx protein (a genotoxic viral product) alters transcriptional activity by modifying the expression of several growth-control genes. Recently, several authors have reported that the accumulation of mutations in basal core promoter and a high viral load (104–5copies/mL) are independent predictors of HCC development [24], [25], [26], and this also applies in the absence of cirrhosis [24]. Therefore, in the forthcoming future, the identification of these mutational patterns could be applied to identify, amongst HBsAg carriers, those patients at high HCC risk regardless of the presence of cirrhosis.

HCV has a far lower direct oncogenic potential than HBV, and it is currently believed that the main mechanism leading to HCC development in chronically infected HCV patients is represented by the sustained necro-inflammatory process promoted by the infection. Therefore, almost all HCV-related tumours occur in a background of advanced liver fibrosis or frank cirrhosis [27], [28], [29]. However, several HCV gene products (core, NS3, NS4B and NS5A) possess a transformation potential in murine fibroblast culture [30], [31], [32], suggesting that HCV also has a direct hepatocarcinogenic potential [33]. In any case, the actual biologic relevance of these findings remains to be established in human beings. HCV proteins are in fact expressed in much lower concentrations in vivo than those utilised in experimental settings [34].

It has also to be pointed out that assessing the presence of HBV and HCV infections by serological markers underestimates their etiologic role, as HBV-DNA and HCV-RNA fragments have been detected in the serum and/or liver tissue of 18% and 33%, respectively, of patients with non-cirrhotic HCC and negative serological markers [35].

More recently, a new group of patients without cirrhosis at risk of HCC has been identified, that is individuals with chronic HCV hepatitis who achieved a sustained viral response (SVR) after antiviral therapy. In fact, there is growing evidence that interferon/ribavirin treatment, the mainstay of treatment for chronic hepatitis C, greatly reduces, but does not annul, the risk of HCC in patients who achieved a SVR. The main risk factor for post-SVR liver carcinogenesis are advanced age, male sex, pre-treatment high serum aspartate-aminotranferase, low platelet count and advanced hepatic fibrosis or cirrhosis [36], [37]. Nonetheless, some HCCs develop even in patients with mild hepatic fibrosis several years after the SVR. Finally, occult HBV infection can represent a further risk factor also in the context of post-SVR HCC [38].

More in general, since patients with successfully treated or spontaneously inactivated chronic hepatitis B or C may show regression of fibrosis or even reversal of cirrhosis, some of them may be classified in non-cirrhotic HCC group due to a regressed cirrhosis at the time of cancer diagnosis. Nevertheless these patients might have a greater HCC risk compared to pre-cirrhotic patients, because the steps sufficient to initiate carcinogenesis may have occurred before the improvement in fibrosis [39].

3.2. Alcohol intake

Heavy alcohol intake, the third major cause of HCC, is remarkably less frequent in non-cirrhotic HCC patients (Table 3). This finding is consistent with the concept that the hepatocarcinogenicity of alcohol abuse is almost entirely due to the development of cirrhosis [40], [41].

Table 3.

Alcohol intake in cirrhotic and non-cirrhotic patients with hepatocellular carcinoma.


Reference and reported alcohol intake	Heavy alcohol intake
	Non-cirrhotic HCC patients (%)	Cirrhotic HCC patients (%)	p-Value
Trevisani et al. [6] >80g/die	15/91 (16.5)	105/350 (30.0)	0.01
Nzeako et al. [8] history of alcoholism	25/342 (7.3)	130/462 (28.1)	<0.0001
Bralet et al. [19] >50g/day for more than 5 years	11/80 (13.7)	73/250 (29.2)	0.009a, b
Shimada et al. [13] alcohol use	44/63 (69.8)	232/433 (53.6)	0.022b
Grazi et al. [11] alcoholic habit	29/135 (21.5)	67/308 (21.7)	n.s.
Chang et al. [12] alcohol abuse	98/223 (43.9)	99/222 (44.6)	n.s.
Kumar et al. [21] >80g/day for at least 5 years	5/52 (9.6)	25/137 (18.2)	n.s.a

HCC: hepatocellular carcinoma. n.s.: not statistically significant.

Calculated by the authors of the present article.

In Refs. [13], [19] the non-cirrhotic group was composed of patients with a non-fibrotic liver parenchyma.

3.3. Genotoxic substances

The development of HCC in the absence of cirrhosis can also be related to the exposure to genotoxic factors including:

•Aflatoxin B1, a toxin produced by the fungus Aspergillus flavus, that can contaminate many alimentary commodities, such as cereals, nuts, spices, figs and dried fruit. This contamination is common in some areas of Africa and Asia with a high HCC incidence. Indeed, the role played by this mycotoxin in the western world may be underestimated because aflatoxin contamination is a worldwide health-threatening problem due to the globalisation of food and feed trade [42]. Aflatoxin has been proven as a powerful hepatocarcinogen in animal experiments, and an epidemiologic study associated the urinary excretion of aflatoxin metabolites with a 4-fold increase in HCC risk. The association of HBV infection heightens the HCC risk to 60-fold with respect to the general population [43]. HBV infection in fact sensitises hepatocytes to the aflatoxin-induced 249ser-p53 mutation [44].

•Chemical industrial carcinogens (such as nitrosamines, azo-dyes, aromatic amines, vinyl chloride, organic solvents, pesticides, arsenic) or derived from tobacco combustion (benzopyrene) have also been implicated in hepatocarcinogenicity in experimental animal models. These substances could also play a role in human carcinogenesis, when patients live in highly industrialised areas.

•Radioactive elements, such as Thorotrast, can cause HCC, although much less frequently than angiosarcoma and cholangiocarcinoma [45].

•Lastly, tissue iron overload may act as a genotoxic co-carcinogen factor, as would suggest the mild parenchymal iron excess found in the non-tumourous liver tissue of most patients with non-cirrhotic HCC [18], [19], [46]. However, it is difficult to understand whether hepatic iron overload plays an independent role in HCC since the main risk factors of this neoplasm (age, male gender and disease severity) are associated with iron overload [47].

3.4. Inherited diseases

Non-cirrhotic HCC may also occur in the setting of rare inherited diseases such as:

•Metabolic diseases, including hereditary haemochromatosis [48], [49], alpha-1-antitrypsin (AT) deficiency [50], porphyria [51], hypercitrullinemia [52], and type I glycogen storage disease [53], [54].

Concerning the pathogenesis of liver cancer in storage diseases, a paradigmatic hypothesis has been provided for AT deficiency: cells accumulating aggregated mutant protein activate a number of stress response pathways such as Nuclear Factor kappa B, mitochondrial caspases, endoplasmic reticulum caspases and autophagy. The stress response, in turn, induces regenerative signals, stimulating proliferation of globule-devoid cells, that are a group of hepatocytes that lack protein accumulation for unknown reason, perhaps because younger [55].

•Congenital diseases, like Alagille's syndrome [56], or congenital hepatic fibrosis [57].

•Hepatic vascular pathology, which are generally primed by inherited coagulation disorders, such as Budd-Chiari syndrome [58], nodular regenerative hyperplasia [59] and hepato-portal sclerosis.

3.5. Sex hormones

Many case-reports describe the occurrence of HCC in non-cirrhotic patients taking anabolic C17-alkylated androgenic steroids for therapeutic purposes or to augment the muscular mass [60], [61]. A direct etiologic role of contraceptive steroids is less evident. Several studies demonstrated an increased risk (from 1.5 to 20.1) due to intake of oestrogens for 8 years or more, caused by their action as initiators or promoters of carcinogenesis [62], [63]. Oestrogens could also induce vascular change or cell hypertrophy, accelerating the clinical presentation of an already developing tumour [64].

HCC may also arise in the context of benign focal liver lesions, mainly the hepatocellular adenoma. The monoclonal mutations of both oncogenes and oncosuppressor genes recently described in this neoplasm are consistent with potential malignant transformation [65]. In particular, activating mutation of β-catenin, found in 15–19% of hepatocellular adenomas, may be associated with malignant transformation [65], [66].

3.6. Germ-line mutations

Familial aggregation of HCC has been reported, and a recent case–control study has shown that a family history of liver cancer strikingly increases the HCC risk regardless of the presence of HBV and HCV markers [67]. This was particular evident in men, in whom the odds ratio after adjustment for many confounding factors was 9.2 (95% confidence interval, 1.9–45.3). Unfortunately, in this article a sub-analysis focused on non-cirrhotic cases was not performed. Conceivably, the association between a positive family history and HCC development is the final result of environmental, behavioural, clinical and genetic risk factors. A genetic predisposition may be indeed inferred from the association between familial adenomatous polyposis and classic or fibrolamellar HCC reported in children [68].

Some molecular mechanisms of carcinogenesis operating in a non-cirrhotic liver are beginning to be delineated. Chaubert et al. [69] found a germ-line mutation of p16INK4 (MTS1) gene, a tumour-suppressor gene, in 3 out of 13 (23%) European patients with non-cirrhotic HCC, and in 1/12 cirrhotic HCC patients. Interestingly, an identical germ-line mutation has been found in a HCC patient and his mother diagnosed with a mixed hepatocellular/cholangiocellular carcinoma, supporting the existence of a familial form of carcinogenesis involving this gene. The confirmation of a hereditary component in the HCC risk awaits further studies of family clusters.

4. Hepatocarcinogenetic pathways

Some authors have hypothesised a different hepatocarcinogenetic pathway in HCC with and without cirrhosis. This assumption is based on the detection of a different scenario of genetic alterations found in non-cirrhotic HCC, that is, a trend towards a lower rate of p53 mutation and a higher prevalence of β-catenin mutation, p14 inactivation and global gene methylation [70].

A recent study analysed the presence of microsatellite instability (MSI), a sign of deficiency in DNA mismatch repair system, in 37 non-cirrhotic HCC patients with a histologically normal liver, low alcohol intake and absence of HBV and HCV infection [71]. Twenty-six (43%) presented MSI (16% of high grade) suggesting that, in this setting, an altered mismatch of repair genes is likely involved in hepatocarcinogenesis. Conversely, other authors did not find MSI in a small group of elderly patients with non-cirrhotic HCC [72].

5. Pathologic findings of HCC and the surrounding non-cirrhotic liver

The non-tumoural liver of these patients ordinarily presents with chronic hepatitis, varying degrees of fibrosis, steatosis, iron overload or other metabolic disorders, so that very few cases show a normal parenchyma [2], [6], [13]. Moreover, cell dysplasia, more often the large cell type, can be found in 27–40% of the cases [2], [18]. These figures decrease to 6–20% in the subgroup of non-fibrotic liver [13], [19].

A single large mass (around 10cm in many series) is the most common macroscopic feature of non-cirrhotic HCC at diagnosis (49–85%) [5], [6], [10], [73], [74]. The size is indeed bigger and the multinodular type of the tumour is less common (18% vs. 34%) than in cirrhosis [6], likely due to both the delayed diagnosis (see Section 6) and different mechanisms of hepatocarcinogenesis.

According to histological classification criteria of the World Health Organization (WHO), the trabecular type is the most frequent form (41–76%) in non-cirrhotic HCCs, as it is in cirrhotic subjects [2], [6], [8], [10], [19]. The scirrhous type and the hepato-cholangiocarcinoma mixed form are rarely found, but tend to be more frequent in a non-cirrhotic background [75], [76], whilst FL-HCC is almost exclusively limited to non-cirrhotic livers (11% vs. 1.5%) [8].

Two large series have reported that encapsulation is more common in non-cirrhotic tumours [8], [13], but this feature has not been confirmed in other studies [11], [12].

Finally, one large Western series showed that the extrahepatic extension of HCC (invasion of surrounding structures and/or metastases) is more common in non-cirrhotic patients with respect to their counterpart (20.5% vs. 6.5%) [6].

As reported above, the more advanced stage of the tumour at the time of diagnosis in non-cirrhotic patients may simply result from a delayed identification. However, a greater biological aggressiveness cannot also be excluded, as some authors reported poor cancer differentiation and early portal tree invasion [11], [13]. In any case, the available data on this issue are conflicting, as others have reported comparable tumour differentiation and portal tree invasion between cirrhotic and non-cirrhotic HCCs [6], [12]. Lastly, Nzeako et al. [8] found that cirrhotic patients, as compared with non-cirrhotic individuals, have a risk of harbouring grade 3–4 tumours and venous invasion of 1.7 and 1.6, respectively.

6. Diagnosis

In developed countries, a growing number of patients with chronic liver diseases evolving to high grade fibrosis or cirrhosis are now being included in scheduled ultrasonographic surveillance, as recommended by the recent international guidelines for HCC management [28], [29]. Surveillance in fact succeeds in achieving an early diagnosis of the tumour, usually before the clinical symptoms become manifest. Instead, in otherwise healthy patients (or with an undiagnosed liver disease), investigations able to detect HCC are generally prompted by the appearance of symptoms, such as abdominal pain or discomfort in the right upper quadrant, jaundice, nausea, or “toxic syndrome” (weight loss, fever, malaise, asthenia, anorexia). Haemoperitoneum due to cancer rupture may be a life-threatening presentation of non-cirrhotic HCC. However, the prevalence of this event, which occurs in less than 5% of unselected HCCs in Western countries [4], [77], [78], [79], is unknown for non-cirrhotic cases. Indeed, two European series have shown that non-cirrhotic HCC has a symptomatic presentation in about 70% of cases [4], [6]. In the remaining patients the cancer was incidentally detected in the course of investigations for extrahepatic disease or during a check-up [6]. Therefore, delayed diagnosis accounts for most differences in pathologic features between non-cirrhotic and cirrhotic cases.

Serum α-foetoprotein (AFP) exceeds 20ng/dL less frequently in non-cirrhotic than cirrhotic HCC patients (31–67% vs. 59–84%) [5], [6], [8], [10]. Rather than a diverse propensity to produce AFP, this phenomenon likely reflects the role of cirrhosis as an independent promoter of a moderate AFP elevation [6]. Indeed, the prevalence of level of AFP considered “diagnostic” for HCC (400ng/dL) is similar in the two groups [5], [6].

7. Treatment and survival

Hepatic resection is the best therapeutic choice for patients with non-cirrhotic HCC. Although data regarding its feasibility in unselected (non-surgical) series are not available, it is likely that the proportion of patients with non-cirrhotic HCC eligible for resection is much greater than the 12–28% reported for those with underlying cirrhosis [80], [81]. In fact, despite a larger tumour burden, the preserved function of non-cirrhotic liver generally offers the chance of performing very large resections (up to extended lobectomy) quite safely. Indeed, the perioperative mortality (0–6%) and morbidity (8–40%) of these patients are rather low [11], [73], [74], [82], [83], [84]. The post-operative overall survival (especially up to 2 years after hepatectomy and beyond) and the disease-free survival are better than in patients with underlying cirrhosis [11], [12], [13], [83], [85], the presence of which is the main determining factor of survival when they present with an early stage HCC [12], [22].

Table 4, Table 5 report the overall and disease-free survivals of patients resected for non-cirrhotic HCC observed in different surgical series. The 5-year overall survival rate ranged from 25% to 81%, with the best values achieved in patients with a non-fibrotic liver [83] and/or fulfilling the Milano criteria [22]. The 5-year disease-free survival rate ranged from 24% to 58%, with the best figure reported in the non-fibrotic patients.

Table 4.

Overall survival rate of non-cirrhotic HCC patients treated with hepatic resection.


Reference (no. of cases)	Survival rate
	1 year	3 years	5 years	10 years
Smalley et al. [10] (no. 29)a	n.r.	n.r.	25%	n.r.
Sasaki et al. [85] (no. 48)a	n.r.	n.r.	68%	n.r.
Bismuth et al. [82] (no. 68)a	74%	52%	40%	26%
Poon et al. [86] (no. 155)a	80%	59%	46%	37%
Chen et al. [20] (no. 254)	62%	46%	36%	n.r.
Nagasue et al. [87] (no. 100)a	97%	76%	50%	47%
Grazi et al. [11] (no. 135)a	84%	68%	51%	n.r.
Chang et al. [12] (no. 222)	n.r.	n.r.	53%	37%
Dupont-Bierre et al. [88] (no. 84)	78%	55%	44%	n.r.
Bège et al. [84] (no. 116)	72%	54%	40%	29%
Laurent et al. [89] (no. 108)a	n.r.	43%	29%	n.r.
Capussotti et al. [74] (no. 47)	n.r.	51%	31%	n.r.
Lang et al. [90] (no. 83)a	77%	48%	30%	n.r.
Lubrano et al. [83] (no. 20)b	85%	70%	64%	n.r.
Taura et al. [22] (no. 127)c	n.r.	n.r.	81%	49%
Rayya et al. [91] (no. 54)	69%	48%	48%	n.r.
Sotiropoulos et al. [92] (no. 61)a	84%	55%	40%	n.r.
Xu et al. [73] (no. 96)	84%	62%	48%	38%

n.r.: not reported.

Specified that patients underwent curative resection.

Only cases with non-cirrhotic non-fibrotic liver parenchyma.

Only patients meeting the Milano criteria [94].

Table 5.

Disease-free survival rate of non-cirrhotic HCC patients treated with hepatic resection.


Reference (no. of cases)	Survival rate
	1 year	3 years	5 years	10 years
Sasaki et al. [85] (no. 48)a	n.r.	58%	54%	n.r.
Bismuth et al. [82] (no. 68)a	70%	43%	33%	19%
Poon et al. [86] (no. 155)a	57%	42%	35%	35%
Chen et al. [20] (no. 254)	49%	31%	24%	n.r.
Nagasue et al. [87] (no. 100)a	79%	38%	31%	22%
Grazi et al. [11] (no. 135)a	78%	58%	46%	n.r.
Chang et al. [12] (no. 222)	n.r.	n.r.	37%	26%
Bège et al. [84] (no. 116)	60%	40%	33%	15%
Laurent et al. [89] (no. 108)a	n.r.	55%	43%	n.r.
Capussotti et al. [74] (no. 47)	n.r.	37%	34%	n.r.
Lubrano et al. [83] (no. 20)b	84%	66%	58%	n.r.
Sotiropoulos et al. [92] (no. 61)a	59%	39%	25%	n.r.
Xu et al. [73] (no. 96)	56%	40%	33%	27%

n.r.: not reported.

Specified that patients underwent curative resection.

Only cases with non-cirrhotic non-fibrotic liver parenchyma.

Recurrence, the rate of which varies from 27% to 73% (Table 6), is an independent predictor of overall survival [83]. Most recurrences (two out of three) develop in the first two post-operative years, but late recurrences can arise even 10 years after surgery. From 11% to 39% of recurrences are treatable with a second hepatectomy, with longer survivals when they are detected early [10], [22], [73], [82], [83], [84], [87]. These results indicate the need for a very stringent follow-up during the first two post-operative years and the value of a prolonged surveillance, encouraging an aggressive management of recurrences. Also, a recent study showed that systemic chemotherapy (epirubicin, cisplatin and 5-fluorouracil or epirubicin, cisplatin and capecitabine regimens) was well tolerated by 24 patients with non resectable HCC (metastatic or locally advanced) and it was associated with an objective response in one fourth of them, including two cases in whom a second line surgical resection became possible [93]. Generally speaking, however, systemic chemotherapy should be still considered as an experimental approach for HCC.

Table 6.

Time interval and rate of tumour recurrence in non-cirrhotic HCC treated with hepatic resection.


Reference	Time interval to recurrence	Recurrence rate (median follow-up)
Sasaki et al. [85]	n.r.	44% (n.r.)
Bismuth et al. [82]	Range 1–11 years	59% (n.r.)
Poon et al. [86]	n.r.	51% (n.r.)
Chen et al. [20]	Median: 8.6 months (range 10–164)	57% (11.8 months)
Nagasue et al. [87]	Mean: 2.4 years (range 1 month to 11 years)	51% (n.r.)
Grazi et al. [11]	n.r.	30% (28.4 months)
Chang et al. [12]	Range 6–108 months	59.5% (52.4 months)
Dupont-Bierre et al. [88]	Mean: 14 months (range 1–36 months)	41% (25 months)
Bège et al. [84]	Median: 14 months (range 2–155)	65% (79 months)
Laurent et al. [89]	Median: 23 months (range 0–180)	52% (6.8 months)
Lang et al. [90]	Median: 8 months (range 2–54)	63% (25 months)
Lubrano et al. [83]	Median: 15 months (range 2–70)	40% (n.r.)
Taura et al. [22]	n.r.	44% at 3 years 54% at 5 years
Rayya et al. [91]	n.r.	27% at 2 years
Sotiropoulos et al. [92]	Median: 17 months	62% (28 months)
Xu et al. [73]	n.r.	73% (57 months)

n.r.: not reported.

New molecular drugs, one of which (sorafenib) has been proven to be an effective therapy for unresectable HCC [95], have opened new perspectives for non-cirrhotic HCC. A phase 3 clinical trial with sorafenib about the prevention of tumour recurrence after surgery is ongoing (http://www.clinicaltrials.gov/ct2/show/NCT00692770?term=STORM&rank=2) and, if proven to be effective, this adjuvant treatment could also improve the prognosis of patients who undergo hepatic resection for a non-cirrhotic HCC.

Several studies have suggested that FL-HCC is less aggressive and has a better outcome than conventional HCC [15], [96], [97], [98], but not all series provide results consistent with this view [14], [99], [100], [101], [102], [103]. In fact, a recent study that adopted well-established criteria to diagnose FL-HCC has reported an aggressive behaviour of this neoplasm, leading to a 5-year survival rate after resection of only 45% [14]. In the same series, amongst the non-metastatic resectable cases, the prognosis of FL-HCCs and conventional non-cirrhotic HCCs was similar, and better than that of cancers occurring in a cirrhotic background. These results would suggest that the longer survival of FL-HCC patients is due to the absence of cirrhosis rather than to the clinico-pathological features of this tumour. However, the favourable outcome of some FL-HCCs could also be due to the low number of cytogenetic aberrations, as fewer chromosomal abnormalities have been reported in this type of tumour with respect to the conventional one [104].

Whether or not orthotopic liver transplantation (OLT) plays a role in the treatment of patients with non-cirrhotic HCC is matter of debate. A systematic review that included all reported cases of OLT for non-cirrhotic HCC performed from 1966 to 1998 has revealed that the long-term outcome of these patients is poor, the 5-year survival rate being 11.2% for conventional HCC and 39.4% for FL-HCC [105]. These dismal figures are justified by the advanced tumour stage at the time of OLT, which led to recurrence in about 50% of cases, mostly (75%) in the first 2 years, suggesting the frequent presence of micrometastases outside the liver. On the other hand, specific selection criteria for transplantation are lacking, and those commonly adopted for cirrhotic cases are inappropriate in this setting, since most tumours are outside the Milano criteria at the time of diagnosis, and those fulfilling these criteria are resectable. Moreover, the pressure toward OLT is curbed in these patients by the reported 5-year overall and disease-free survival rates achievable with resection of HCC within the Milano criteria. The outcome is in fact comparable to that expected in cirrhotic patients transplanted with a small HCC [12], [22]. Pragmatically, OLT could be seen as a salvage treatment to be reserved for patients with post-resection tumour recurrence in the liver, but judged to be at high risk of post-operative liver failure if newly resected, due to insufficient liver regeneration after the initial treatment.

Finally, only two studies have compared the cumulative survival of unselected non-cirrhotic and cirrhotic HCC patients, regardless of the type of treatment performed [8], [10]. In both series, the life expectancy tended to be slightly better in the absence of cirrhosis but, in any case, dismal (5-year survival: 5–15% vs. 0–2%).

8. Conclusions

As compared to a tumour developing in a cirrhotic liver, non-cirrhotic HCC presents some peculiarities:

(a)Lower male preponderance and a bimodal age distribution.

(b)Lower prevalence of the three main risk factors for HCC, that is, HBV and HCV infections and alcohol abuse.

(c)More advanced tumour stage at the time of diagnosis, since it is generally detected at a symptomatic stage.

(d)Much higher amenability to hepatic resection, due to the low risk of liver failure even in the case of extended parenchymal mutilation.

(e)Overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that achieved with liver transplantation in cirrhotic patients carrying an early tumour.

(f)Overall survival more strictly dependent on tumour burden (and its recurrence rate after resection) and much less influenced by liver function.

Conflict of interest

None declared.

Acknowledgment

The authors thank Ms. Susan West for the linguistic revision of the manuscript.

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Dipartimento di Medicina Clinica, Semeiotica Medica, Alma Mater Studiorum – Università di Bologna, Italy

Corresponding author at: Dipartimento di Medicina Clinica, Semeiotica Medica, via Albertoni, 15, 40138 Bologna, Italy. Tel.: +39 051 6362923; fax: +39 051 6362930.

PII: S1590-8658(09)00370-3

doi:10.1016/j.dld.2009.09.002

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