We sought to determine whether pseudocapsule (PS) features have prognostic implications in patients with metastatic renal cell carcinoma (mRCC).

We retrospectively reviewed 231 patients diagnosed with mRCC and treated with tyrosine kinase inhibitors; 188 patients with data available regarding the tumor-parenchyma interfacial PS of the primary tumor were enrolled for analysis. PS status was evaluated as intact (grade 0), merely involved (grade 1), penetrated (grade 2), and absent (grade 3). We applied the Kaplan-Meier method and Cox regression model to assess the survival impact.

Of the 188 patients, 19 (10.1%), 61 (32.4%), 96 (51.1%) and 12 (6.4%) had grade 0, 1, 2 and 3 PS, respectively. PS status was significantly associated with histology (P=0.0206), venous tumor embolus (P=0.0511), microvascular invasion (P=0.0108) and microsatellite formation (P=0.0097). Patients without a PS had the worst overall survival (OS), with a 3-year OS rate of 12.7%, whereas the OS rates for grades 0, 1 and 2 were 78.8%, 50.8% and 43.6%, respectively. Adjusted by other variables, grade 3 and grade 2 PS gave rise to a much higher risk of death across the cohort [hazard ratio (HR) =5.217, P=0.0182; HR =3.765, P=0.0281, respectively]. Sarcomatoid change was also an independent factor for OS (HR =2.932, P=0.0075). In contrast, microsatellite formation was not associated with survival in the cohort.

PS status has prognostic implications for OS in metastatic renal cancer. The absence of the PS and sarcomatoid change are two pathological features related to an extremely poor prognosis.

Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients.

Microvascular invasion is a well-known risk factor for hepatocellular carcinoma recurrence and mortality after hepatic resection and liver transplant. We sought to determine the clinico-pathological predictive factors associated with microvascular invasion.

We studied all patients who had undergone liver transplant because of hepatocellular carcinoma between July 2001 and December 2010 at our institution. Laboratory tests, clinical, and demographic data were obtained. Histopathological hematoxylin and eosin specimens were performed by a single liver pathologist.

During the study, 107 patients had LT because of HCC and they were selected for this investigation: 76 were men (71%) and 31 women (29%) (mean age, 56.8 ± 8.7 y). It was not possible to retrieve histologic samples from 5 patients; therefore, the final studied analysis was 102 individuals. Tumor recurrence rate was 12.9%. One-, three- and five-year overall survivals were 75.0%, 71.4%, and 67.5%. Mitotic index, histologic grade, tumor architecture, alpha-fetoprotein, and tumor fibrosis were associated with microvascular invasion on univariate analysis. Significant independent predictors of microvascular invasion on logistic regression analysis were histologic grade and mitotic index (P < .001; odds ratio, 3.16; 95% confidence interval, 1.525-4.156, and P = .046; odds ratio, 2.56; 95% confidence interval, 1.061-6.451).

Mitotic index and histologic grade are significant predictors of microvascular invasion. No other risk factor was identified in the logistic regression. As both pathological characteristics may be assessed by liver biopsy, these results highlight the importance of discussing pretransplant liver biopsy to access prognosis and define treatment modalities in the setting of liver transplant.

Downsizing strategies are often attempted for patients with hepatocellular carcinoma (hcc) before liver transplantation (lt). The objective of the present study was to determine clinical predictors of favourable survival outcomes after transarterial chemoembolization (tace) before lt for hcc outside the Milan criteria, so as to better select candidates for this strategy.

In this retrospective study, patients with hcc tumours either beyond Milan criteria (single lesion > 5 cm, 3 lesions with 1 or more > 3 cm) or at the upper limit of Milan criteria (single lesions between 4.1 cm and 5.0 cm), with a predicted waiting time of more than 3 months, received carboplatin-based tace treatments. Exclusion criteria for tace included Child-Pugh C cirrhosis or the presence of portal vein invasion or extrahepatic disease on imaging. Only patients without tumour progression after tace underwent lt.

Of 160 hcc patients who received liver grafts between 1997 and 2010, 35 were treated with tace preoperatively. The median of the sum of tumour diameters was 6.7 cm (range: 4.8-8.5 cm), which decreased with tace to 5.0 cm (range: 3.3-7.0 cm) at transplantation (p < 0.0004). The percentage drop in alpha-fetoprotein (αfp) was a positive predictor (p = 0.0051) and the time from last tace treatment to transplantation was a negative predictor (p < 0.0001) for overall survival.

The percentage drop in αfp and a shorter time from the final tace treatment to transplantation significantly predicted improved overall survival after lt for hcc downsized with tace. As a serum marker, αfp should be followed when tace is used as a strategy to stabilize or downsize hcc lesions before lt.

The purpose of the study was to determine significant imaging features to differentiate between infiltrative hepatocellular carcinoma (HCC) and confluent fibrosis (CF) in liver cirrhosis using Gd-EOB-DTPA-enhanced 3-T magnetic resonance imaging.

Nineteen infiltrative HCCs and eight CFs were included. We evaluated the difference in imaging findings and apparent diffusion coefficient (ADC) between the two entities. We compared T2-weighted image (WI) and hepatobiliary phase (HBP) in terms of the clarity of the lesion outer margin.

Seventeen infiltrative HCCs showed lobulated margin, while focal CFs showed either straight (n=3) or irregular margins (n=5) (P=.001). All infiltrative HCCs had intact or bulging contours, and all focal CFs showed capsular retraction (P=.001). Fourteen infiltrative HCCs and two focal CFs showed arterial enhancement (P=.035). The ADC of infiltrative HCCs was significantly lower than that of CFs (P=.001). Satellite nodules were noted in 10 infiltrative HCCs. In terms of outer margin clarity, infiltrative HCCs showed a more distinct margin on HBP than on T2-WI (P=.005), while these two sequences were not significantly different in focal CFs (P=1.000).

HBP improved the imaging characteristics of infiltrative HCC, allowing it to be distinguished from focal CF. Infiltrative HCC showed lower ADC values than focal CF. Lobular configuration, contour bulging, enhancement pattern, associated satellite nodules and portal vein thrombosis were still found to be highly suggestive MR findings for infiltrative HCC.

To evaluate the characteristics of hepatocellular carcinoma (HCC) with a pseudocapsule on dynamic magnetic resonance (MR) images.

The institutional review board approval was obtained, and the requirements for informed consent were waived for this retrospective study. Dynamic MR studies of surgically resected 106 HCCs in 93 patients were retrospectively reviewed. A false-positive fibrous capsule (FC) on dynamic MR images was considered to be a pseudocapsule. Pathologic specimens of HCCs with a pseudocapsule were reviewed. The differences in size, tumor grade, the degree of liver fibrosis and background liver diseases, and the incidence of vascular invasion were compared between HCCs with a pseudocapsule on MR images and those with FC at histologic examination by using Student t, Kruskal-Wallis, and chi(2) tests.

The sensitivity, specificity, and accuracy of dynamic MR in the diagnosis of histologic FC were 94.0% (47 of 50), 73.2% (41 of 56), and 83.0% (88 of 106), respectively. There were 15 (14.2%) HCCs with a pseudocapsule. The pathologic specimens suggested possible causes of the pseudocapsule that included prominent sinusoids (n = 6), peritumoral fibrosis mimicking bridging fibrosis (n = 3), and both (n = 5). In one case, the capsulated HCC was surrounded by a well-differentiated HCC component. The mean size of a HCC with a pseudocapsule tended to be smaller than that with histologic FC, although it was not significant (mean +/- standard deviation: 2.8 cm +/- 1.0 vs 3.5 cm +/- 2.0, P = .09). Liver cirrhosis was less frequent in HCCs with a pseudocapsule than in those with a histologic FC (one of 14 [7.1%] vs 20 of 49 [40.8%], P < .05). The tumor grades were not significantly different, and the incidence of vascular invasion after standardizing the tumor size (<or=4 cm) was similar (five of 14 [35.7%] vs 12 of 37 [32.4%]).

Dynamic MR imaging is accurate in depicting FC in HCCs. HCC with a pseudocapsule at MR possibly consists of peritumoral sinusoids and/or fibrosis. The pseudocapsule may be similar to histologic FC in terms of tumor invasiveness.

Features of hepatocellular carcinoma (HCC) observed by contrast-enhanced ultrasonography (CEUS) were compared to pathological features of corresponding resected HCC specimens, to evaluate the ability of CEUS to depict the pathological features of HCC. We investigated 50 HCC nodules that were treated by surgical resection. All nodules had been examined by CEUS with intravenous contrast agent (Levovist) before surgery. CEUS findings were divided into three phases for evaluation and classification of enhancement patterns: two vascular phases (arterial phase and portal venous phase) and the delayed phase. Pathological examination focused on differentiation and on the presence or absence of a tumor capsule, intratumoral septum, and intratumoral necrosis. All 21 nodules that showed a linear or annular vessel around the tumor margin in the arterial phase had capsular formation. Of the 27 nodules that showed heterogeneous perfusion in the portal venous phase, 21 (77.8%) had an intratumoral septum and 23 (85.2%) showed intratumoral necrosis. All nodules that were depicted as a defect with an unclear margin in the delayed phase were well-differentiated HCCs, whereas all nodules that were depicted as a defect with a clear margin were moderately or poorly differentiated HCCs. From our observations, the arterial, portal venous, and delayed phases of CEUS could reflect different pathological aspects of HCC. Some pathological characteristics of HCC might be evaluated preoperatively and non-invasively, by means of combined analysis of three phases of CEUS findings.

This study is a retrospective evaluation of the correlations between the presence and integrity of the capsule of nodular hepatocellular carcinomas (HCC) by dynamic CT and histopathology, with histopathologic evidence of tumor propagation to surrounding hepatic parenchyma. Dynamic CT scans of 75 nodular HCCs in 73 patients (61 men, 12 women; age range, 32-81; mean, 53) were evaluated regarding capsule visualization and integrity. Histopathologic findings of HCCs in resected specimens were correlated with the presence of a capsule, tumor invasion onto the capsule, and with the presence of microvascular emboli in the surrounding liver parenchyma. On histopathologic examination, capsules were present in 57 of 75 nodular HCCs; the capsules were invaded by tumor in 18 nodules and there were microvascular emboli around the nodular HCC in 49 cases. Capsule visualization by CT was correlated with the presence of capsule by histopathology (P<0.001). Disruption of capsule by CT was correlated with tumor invasion by histopathology (P=0.003) and with microvascular tumor emboli (P<0.001). The presence and structural integrity of HCC capsules on CT was closely correlated with the presence of capsule on histopathology and the absence of microvascular tumor emboli.

Vascular invasion and high histologic grade predict poor outcome after surgical resection or liver transplantation for hepatocellular carcinoma (HCC). Despite the known association between tumor size and vascular invasion, a proportion of patients with large tumors can be treated surgically with excellent outcomes. Clarification of the association between tumor size, histologic grade, and vascular invasion has implications for patient selection for resection and transplantation. The objective of this study was to examine the relationship between HCC tumor size and microscopic (occult) vascular invasion and histologic grade in a multicenter international database of 1,073 patients who underwent resection of HCC. The incidence of microscopic vascular invasion increased with tumor size (< or =3 cm, 25%; 3.1-5 cm, 40%; 5.1-6.5 cm, 55%; >6.5 cm, 63%) (P < 0.005). Both size and number of tumors were important factors predicting vascular invasion. Among all patients with tumors 5.1 to 6.5 cm, microscopic vascular invasion was present in 55% compared with 31% for all patients with tumors 5 cm or smaller (P < 0.001). Among patients with solitary tumors only, microscopic vascular invasion was significantly more common in tumors measuring 5.1 to 6.5 cm (41%) compared with 27% of tumors 5 cm or smaller (P < 0.003). Tumor size also predicted histologic grade: 36% of tumors 5 cm or smaller were high grade, compared with 54% of lesions 5.1 to 6.5 cm (P = 0.01). High histologic grade, an alpha-fetoprotein level of at least 1000 ng/mL, and multiple tumor nodules each predicted occult vascular invasion in tumors larger than 5 cm. The high incidence of occult vascular invasion and advanced histologic grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients.

To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC).

HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate.

Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC.

On histologic examination, 38% of the entire group of 48 patients did not meet the "Milan criteria" and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates.

The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.

Encapsulation in hepatocellular carcinoma is associated with decreased invasiveness and improved survival in several series. Although active fibrogenesis by myofibroblasts has been demonstrated in the capsule, it is unclear if the capsule results from a general increase in peritumoral fibrosis, or an inherently less invasive tumor phenotype. The relationship between collagen deposition within tumor stroma, presence of cirrhosis and invasiveness also needs clarification.

We performed immunohistochemistry for collagens I, III, IV and VI on sections of encapsulated and non-encapsulated hepatocellular carcinoma, arising in cirrhotic and non-cirrhotic livers. Staining was graded semi-quantitatively in tumor stromal elements and adjacent parenchymal sinusoids. The relationship of this staining with encapsulation, cirrhosis, and vascular invasion was analyzed.

Formation of a discrete capsular layer was associated with reduced vascular invasion, but not with a pervasive increase in peritumoral fibrosis. Increased collagen I content of tumor stroma and adjacent parenchymal sinusoids was associated with non-encapsulated tumors and vascular invasion. The presence of cirrhosis had little effect on capsule composition.

Encapsulation of hepatocellular carcinoma reflects reduced invasiveness, rather than increased peritumoral collagen synthesis, which may instead enhance invasion. Increased intratumoral collagen I protein is also associated with increased tumor invasiveness. Pre-existing cirrhosis has little effect on tumor progression, possibly because the characteristics of cirrhosis are overwhelmed by tumor-induced changes in the adjacent parenchyma.

Although controversy persists about the influence of cirrhosis on the incidence of portal vein invasion and other prognostic indicators of recurrence and survival (e.g., histologic grade, mitotic activity, multiplicity), it is clear that the degree of cirrhosis is important for the long-term survival of patients with HCC. Multicentricity is especially important because it reflects the field carcinogenesis associated with viral hepatitis and particularly chronic HCV infection [59]. A better understanding of the different mechanisms linked to tumor recurrence will help select the best candidates for curative surgery and help tailor adjuvant therapy, such as interferon therapy, to each patient [60]. Finally, the importance of vascular invasion, number of tumors, and tumor size of HCCs in addition to the effect of fibrosis has led Vauthey et al [20] to propose a simplified staging of HCC with better prognostication of survival.

To evaluate the treatment outcome, patterns of failure, and prognostic factors for patients with unresectable hepatocellular carcinoma (HCC) treated with local radiotherapy alone or as an adjunct to transcatheter arterial chemoembolization (TACE).

From March 1994 to December 1997, 25 patients with unresectable HCC underwent local radiotherapy to a portion of the liver. Twenty-three patients were classified as having cirrhosis in Child-Pugh class A and 2 in class B. Mean diameter of the treated hepatic tumor was 10.3 cm. Mean dose of radiation was 46.9 +/- 5.9 Gy in a daily fraction of 1.8-2 Gy. Sixteen patients were also treated with Lipiodol and chemotherapeutic agents mixed with Ivalon or Gelfoam particles for chemoembolization, either before and/or after radiotherapy. Percutaneous ethanol injection therapy (PEIT) was given to one patient. All patients were monitored for treatment-related toxicity and for survival and patterns of failure.

In a median follow-up period of 23 months, 11 patients were alive and 14 dead. The median survival duration from treatment was 19.2 months with a 2-year survival of 41%. Only 3 of 25 patients had local progression of the treated hepatic tumor. The recurrences were seen within the liver or extrahepatic. The 2-year local, regional, and extrahepatic progression-free survival rates were 78%, 46%, and 39%, respectively. The local control ranked the highest. Patients with Okuda Stage I disease had significantly longer survival than those with Stage II and III (p = 0.02). Patients with T4 disease (p = 0.02) or treated with radiotherapy alone (p = 0.003) had significantly shorter survival. T4 disease (p = 0.03) and pretreatment alpha-fetoprotein level of more than 200 ng/ml (p = 0. 03) were associated with significantly worse regional progression-free survival. A significant difference was observed in both regional progression-free survival (p = 0.0001) and extrahepatic progression-free survival (p = 0.005) between patients with and without portal vein thrombosis before treatment. The presence of satellite nodules had a significantly worse impact on regional progression-free survival (p = 0.04) and extrahepatic progression-free survival (p = 0.03). Patients with hepatic tumor more than 6 cm in diameter or portal vein thrombosis tended to have shorter survival. Radiation-induced liver disease (RILD) and gastrointestinal bleeding were the most common treatment-related toxicities.

Radiotherapy is effective in the treatment of patients with unresectable HCC. Its effect appeared to be more prominent within the site to which radiation was given. The combination of TACE and radiation was associated with better control of HCC than radiation given alone, probably due to the selection of patients with favorable prognosis for the combined treatment. A dose-volume model should be established in the next phase of research in the treatment of unresectable HCC.

Hepatocellular carcinoma (HCC) is increasing in many countries as a result of an increase in hepatitis C virus (HCV) infection since World War II. The epidemiology of HCC varies with the global region. There have been conflicting observations from different parts of the world concerning the frequency of HCC in patients who in the distant past had post-transfusion non-A, non-B hepatitis. The genetic basis of hepatocarcinogenesis is still poorly understood. In hepatitis B virus (HVB) associated HCC, codon 249 mutation in the p 53 gene seems more related to exposure to aflatoxin B1 than to hepatocarcinogenesis itself. HCC that occurs in children in high HBV endemic regions could be associated with germ-line mutations, but little information is available; not much is known about chemical hepatocarcinogens in the environment other than aflatoxins. The X gene of HBV seems to play an important role in HBV-associated hepatocarcinogenesis. There are preliminary observations on the molecular mechanism of HCV-associated HCC, such as HCV core protein inducing HCC in transgenic mice and the NS3 genome transforming NIH 3T3 cells. Pathological distinction between preneoplastic and very early transformed lesions still depends on classical morphology, and a more genetically oriented differential diagnosis is required. Clinical diagnosis based on modern imaging has improved greatly, but is still unsatisfactory in the differential diagnosis of preneoplastic and early transformed nodules, because the vasculature changes that occur within the nodule are not accurately discerned with the current imaging. Use of sensitive des-gamma-carboxy prothrombin (PIVKA II) assay, and lectin affinity chromatography separating HCC specific subspecies of AFP molecules with a more practical biochemical technique will further improve diagnosis. Early diagnosis and transplantation are the best treatment at the moment, but transplantation is not widely available because of the donor shortage. Despite successful resection, the remnant cirrhotic liver frequently develops new HCC lesions, seriously curtailing long-term survival. All-out efforts should be directed to the prevention of HCC, through prevention of viral hepatitis, prevention of acute hepatitis from becoming chronic, prevention of chronic hepatitis from progressing to cirrhosis, and prevention of the cirrhotic liver from developing HCC (chemoprevention). At the moment, very few such studies exist.

Several aspects are revised on the subject hepatocellular carcinoma related to its incidence/prevalence, risk and prognostic factors, cellular proliferation, pathological aspects, progression of chronic hepatitis B and C to cirrhosis and hepatocellular carcinoma, natural course of hepatocellular carcinoma, some clinical data, morphological diagnosis with special emphasis on radiological findings as ultrasound, dynamic computed tomography and magnetic resonance imaging, color-power Doppler, tissue and contrast harmonic.

To compare the magnetic resonance (MR) imaging findings of primary hepatocellular carcinoma (HCC) in cirrhotic versus noncirrhotic livers.

MR images in 36 patients with HCC (30 men and she women aged 42-84 years [mean age, 65 years]) were retrospectively reviewed. The number and size of hepatic lesions were assessed. Lesion margins were categorized as well circumscribed or ill defined. The presence of a capsule, intratumoral high signal intensity on T1-weighted MR images, and a stellate scar were determined.

Eleven (31%) patients had MR imaging evidence of cirrhosis, and 25 (69%) did not: Lesions in cirrhotic livers differed significantly from those in noncirrhotic livers in terms of size (22 cm2 vs 99 cm2, P < .05), frequency of a solitary lesion (27% vs 72%, P < .05), and frequency of a central scar (6% vs 50%, P < .05). There was no difference between the cirrhotic and noncirrhotic livers with regard to tumor margin, intratumoral high signal intensity on T1-weighted images, or tumor capsule.

Differences exist in the MR imaging appearance of HCC between patients with and those without cirrhosis, although there is overlap of imaging findings.

Prognostic factors in hepatocellular carcinoma (HCC) conventionally consist of staging with the tumour node metastasis system and grading by tumour cellular differentiation. There are also other factors useful in prognostication but most of them are clinical. With new discoveries in the pathobiology of cancers and introduction of new medical technology, pathological and biological factors of HCC in relation to prognosis have been studied quite extensively. Morphological features of the tumour, both gross and histological, have been found to be significantly related to tumour recurrence and patient survival. Recently, applications of new antibodies and techniques have enabled studies on cellular proliferation using different antibodies such as those for proliferating cell nuclear antigen and Ki-67 protein. These studies on cellular proliferation, as well as assessment of argyrophilic nucleolar organizing regions, have been shown to provide good prognostic significance. Flow cytometric studies on DNA ploidy and studies on expression of genes including the p53 gene, hormone receptors and others show less unanimous results in their prognostic significance. The influence of gender on survival is also reviewed. In conclusion, pathological and biological factors are useful and help to guide clinicians in the management of patients and in assessment of long-term prognosis.

The postoperative intrahepatic recurrence of hepatocellular carcinoma (HCC) is high. It is difficult to distinguish whether the recurrence is metastatic or new primary lesion. To determine the malignant potential of HCC itself, we analyzed the risk factors associated with portal venous invasion since this is direct evidence of tumor invasiveness.

Two hundred and thirty-two patients who underwent curative hepatectomy for HCC without preoperative treatments were included in this study, because preoperative treatment caused the tumor to undergo a variety of histologic change. We analyzed the risk factors linked to portal venous invasion by both univariate and multivariate analyses.

In an univariate analysis, tumors larger than 3 cm, high histologic grade (III or IV), the presence of fibrous capsule, necrosis, mitotic rate of more than 4/10 high power fields, peliotic change, presence of tumor giant cells, high platelet count, low level of indocyanine green retention rate at 15 minutes, and the absence of cirrhosis were significantly correlated with portal venous invasion. In multiple stepwise logistic regression analysis, tumors larger than 3 cm, high histologic grades, and the presence of fibrous capsule were strong predictors of portal venous invasion by HCC.

Because the blood vessels of the fibrous capsule were frequently invaded by cancer cells, it may have been possible to prevent postoperative metastatic recurrence if HCC were resected before becoming large enough to have a fibrous capsule.

Ninety-seven patients with small hepatocellular carcinomas (HCCs) measuring 3 cm or less in size and three patients with adenomatous hyperplasia who underwent radical hepatic resection were examined in this study.

The lesions were classified into four groups according to the following histologic grading criteria: group A, adenomatous hyperplasia (n = 3); group B, early HCC (n = 6); group C, well-differentiated HCC (wHCC) (n = 32); and group D, moderately or poorly differentiated HCC (n = 59). The involvement factors that seemed to be important or to characterize the progression of HCC and the survival rates were compared among the four histologic groups.

The frequency of patients with tumors larger than 2.0 cm in size and that of patients with 200 or more ng/ml serum alpha-fetoprotein increased with the progression of histologic malignancy. Tumor staining on the angiogram, capsular formation, and extranodular invasion were never seen in groups A and B, but they began to appear in group C and increased remarkably in group D. The 5-year survival rates of the patients in groups B, C, and D were 100%, 60%, and 27%, respectively, and statistically significant differences were seen among them. In comparative evaluation of the group C patients the lesions that showed no tumor staining had no capsule, and those that had no capsule had no extranodular invasion. The 5-year survival rate of patients with wHCC without extranodular invasion (81%) was significantly higher than that of patients with extranodular invasion (35%) (p < 0.05).

It may be recommended to provide the category of wHCC without extranodular invasion for pathologic classification of clinically early HCC (i.e., HCC of high curability).

Prognostic analysis on hepatocellular carcinoma (HCC) in patients undergoing hepatectomy is necessary to determine the clinical value of hepatectomy on prognosis.

Survival and disease-free survival were analyzed in 104 HCC patients undergoing hepatectomy using clinicopathologic factors by univariate and multivariate analyses. The value of the International Union Against Cancer (UICC) TNM classification on prognosis was assessed in the patients.

In multivariate analysis, portal vein invasion was the most influential factor. The difference between stage 1 and 2 or stage 3 and 4A using UICC's TNM classification was not significant with respect to survival or disease-free survival. The UICC's classification was modified as follows; stage 1, solitary tumor without vascular invasion; stage 2, solitary or multiple tumor(s) involving adjacent to vessel branch; stage 3, tumor(s) involving major vessel branch or with regional lymph nodal metastasis; and stage 4, tumor(s) with distant metastasis. The differences between each stage in the modified classification were significant with respect to disease-free survival.

The UICC's TNM classification was not of prognostic significance. Further studies on survival in patients with HCC are necessary to evaluate the value of the UICC's TNM classification; some modification may be necessary.

Screening is widely used to detect early hepatocellular carcinoma in Asian patients with cirrhosis. Its effectiveness in Caucasian patients has been suggested, but remains to be proven. Therefore we prospectively studied 118 French patients (68 males, 50 females, age 55 +/- 12) with Child-Pugh A or B cirrhosis (alcoholic in 82) and without detectable hepatocellular carcinoma. The screening program consisted of ultrasound examination of the liver and determination of blood alpha-fetoprotein and des-gamma-carboxyprothrombin levels every 6 months. The median follow up was 36 months (range 4-48). Only four patients were lost to follow up. Fourteen hepatocellular carcinomas were detected, in six cases by ultrasonography alone, in four by alpha-fetoprotein alone, in three by ultrasonography and alpha-fetoprotein and in one case by ultrasonography and des-gamma-carboxyprothrombin, but never by des-gamma-carboxyprothrombin alone. The tumor presented as a unique nodule in nine patients. The tumor was less than 3 cm in diameter without portal thrombosis or metastasis in three cases. Surgery was performed in only one case. In this study, the annual incidence of hepatocellular carcinoma was high (5.8%), but the screening methods used did not effectively identify potentially resectable tumors in Caucasian patients with cirrhosis.

Although many studies have been concerned with a clarification of the relation between various clinicopathologic factors and the prognosis of operated hepatocellular carcinoma (HCC), few studies have focused on the prognostic predictability of mitotic index and anti-hepatitis C virus (anti-HCV).

One hundred forty cases of HCC with hepatic resection were observed from 1 to 11 years, and the relationship among various clinicopathologic factors, including the mitotic index and anti-HCV, and prognosis was evaluated.

Age at the time of operation, positive results for hepatitis B surface antigen or anti-HCV, accompanying cirrhosis, and the degree of tumor necrosis due to transarterial embolization did not influence the prognosis significantly. Patients with hepatitis C virus-related cases had a better prognosis than patients with hepatitis B-related cases. Patients with a single and small carcinoma smaller than 2 cm had a significantly better prognosis than those who had larger and/or multiple tumors. A better prognosis also was observed in the carcinomas with no histologic invasion into portal vein branches, low Edmondson grades, and low mitotic activities when compared with the counterpart of each group. Among these factors, the mitotic index was correlated best with prognosis in the current study.

The examination of mitotic index was quite simple, and the index was a helpful factor in predicting prognosis.

This study assesses the usefulness of intra-arterial injection of iodized oil (Lipiodol) as a tool for evaluating the therapeutic choice in a series of 72 consecutive patients with hepatocellular carcinoma (HCC). In 52 of these patients a scintigraphic study of the biodistribution of iodized oil was done, using 131I-iodized oil injection. A single tumor was detected in only 17 cases; 18 patients had a tumor involving only 1 lobe; in 7 cases CT scan disclosed a minute nodule in the opposite lobe of the main tumor. Eighteen patients had a portal thrombosis; in 12 of these cases CT scan showed iodized oil in the tumor emboli. The degree of intratumoral retention of iodized oil depended on the size of tumors and on the presence of arterioportal shunts. Our study demonstrates that only a few patients (4%) with HCC might benefit from curative surgery. The therapeutic benefit of methods using iodized oil injection might be estimated by means of its biodistribution variables (CT and/or scintigraphic data).

Antihepatitis C virus (HCV) status was investigated in 100 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) between 1980 and 1989. The clinicopathological findings and operative results, in patients with or without HCV marker, were compared retrospectively. The positivity rate of anti-HCV was 51 per cent. In this group there was a higher mean age, fewer symptoms, raised alanine aminotransferase level, higher 15-min indocyanine green clearance rate and earlier tumour stage compared with the anti-HCV negative group. Positive tumour margins and vascular invasion were seen less frequently in the anti-HCV positive group. HCC with HCV marker showed characteristic features of chronic non-A non-B hepatitis and of HCC originating from liver cirrhosis. There was a better cumulative 1-year survival rate for anti-HCV positive patients, but 3- and 5-year survival rates after hepatectomy were similar in both groups. Although HCV-related HCC had typical features of chronic non-A non-B hepatitis and a relatively early stage of tumour, biological features and operative results were similar with or without the HCV marker.

One hundred eighty-nine surgically resected hepatocellular carcinomas (HCC) were analyzed to study tumor encapsulation and the pathologic features that might account for the better prognosis in relation to it, and to examine the prognostic and pathobiologic significance of capsular thickness. Tumor encapsulation was found in 72 (46.8%) of the 154 cases with adequate histologic sections of the tumor-nontumor junctions. Encapsulated tumors showed a much lower incidence of direct liver invasion (P less than 0.0001), tumor microsatellites (P less than 0.0001), and venous permeation (P = 0.02) when compared with nonencapsulated ones. Significantly better disease-free and actuarial survival times were observed in patients with encapsulated tumors (medians, 9.9 and 18.3 months, respectively), compared with those with nonencapsulated ones (medians, 4.0 and 5.9 months, respectively; P = 0.0001 and 0.001, respectively). The incidence of tumor encapsulation did not increase or decrease with tumor size. Tumor encapsulation did not correlate with the presence of cirrhosis or the abundance of tumor stroma, suggesting that formation of the tumor capsule was independent of the degree of fibrosis within and outside the tumor. Among the 72 cases of encapsulated HCC, the capsular thickness ranged from 0.13 to 3.09 mm (mean +/- standard deviation = 0.87 +/- 0.59 mm), and it was unrelated to tumor size or presence of cirrhosis. Although it was apparent that a lower extensive tumor invasiveness contributed significantly to the better prognosis in encapsulated HCC, there was no correlation between capsular thickness and liver invasion, microsatellites, venous permeation, or survivals. Therefore, the thickness of tumor capsules was not helpful in prognostication.

Insulin-like growth factor II is a fetal growth factor structurally and functionally related to insulin and insulin-like growth factor I. Its mRNA expression is developmentally regulated in human liver, the reexpression of insulin-like growth factor II fetal transcripts being often observed in primary liver cancer. Insulin-like growth factor II and alpha-fetoprotein mRNAs were studied in 16 human primary liver cancers, most of which were highly differentiated. Hepatitis B virus transcripts were also analyzed in the tumors from hepatitis B virus chronic carriers. alpha-Fetoprotein mRNA was detected in only four tumors and in one nontumorous cirrhotic tissue; all these samples also displayed insulin-like growth factor II fetal transcripts. Furthermore, fetal insulin-like growth factor II mRNAs were observed in five tumors and six nontumorous cirrhotic areas not expressing alpha-fetoprotein mRNA. The presence of hepatitis B virus RNA was only observed in tissues not expressing alpha-fetoprotein or fetal insulin-like growth factor II mRNA. In conclusion, fetal insulin-like growth factor II transcripts are more frequently observed than alpha-fetoprotein mRNA in highly differentiated liver cancers and in surrounding cirrhotic areas. The reexpression of fetal insulin-like growth factor II transcripts might then be a marker of early steps of liver cell transformation.

The prognostic value of nuclear DNA content was studied retrospectively using flow cytometry in 203 cases of resected hepatocellular carcinoma. The occurrence of DNA aneuploidy, which was detected in 50% of patients, correlated significantly with tumor size and the presence of vascular invasion or intrahepatic metastasis. Overall, patients with DNA aneuploid tumors had a significantly worse prognosis than those with DNA diploid tumors (P less than 0.001) and, also in subdivided groups by tumor size (P less than 0.01). Among DNA aneuploid patients, the survival times were significantly shorter for patients with a low DNA index (less than 1.5) than for those with a high DNA index (greater than or equal to 1.5) (P less than 0.05). In a Cox multivariate analysis, nuclear DNA content provided significant prognostic value (P = 0.008), as did vascular invasion (P = 0.001) and intrahepatic metastasis (P = 0.005). These results indicated that nuclear DNA content has an important prognostic value in hepatocellular carcinoma.

To investigate the prognostic factors in Western patients with hepatocellular carcinoma, 206 patients with confirmed diagnoses of hepatocellular carcinoma were studied in terms of survival. All patients were diagnosed between 1983 and 1987. A multivariate survival analysis (Cox regression model) using clinical, biochemical, ultrasonographical and pathological data obtained at diagnosis disclosed that bilirubin (p = 0.0001), ascites (p = 0.0001), toxic syndrome (defined by the presence of weight loss greater than 10% premorbid weight, malaise and anorexia) (p = 0.009), blood urea nitrogen (p = 0.025), tumor size (p = 0.001), gamma-glutamyltranspeptidase (p = 0.0006), age (p = 0.0005), serum sodium (p = 0.003) and presence of metastases (p = 0.002) were independent predictors of survival. According to the contribution of each of these factors to the final model, a prognostic index was constructed allowing division of patients in different groups according to their relative risk of death: RRD = EXP (Age x 0.03 + Ascites x 0.8281 + BUN x 0.0137 + Serum sodium x (-0.0538) + gamma-Glutamyltranspeptidase x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4965 + Metastases x 0.55). These results facilitate the stratification of hepatocellular carcinoma patients to design and evaluate future controlled trials.

Recurrent or metastatic disease is frequently encountered among patients who have had resection of their primary hepatocellular carcinoma. A retrospective study on 117 patients (104 men, 13 women; mean age +/- standard deviation: 53.8 +/- 12.4 yr) who had hepatectomy for large hepatocellular carcinoma (diameter greater than or equal to 5 cm) was conducted to identify an at-risk population for tumor recurrence. Disease-free survival was correlated with 22 clinical (n = 5), serological (n = 2), gross pathological (n = 3) and histological (n = 12) features of the resected specimens using Cox's multivariate regression analysis. Recurrent hepatocellular carcinoma was detected in 74 patients within a median follow-up period of 13.7 mo. Although 17 patients had extrahepatic disease alone, recurrence was confined to the hepatic remnant in 40 patients. Disease-free survival rates at 1, 3 and 5 yr were 40%, 19% and 12%, respectively. Two of the five histological parameters isolated, negative resection margin (p less than 0.01) and encapsulation (p less than 0.006), were identified as favorable independent prognostic predictors. When patients with positive margins were excluded from the analysis, repeated calculation showed that encapsulation was the only important determinant. From this analysis, detailed histological study of the resected tumor is seen to be the only satisfactory means for assessing long-term prognosis. An aggressive approach is warranted among patients with encapsulated tumors. Even with a clear resection margin, adjuvant treatment should be considered for those patients who have unencapsulated lesions.

This study was undertaken to determine the results of resection of hepatocellular carcinoma in cirrhotic patients in Europe, using the same criteria as in the Orient for detection, surgical management, and pathology of the tumors. Seventy-two patients had a liver resection. One- and 3-yr survival rates were 68% and 51%, respectively. Survival rate was significantly higher in Child's/Pugh's class A than in class B-C patients. Patients with a thickly encapsulated tumor lived longer than those with an infiltrating tumor and had in addition a significantly lower incidence of cancer recurrence. Class A patients with a thickly encapsulated hepatocellular carcinoma had a 77% 3-year survival rate. There was no relation between the size of the tumor or the presence of symptoms and survival. These data suggest that good results can be achieved by resection of hepatocellular carcinomas in European cirrhotic patients. A thickly encapsulated tumor and an adequate liver function are the main determinants of low cancer recurrence and high survival. The clinical results in this series are similar to those reported from the Orient.