From liver cirrhosis to HCC

Hepatocellular carcinoma represents the main cause of death in patients with Child-A cirrhosis. Surveillance programs aimed at the early diagnosis of hepatocellular carcinoma, at potentially treatable stages, are mandatory in Child-A cirrhotic patients and in Child-B cirrhotic patients, provided liver transplantation can be pursued. Surveillance allows stage migration and in definite subgroups of patients, it improves survival as well. Even though several circulating markers have been tested, none of them, including serum AFP determination, is actually recommended in the setting of surveillance. Thus ultrasound scan is the only recommended test, and it should be performed at 6-month intervals. Upon detection of a new nodule, a diagnostic algorithm based on the size of the nodule should be applied. In the western countries, the BCLC proposal is the most widely used and validated staging system and it helps to choice of the best treatment option even though each patient deserves a multidisciplinary evaluation due to the complexity of the coexistence of two diseases: hepatocellular carcinoma and liver cirrhosis.     

Emergence of malignant lesions within an adenomatous hyperplastic nodule in a cirrhotic liver. Observations in five cases

Five cases of an adenomatous hyperplastic nodule or a similar lesion resected from a cirrhotic liver in which early malignant foci were seen as small nodule-in-nodule lesions are described. These hyperplastic lesions were detected by imaging diagnosis in patients with nonalcoholic cirrhosis, mostly during routine clinical follow-up. In 2 patients, recurrence of hepatocellular carcinoma occurred 11 mo and 15 mo postresection. Thus, these nodule-in-nodule lesions in an adenomatous hyperplastic nodule seem to represent an early stage of hepatocarcinogenesis in humans. In nonalcoholic cirrhotic patients from Japan and Southeast Asia, in whom hepatocellular carcinoma is endemic, an adenomatous hyperplastic nodule or a similar hyperplastic lesion that occurs in cirrhotic livers may be preneoplastic and already committed to malignant transformation.     

Incidental solitary hepatocellular carcinomas smaller than 1 cm in size found at autopsy: a morphologic study

The morphologic features and growth pattern of single hepatocellular carcinomas less than or equal to 1 cm in size, found incidentally at autopsy, were studied in nine cases. In all but one case, the hepatic parenchyma showed advanced cirrhosis. In three cases, the hepatocellular carcinomas were localized within a regenerative nodule as a form of "nodule within nodule." The carcinoma was rimmed by nonneoplastic hepatic tissue. A fourth carcinoma consisted of an expansile hepatocellular carcinoma nodule enclosed by a fibrous band of cirrhotic stroma. The remaining five cases consisted of hepatocellular carcinomas which infiltrated the surrounding regenerative nodules or hepatic lobules. These observations suggested that hepatocellular carcinomas arise within regenerative nodules, some of which still retain residual nonneoplastic tissue around the tumor. Others invaded the adjacent liver tissue. The grossly visible fibrous capsule, often seen in more advanced hepatocellular carcinomas, was absent in all cases. All of the hepatocellular carcinomas were well-differentiated. Four cases showed a trabecular pattern with slight sinusoidal dilatation, 3 showed a scirrhous pattern and 2 showed a compact pattern. Their histologic features included marked bile production, Mallory body formation by clusters of tumor cells, resistance to hemosiderin deposition in a markedly siderotic background and loss or decrease of reticulin fibers. These features were hallmarks of small hepatocellular carcinomas. Pathologists should study cirrhotic livers carefully so as not to miss small carcinomas. Clinicians should be aware that even small liver nodules may be hepatocellular carcinomas.     

Liver transplantation for hepatocellular carcinoma

Liver transplantation has become the best option in patients with decompensated cirrhosis and a small hepatocellular carcinoma. Indeed, because of the severity of cirrhosis, resection is usually impossible and in addition, transplantation provides survival rates close to those obtained in cirrhotic patients without malignancy (70 to 80% 3-year survival rate). In patients with a small hepatocellular carcinoma and compensated cirrhosis, both resection and transplantation can be performed. Because of the scarcity of donors, there have been reservations concerning transplantation in patients who otherwise could have undergone resection. However, there is increasing evidence that long-term results of transplantation are significantly superior to those of resection. Therefore, patients with a small hepatocellular carcinoma and compensated cirrhosis are increasingly considered as suitable candidates for transplantation. In contrast to cirrhotic patients with a small hepatocellular carcinoma, patients with large and/or multifocal tumors should no longer be transplanted because of a high rate of early recurrence and the accelerated course of tumor progression due to immunosuppression, both factors being the source of poor results. On rare occasions, hepatocellular carcinoma develops in patients without underlying liver disease. In such cases the tumor is usually recognized when it is large and symptomatic. The absence of underlying liver lesions offers the possibility of extended resection. However, in case of nonresectable (bilobar) tumors or limited recurrence after resection, transplantation may be considered due to the slow progression this subtype of hepatocellular carcinoma. Whatever the underlying liver parenchymal status, efforts should be made to reduce the risk of recurrence.     

Hepatocellular carcinoma in a patient with hereditary hemochromatosis without cirrhosis

Hepatocellular carcinoma in patients with hereditary hemochromatosis in the cirrhotic phase is one of the complications causing greatest mortality and may present in spite of removal of excess iron by bloodletting. Hepatocellular carcinoma is usually considered to occur in cirrhotic livers and consequently measures for the early diagnosis of this complication are only recommended in this type of patient. We present the case of a 69-year-old female patient with non-cirrhotic hemochromatosis who, 6 years after undergoing successful treatment, developed hepatocellular carcinoma. This observation should be added to the 12 cases published in the literature. Criteria should be established for the early diagnosis of hepatocellular carcinoma in patients with hereditary hemochromatosis, irrespective of whether they have cirrhosis.     

Focal ultrasound lesions in liver cirrhosis diagnosed as regenerating nodules by fine-needle biopsy

In the period 1985–1988, 62 focal liver lesions in 58 cirrhotic patients were studied by ultrasonography; 12 of these focal lesions were documented to be regenerating lesions by echo-guided fine-needle biopsy. During an average follow-up period of 10.2 months (range 3–22 months), hepatocellular carcinoma was subsequently found in 10 of the cases of regenerating nodules, whereas the initial diagnosis of regenerating nodule was confirmed in the remaining two cases. Based upon this finding, it is suggested that every focal mass visualized by ultrasonography in a cirrhotic liver should either be considered to be a neoplastic lesion or at least a preneoplastic lesion if the possibility of either a metastatic or benign lesion (eg, hemangiomas, focal fatty liver change areas) can be excluded. Therefore either fine-needle aspiration or biopsy of all ultrasonographically revealed mass lesions within a cirrhotic liver is advised, such that early appropriate treatment for hepatocellular carcinoma can be instituted.     

Unique hypervascular nodules in alcoholic liver cirrhosis: identical to focal nodular hyperplasia-like nodules?

BACKGROUND/AIMS: Currently, focal nodular hyperplasia (FNH)-like nodules in cirrhotic liver is spotlighted. Unique hypervascular nodules mimicking FNH-like nodule in alcoholic liver cirrhosis were clinicopathologically clarified. METHODS: Six resected and six biopsy cases of small hypervascular nodules found in alcoholic cirrhosis were studied clinicopathologically. RESULTS: All cases were male and consumed 90-150 g/day of ethanol for longer than 20 years, and hepatitis virus markers were negative. The nodules, 9-21 mm in diameter, were detected by ultrasonography during follow-up of alcoholic cirrhosis, and showed hypervascularity on angiography. Six patients were diagnosed as hepatocellular carcinoma and six were as hyperplastic nodule by biopsy, and the former six cases received partial hepatectomy. All of the resected nodules were completely or incompletely encapsulated. Histologically, all resected and biopsy nodules showed moderate increase of cell-density with an irregular trabecular pattern, and scar-like fibrosis with anomalous blood vessels, and unpaired arteries. All nodules showed marked or mild iron deposits in hepatocytes and/or kupffer cells, and a diffuse capillarization of the sinusoids. CONCLUSIONS: The nodules in the present series seem to fall in the same category as FNH-like nodules in cirrhotic liver, and should be taken account in screening programs including patients with alcoholic cirrhosis.     

The risk of hepatocellular carcinoma in cirrhotic patients with small liver nodules on MRI

BACKGROUND AND AIM: The presence of hepatocellular carcinoma (HCC) has important implications for patients with cirrhosis. Studies have not compared the risk of cancer in cirrhotic patients with small liver nodules to cirrhotic patients without nodules. Our aim was to determine the risk of HCC in cirrhotic patients with small liver nodules on MRI compared to those without nodules. METHODS: We conducted a prospective study to determine the rate of HCC in cirrhotic patients with and without liver nodules. Cases were patients with liver nodule(s) less than 2 cm on MRI and controls were cirrhotic patients without nodules. Kaplan-Meier estimates and multivariate analysis were performed to estimate the risk of HCC in the two groups. RESULTS: A total of 310 liver transplant candidates with a mean follow-up of 663 days were included in the study and 133 underwent liver transplant during follow-up. The 1-yr incidence of HCC in the liver nodule group and control group was 11% and 0.5%, respectively, p < 0.001. The adjusted risk for HCC in the liver nodule group was 25 times higher compared to the control group, HR = 25.1 [95% CI 8.0, 78.9]. In 133 candidates who underwent transplant with and without liver nodules the rate of HCC was 11 (50%) and 4 (3.6%), respectively, p < 0.001. CONCLUSION: The incidence of HCC in patients with small liver nodules is significantly higher compared to patients with cirrhosis without liver nodules. The presence of small liver nodules warrants increased imaging surveillance for HCC.     

Imaging diagnosis of hepatocellular carcinoma]

In patients with chronic liver disease, hepatocellular carcinomas are developed from regenerative nodule via dysplastic nodule and early hepatocellular carcinoma to advanced hepatocellular carcinoma during multistep hepatocarcinogenesis. In this article, imaging findings of various imaging modalities are described pertaining to the above mentioned hepatocellular nodules occurring in the cirrhotic liver, correlating with pathologic findings.     

Early diagnosis of liver cancer

Hepatocellular carcinoma is a frequent neoplasm that usually develops in patients with liver cirrhosis. Because it is the main cause of death in these patients, they should be included in a surveillance program in order to identify these tumors at an early stage and be able to indicate curative treatment (liver transplantation, surgical resection or percutaneous ablation therapy) and to reduce mortality. Surveillance should include determination of alpha-fetoprotein and abdominal ultrasound every 6 months. This strategy should only be applied to patients suitable to receive curative treatment if diagnosed of hepatocellular carcinoma. Using this approach, 40-80% of tumors identified are solitary at diagnosis, although only half of these patients can benefit from curative treatment.     

Histological and morphometrical indicators for a biopsy diagnosis of well-differentiated hepatocellular carcinoma.

Among 597 patients with nodular hepatic lesions who underwent ultrasonically guided needle biopsy, 305 were histologically confirmed as having hepatocellular carcinoma, and 37 patients had borderline lesions. Histological reexamination was correlated with morphometrical analysis on selected cases of well-differentiated, microtrabecular hepatocellular carcinomas (n = 29), borderline lesion (n = 10), typical (mid-sized and macrotrabecular) hepatocellular carcinomas (n = 15) and cirrhotic liver tissue obtained from extranodular hepatic parenchyma of hepatocellular carcinoma patients (n = 47). Morphometrical analyses revealed that the mean cell size and nucleocytoplasmic ratio were most useful for distinguishing well-differentiated, microtrabecular hepatocellular carcinoma from cirrhosis. These two parameters were well correlated with nuclear density. The grade of nuclear density, therefore, seemed to be a convenient semiquantitative indicator for diagnosing well-differentiated hepatocellular carcinoma. A comparison between intranodular and extranodular hepatic tissues was particularly important for its assessment. It is concluded from the results that hepatic nodules presenting a nuclear density larger than two times that of controls could be classified into the overt hepatocellular carcinoma group. From the statistical aspect, the possibility of microtrabecular hepatocellular carcinoma should be considered when a nodule has a nuclear density exceeding 1.3 times that of the extranodular tissue.     

Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment

Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared with those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared with nonresponders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients should be monitored after a sustained virological response is obtained, because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis.     

Cirrhotic patients and older people

The global population is aging, and so the number of older cirrhotic patients is increasing. Older patients are characterised by a risk of frailty and comorbidities,and age is a risk factor for mortality in cirrhotic patients. The incidence of nonalcoholic fatty liver disease as an aetiology of cirrhosis is increasing, while that of chronic viral hepatitis is decreasing. Also, cirrhosis is frequently idiopathic. The management of portal hypertension in older cirrhotic patients is similar to that in younger patients, despite the greater risk of treatment-related adverse events of the former. The prevalence of hepatocellular carcinoma increases with age, but its treatment is unaffected. Liver transplantation is generally recommended for patients 70 years of age. Despite the increasing prevalence of cirrhosis in older people, little data are available and few recommendations have been proposed.This review suggests that comorbidities have a considerable impact on older cirrhotic patients.     

Association of hepatocellular carcinoma and a hyperplastic nodule after phosphate diethylstilbestrol therapy

We treated a patient in whom a hepatocellular carcinoma and a hyperplastic nodule of the liver concomitantly grew in association with long term phosphate diethylstilbestrol therapy for a carcinoma of the prostate. A 72-year-old Japanese man was admitted for investigation of hepatic masses. A diagnosis of prostate carcinoma had been made seven years ago and phosphate diethylstilbestrol 200 mg daily had been prescribed. A small mass was first detected in the liver four years later and another mass appeared three years after the appearance of the first mass. Histology of the excised tissue showed the former mass to be a hyperplastic nodule and the latter one hepatocellular carcinoma. Findings of cirrhosis, hepatitis or fibrosis were nil but fatty metamorphosis of the hepatocytes was apparent. These histological changes were considered to be associated with long-term phosphate diethylstilbestrol therapy therefore careful follow-up using amazing diagnosis is recommended for patients on phosphate diethylstilbestrol therapy.     

Association of hepatocellular carcinoma and a hyperplastic nodule after phosphate diethylstilbestrol therapy

We treated a patient in whom a hepatocellular carcinoma and a hyperplastic nodule of the liver concomitantly grew in association with long term phosphate diethylstilbestrol therapy for a carcinoma of the prostate. A 72-year-old Japanese man was admitted for investigation of hepatic masses. A diagnosis of prostate carcinoma had been made seven years ago and phosphate diethylstilbestrol 200mg daily had been prescribed. A small mass was first detected in the liver four years later and another mass appeared three years after the appearance of the first mass. Histology of the excised tissue showed the former mass to be a hyperplastic nodule and the latter one hepatocellular carcinoma. Findings of cirrhosis, hepatitis or fibrosis were nil but fatty metamorphosis of the hepatocytes was apparent. These histological changes were considered to be associated with long-term phosphate diethylstilbestrol therapy therefore careful follow-up using imazing diagnosis is recommended for patients on phosphate diethylstilbestrol therapy.     

Resection and liver transplantation for hepatocellular carcinoma

Surveillance programs in cirrhotic patients enable the detection of hepatocellular carcinoma (HCC) at early stages, when the tumor is amenable to curative treatments (60% of cases in Japan; 25 to 40% in Europe and the United States). Resection is the mainstay of treatment in noncirrhotic patients and in cirrhotics with well-preserved liver function. In modern series, a perioperative mortality < or = 3% and 5-year survival rates above 50% are expected. Tumor recurrence complicates half of the cases at 3 years, but there is no unquestionable preventive treatment. Liver transplantation provides excellent outcomes applying the Milan criteria (single nodule < or = 5 cm or two or three nodules < or = 3 cm), with 5-year survival rates of 70% and low recurrence rates. Although expansion of selection criteria is appealing, it should be assessed in the setting of prospective well-designed studies. Intention-to-treat analysis has shown that wide extended indications lead to 25% 5-year survival rates. Living donor liver transplantation is having a minor impact in HCC management. Molecular markers are needed to better select the candidates for surgery.     

Halofuginone,a collagen type I inhibitor improves liver regeneration in cirrhotic rats

BACKGROUND/AIMS: Hepatic fibrosis involves excess deposition of extracellular connective tissue of which collagen type I fibers form the predominant component. Left untreated it develops into cirrhosis, often linked with hepatocellular carcinoma. Owing to the fact that cirrhotic liver regeneration is impaired, resection of hepatocellular carcinoma associated with cirrhosis is questionable. The aim of the present study was to determine the potential of halofuginone, a collagen type I inhibitor, in improving liver regeneration in cirrhotic rats. METHODS: Partial hepatectomy (70%) was performed in thioacetamide-induced cirrhotic rats fed a halofuginone-containing diet. Liver regeneration was monitored by mass and proliferating cell nuclear antigen. The Ishak staging system and hydroxyproline content were used to evaluate the level of fibrosis. RESULTS: Halofuginone administered prior to and following partial hepatectomy did not inhibit normal liver regeneration despite the reduced levels of collagen type I mRNA. When given to rats with established fibrosis, it caused a significant reduction in alpha smooth muscle actin, TIMP-2, collagen type I gene expression and collagen deposition. Such animals demonstrated improved capacity for regeneration. CONCLUSIONS: Halofuginone may prove useful in improving survival of patients with hepatocellular carcinoma and cirrhosis undergoing surgical resection.     

Serum levels of estrogens and testosterone in cirrhotic men with and without hepatocellular carcinoma

Serum levels of estrogens and testosterone were measured in 25 male patients with hepatocellular carcinoma and associated cirrhosis of the liver and in another 25 male patients with cirrhosis only. The two groups were statistically comparable in terms of age distribution, duration of liver disease, incidence of alcohol abuse, incidence of hepatitis B surface antigenemia, and grade of hepatic dysfunction. Estrone was significantly elevated in both groups of patients. Estradiol concentrations were above normal in 10 patients with hepatocellular carcinoma and in 11 with cirrhosis only. All patients had normal concentrations of estriol. There were no statistical differences between the two groups in either individual or total estrogen levels (estrone 0.05 less than p less than 0.1). Eight of the patients with hepatocellular carcinoma and 5 of the cirrhotics had lower testosterone levels than normal, but this difference was not significant. However, the estrone to testosterone ratios were significantly higher in the hepatocellular carcinoma group than in the cirrhosis group (p less than 0.05). The present study seems to indicate that hyperestrogenemia commonly seen in male patients with liver cirrhosis may play some role in hepatic carcinogenesis of cirrhotic livers. Further studies are needed to determine if the estrone to testosterone ratio is implicated in hepatocarcinogenesis in cirrhotic men.     

Macroregenerative Nodules of the Liver in Primary Biliary Cirrhosis: Report of Two Autopsy Cases

Recently, macroregenerative nodules of the liver have been regarded as putative precancerous lesions in human cirrhotic livers. We describe the morphologies of two macroregenerative nodules, one benign and another harboring a malignant hepatocellular focus, occurring in two patients with primary biliary cirrhosis, both at the cirrhotic stage. The macroregenerative nodules of both patients were found incidentally at autopsy. The macroregenerative nodule of case 1 (42-yr-old female) was composed of hyperplastic hepatocytes with little atypia. The macroregenerative nodule of case 2 (67-yr-old male) had a malignant focus, in addition to atypical hepatocytes. The atypical hepatocytes showed mild nuclear crowding, slightly increased nucleocytoplasmic ratio, and mild nuclear hyperchromasia. The malignant focus was free of stainable iron against the mildly siderotic background. These findings may support the concept that macroregenerative nodules can also be a preneoplastic lesion in primary biliary cirrhosis.