Sheung T. Fan

β-catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance

β‐Catenin has been recognized as a critical member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis.

Microvessel Density, Vascular Endothelial Growth Factor and Its Receptors Flt-1 and Flk-1/KDR in Hepatocellular Carcinoma

Assessment of angiogenesis may yield important information for an effective antiangiogenic treatment for hepatocellular carcinoma (HCC) because HCC is characteristically hypervascular We examined the relationship of microvessel density (MVD), vascular endothelial growth factor (VEGF), and VEGF receptors Flt-1 and Flk-1/KDR in 50 patients with HCC and in 3 hepatoma cell lines. VEGF messenger RNA (mRNA) was overexpressed in 26 tumors (52%), and the 3 VEGF isoforms (121, 165, and 189) were present in high frequencies. Flt-1 mRNA was overexpressed in 34 tumors (68%), with levels significantly increased in HCCs compared with the nontumorous livers. Tumor Flt-1 mRNA significantly correlated with tumor VEGF mRNA levels. Within the group of tumors 8.5 cm or less in diameter, tumors with intrahepatic metastasis in the form of tumor microsatellite formation had significantly higher VEGF mRNA levels. MVD assessed by immunohistochemical analysis with CD34 antibody was inversely related to tumor size. Angiogenesis as assessed by MVD and tumor VEGF expression seems to have a more important role in tumor growth and intrahepatic metastasis in smaller HCCs. The differential up-regulation of Flt-1 suggests that it may have an important role in angiogenesis in HCC.

Prognostic significance of pathologic features of hepatocellular carcinoma a multivariate analysis of 278 patients

Background. In patients with hepatocellular carcinoma, surgical resection may offer a chance of cure. However, tumor recurrence is not infrequent after resection.

Tumor encapsulation in hepatocellular carcinoma. A pathologic study of 189 cases

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 < 0.0001), tumor microsatellites (P < 0.0001), and venous permeation (P = 0.02) when compared with non‐encapsulated 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.

Prognostic Significance of Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma

Background. Proliferating cell nuclear antigen (PCNA) is a nuclear protein synthesized in G1/S‐phase of the cell cycle and therefore is related to cell proliferative activity. In an attempt to evaluate its prognostic significance and clinicopathologic correlation in patients with hepatocellular carcinoma (HCC), the proliferative activity was studied using immunohistochemical staining with monoclonal antibody to PCNA.

p21/WAF1, p53 and PCNA expression and p53 mutation status in hepatocellular carcinoma.

The cyclin‐dependent kinase inhibitor p21/WAF1 is regulated by p53‐dependent and p53‐independent pathways. In addition, p21/WAF1 binds with proliferating cell nuclear antigen (PCNA) and inhibits the action of PCNA. To investigate the possible role of p21/WAF1 in human hepatocellular carcinomas (HCCs), we examined the expression of p21/WAF1 and its relation with PCNA and p53 expression in 97 surgically resected HCCs by immunohistochemistry and with the mutation status of p53 in 26 HCCs. p53 mutation status was examined by direct DNA sequencing using 3 sets of primers covering exons 5–9. Six of the 26 tumors showed p53 point mutations and only 33% of these HCCs demonstrated p21/WAF1 expression. In contrast, 75% of HCCs without p53 mutations showed p21/WAF1 expression. Of all 97 HCCs, p21/WAF1 expression was significantly higher in the tumors than in corresponding non‐tumorous liver. When the tumors were stratified into 2 groups by the median tumor p21/WAF1 score, those with higher expression were found to have a lower incidence of multiple tumor nodules (p = 0.008) and tumor microsatellite formation (p = 0.050). The tumor p21/WAF1 score was positively associated with tumor PCNA expression (p = 0.036) but not with tumor p53 expression. Thus, in HCC, expression of p21/WAF1 is in part dependent on p53 status, but a p53‐independent pathway also plays a significant role in the regulation of p21/WAF1 expression. High p21/WAF1 expression is significantly associated with solitary tumor nodules and, to a lesser extent, tumor microsatellites but may not be enough to suppress tumor progression. Int. J. Cancer (Pred. Oncol.) 79:424–428, 1998.

Better survival in female patients with hepatocellular carcinoma. Possible causes from a pathologic approach.

BACKGROUNDnHepatocellular carcinoma is notably more prevalent in men than in women.nnnMETHODSnTo examine the sex-related characteristics of patients with primary hepatocellular carcinoma, 35 women were compared with 243 men, both groups having undergone surgical resection of the tumor.nnnRESULTSnWomen had a lower incidence of tumor recurrence, with median disease free survival of 19.5 months compared with 4.5 months for men (P < 0.001). Women also had more favorable actuarial survival than men [36.5 months for women compared with 12.4 months for men (P = 0.002)]. Women had a significantly higher incidence (80%) of tumor encapsulation than men (45%) (P < 0.001). Furthermore, the tumors in women were frequently less invasive in terms of lower incidence of tumor microsatellites, liver invasion, and positive histologic margin. Tumor microsatellite formation was present with 16% of tumors in women, compared with 60% for men (P < 0.0001). Liver invasion was found in 37% of tumors in women and 61% in men (P = 0.03). Only 6% of tumors in women had a positive histologic margin, compared to 24% in men (P = 0.04). There was no statistical significance in the incidence of cirrhosis in the nontumorous liver, hepatitis B surface antigen positivity, mean age, or tumor size, between women and men.nnnCONCLUSIONSnWomen who had hepatocellular carcinoma and hepatic resection had better survival rates and a lower rate of tumor recurrence than male patients. The better prognosis in women with hepatocellular carcinoma appeared to be related to the pathobiologic characteristics of the tumor (i.e., frequent encapsulation and lower tumor invasiveness).Background. Hepatocellular carcinoma is notably more prevalent in men than in women. n n n nMethods. To examine the sex-related characteristics of patients with primary hepatocellular carcinoma, 35 women were compared with 243 men, both groups having undergone surgical resection of the tumor. n n n nResults. Women had a lower incidence of tumor recurrence, with median disease free survival of 19.5 months compared with 4.5 months for men (P < 0.001). Women also had more favorable actuarial survival than men [36.5 months for women compared with 12.4 months for men (P = 0.002)]. Women had a significantly higher incidence (80%) of tumor encapsulation than men (45%) (P < 0.001). Furthermore, the tumors in women were frequently less invasive in terms of lower incidence of tumor microsatellites, liver invasion, and positive histologic margin. Tumor microsatellite formation was present with 16% of tumors in women, compared with 60% for men (P < 0.0001). Liver invasion was found in 37% of tumors in women and 61% in men (P = 0.03). Only 6% of tumors in women had a positive histologic margin, compared to 24% in men (P = 0.04). There was no statistical significance in the incidence of cirrhosis in the nontumorous liver, hepatitis B surface antigen positivity, mean age, or tumor size, between women and men. n n n nConclusions. Women who had hepatocellular carcinoma and hepatic resection had better survival rates and a lower rate of tumor recurrence than male patients. The better prognosis in women with hepatocellular carcinoma appeared to be related to the pathobiologic characteristics of the tumor (i.e., frequent encapsulation and lower tumor invasiveness).

Predictive Genes in Adjacent Normal Tissue Are Preferentially Altered by sCNV during Tumorigenesis in Liver Cancer and May Rate Limiting

Background In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. Methodology/Principal Findings Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types.

Outcomes of patients with hepatocellular carcinoma presenting with variceal bleeding

OBJECTIVE:Variceal bleeding is an important manifestation of hepatocellular carcinoma (HCC). However, little has been documented in the literature regarding the outcomes of HCC patients presenting with variceal bleeding. This study evaluated the clinical characteristics, management, and outcomes of this specific group of patients.METHODS:A retrospective analysis of a prospectively collected database comprising 2,928 HCC patients managed from January 1989 to December 2002 identified 78 patients who had presented with variceal bleeding. Their clinical outcomes were compared to those patients who did not present with variceal bleeding, and a multivariate analysis was performed to identify prognostic factors for their survival.RESULTS:HCC patients who presented with variceal bleeding had more severe cirrhosis than those who did not, with a significantly higher serum bilirubin level, lower albumin level, lower platelet count, and longer prothrombin time. They had significantly smaller HCCs but more frequent portal vein thrombosis. There was a significant difference in the overall survival between HCC patients who presented with variceal bleeding and those who did not (median 3.5 months vs 7.5 months, p < 0.001). In the variceal bleeding group, by multivariate analysis, treatment with transarterial chemoembolization was the only significant independent prognostic factor for survival (odds ratio 17.16, 95% CI: 2.81–104.91, p = 0.002).CONCLUSIONS:HCC patients who presented with variceal bleeding can be expected to have a significantly worse survival outcome than the general HCC patients. However, transarterial chemoembolization may offer some survival benefit to a selected group of HCC patients presenting with variceal bleeding.

Microsatellite Analysis in Post-Transplantation Lymphoproliferative Disorder to Determine Donor/Recipient Origin

Post-transplantation lymphoproliferative disorders (PTLD) are a group of heterogeneous diseases that occur after organ transplantation. Determination of the origin of the tumor cells not only provides clues to its possible pathogenetic mechanism, but also gives prognostic guidance in the clinical management of patients. We reviewed the clinicopathological features of four cases of PTLD that developed after solid organ transplantation. Using microsatellite analysis performed on paraffin-embedded tissue and using multiple, highly polymorphic markers, we have successfully determined the recipient/donor origin of the tumor cells in all of them. The time of onset of the PTLD ranged from 5 to 11 mo. All cases were diffuse large cell lymphomas of B-cell lineage, and the two cases that have been tested for EBV by in situ hybridization were positive. Three of the 4 PTLD were of donor origin and these three patients died of diseases unrelated to PTLD. The single patient with PTLD of recipient origin died of disseminated PTLD. The mean survival length of the three patients with donor origin was 26.3 mo, whereas that of the patient with recipient origin was 12 mo. Our results indicate a relatively high incidence of PTLD of donor origin among our patients with solid organ transplantation, as compared to other reported series. Moreover, the finding of the relatively indolent nature of PTLD of donor origin supports that determination of the donor/recipient origin of PTLD is of prognostic significance.