Takahiro Uenishi

Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence.

Clinicopathologic features and postoperative outcomes were investigated for patients who underwent curative surgery for biliary marker (CK7 and CK19)‐positive hepatocellular carcinoma (HCC). Of 157 HCCs, 93 were CK7(‐)CK19(+), 49 were CK7(+)‐CK19(‐), 1 was CK7(‐)CK19(+), and 14 were CK7(+)‐CK19(+). Semiquantitative analysis of expression levels demonstrated a significant correlation between CK7 and CK19 expression. Of various clinicopathologic parameters, tumor differentiation exhibited a significant correlation with CK7 and CK19 expression. All 15 patients with CK19‐positive HCC also had anti‐HBc. Log‐rank test revealed that CK7 expression, CK19 expression, high aspartate aminotransferase (AST) activity, low albumin concentration, portal invasion, intrahepatic metastasis, and severe fibrosis (cirrhosis) reduced the tumor‐free survival rate. Multivariate analysis demonstrated that CK19 expression, intrahepatic metastasis, and severe fibrosis were independent predictors of postoperative recurrence, while CK7 expression was not. Twelve of 15 patients with CK19‐positive HCC had tumor recurrence within 2 years after surgery, a significantly higher incidence of early recurrence than for CK19‐negative HCC. The incidence of extrahepatic disease, especially lymph node metastasis, was significantly higher for patients with CK19‐positive HCC. These findings indicate that CK19 expression is a predictor of early postoperative recurrence due to increased invasiveness.

Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma

Although hepatitis C virus (HCV)‐related cirrhosis has been suggested as a risk factor for intrahepatic cholangiocarcinoma (ICC), few sizeable studies have tested this hypothesis. We investigated ICC risk factors, with special reference to HCV infection. We conducted a hospital‐based case‐control study including 50 ICC patients and 205 other surgical patients without primary liver cancer. HCV seropositivity was detected in 36% of ICC patients and 3% of controls. By univariate analysis, the odds ratio (OR) for association of anti‐HCV antibodies with development was 16.87 (95% confidence interval (CI), 5.69 to 50.00). History of blood transfusion or diabetes mellitus, elevated serum total bilirubin, elevated aspartate aminotransferase and alanine aminotrans‐ferase, decreased serum albumin and decreased platelet count were identified as other possible ICC risk factors. By multivariate analysis, anti‐HCV antibodies (adjusted OR, 6.02; 95% Cl, 1.51 to 24.1), elevated alanine aminotransferase, decreased serum albumin, and decreased platelet count were found to be independent risk factors for ICC development. As liver status worsened, the adjusted OR for ICC tended to increase. HCV infection is a likely etiology of ICC in Japan.

Incidence and management of Bile leakage after hepatic resection for malignant hepatic tumors

BACKGROUND Bile leakage is one of the frequent and disturbing complications of hepatic resection. STUDY DESIGN Clinical records of the 363 patients who underwent hepatic resections without biliary reconstruction for hepatic cancers between January 1994 and June 2001 were reviewed. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration of 20 mg/dL or 1,500 mg/d lasting 2 days. Leakage that continued longer than 2 weeks or that required surgical intervention was defined as uncontrollable. Differences in incidence and frequency of uncontrollable leakage for the different types of hepatic resection, tumors, and underlying liver disease were investigated. Outcomes after treatment for uncontrollable bile leakage were also reviewed. RESULTS Postoperative bile leakage occurred in 26 of 363 patients (7.2%). Although the incidence in patients with cholangiocellular carcinoma (3/9 [33%]) was higher (p = 0.03) than in patients with hepatocellular carcinoma, rates of occurrence were similar among the different types of hepatic resection and underlying liver disease. Eight of the 26 patients (31%) had uncontrollable leakage. Two patients required reoperation to control leakage; one of these developed hepatic failure and died 2 months after surgery. Four patients underwent endoscopic nasobiliary drainage 21 to 34 days after hepatectomy, and the leakage resolved within 3 to 21 days. Fibrin glue sealing was effective in two patients whose leaking bile ducts were not connected to the common bile duct. CONCLUSIONS Although meticulous surgical technique can minimize the risk of postoperative bile leakage, some instances of leakage are unavoidable. Nonsurgical treatments, such as nasobiliary drainage or fibrin glue sealing, are preferable to reoperation.

Indications for surgical treatment of intrahepatic cholangiocarcinoma with lymph node metastases

BACKGROUND/PURPOSE The postoperative outcome of patients who have intrahepatic cholangiocarcinoma with lymph node metastases is extremely poor, and the indications for surgery for such patients have yet to be clearly established. METHODS The demographic and clinical characteristics of 133 patients who underwent lymph node dissection during hepatic resection of intrahepatic cholangiocarcinoma were retrospectively analyzed. RESULTS Multivariate analysis identified three independent prognostic factors: intrahepatic metastasis, nodal involvement, and tumor at the margin of resection. Of the patients with tumor-free surgical margins, none of the 24 patients who had both lymph node metastases and intrahepatic metastases survived for 3 years. In contrast, the survival rates for the 23 patients who had lymph node metastases associated with a solitary tumor were 35% at 3 years and 26% at 5 years. CONCLUSIONS Surgery alone cannot prolong survival when both lymph node metastases and intrahepatic metastases are present, while surgery may provide a chance for long-term survival in some patients who have lymph node metastases associated with a solitary intrahepatic cholangiocarcinoma tumor.

Surgical management of cystic hepatic neoplasms.

Background. The clinicopathologic features of cystic neoplasms of the liver, such as cystadenoma and cystadenocarcinoma, are poorly defined because these lesions are extremely rare. Methods. Clinicopathologic findings in six patients who underwent surgery for a cystic hepatic neoplasm were reviewed retrospectively to determine the best surgical strategy to treat this condition. Results. Five patients had a multilocular cyst or elevated lesions detected on preoperative imaging studies. The remaining patient had elevated serum concentrations of carcinoembryonic antigen and carbohydrate antigen 19-9, even though preoperative imaging studies of the hepatic cystic lesion revealed no imaging features of cystadenocarcinoma. Cytology failed to detect malignant cells in the cyst contents of any patient. One patient underwent palliative resection because pleural dissemination was present, and five patients underwent curative resection. Three patients had cystadenoma diagnosed in the surgical specimen. One patient with cystadenocarcinoma has survived for more than 8 years after a curative resection that was limited to the cyst wall, and another patient died of recurrence 13 months after surgery. Conclusions. When a cystic neoplasm is suspected of being cystadenocarcinoma, hepatic resection should be considered, because reliable criteria for distinguishing cystadenoma from cystadenocarcinoma clinically do not exist.

The clinical significance of lymph node metastases in patients undergoing surgery for hepatocellular carcinoma.

The frequency of lymph node (LN) metastasis in patients undergoing surgery for hepatocellular carcinoma (HCC) has rarely been studied. We evaluated the clinicopathologic characteristics and outcomes of six patients with nodal metastases from HCC among a total of 504 patients who underwent hepatic resection for HCC in our department over a 16-year period. The nodal metastases were diagnosed preoperatively in two patients. The average diameter of the resected tumors was 7.8 cm and all were confirmed as poorly differentiated HCC. All of the six patients had intrahepatic metastatic nodules and five also had portal vein invasion. One patient underwent limited resection, and the other five underwent bisegmentectomy. All of the regional LNs were removed in one patient, while only enlarged LNs were removed in the other five. One patient died of postoperative liver failure and the others all died later of intrahepatic or nodal recurrence. Our findings suggest that the prognosis of patients with nodal metastasis from HCC is generally poor, even if hepatic resection with regional LN dissection is performed.

Outcomes of hepatic resection for hepatolithiasis

BACKGROUND Hepatic resection is main approach to treatment of hepatolithiasis, but the long-term follow-up results of hepatic resection for hepatolithiasis are rarely reported. METHODS A retrospective study was conducted of 87 patients with hepatolithiasis who underwent hepatic resection. RESULTS The final stone clearance rates were 95%. There was a significant difference in the incidence of recurrent stones between patients with and without remaining biliary strictures. On multivariate analysis, the presence of residual or recurrent stones was an independent risk factor associated with recurrent cholangitis. The 10-year overall survival rate was 80.3%. On multivariate analysis, the development of cholangiocarcinoma was an independent predictor of survival in patients who underwent hepatic resection for hepatolithiasis. CONCLUSIONS The long-term outcomes after hepatic resection were satisfactory in patients whose intrahepatic stones and strictures were completely removed. Cholangiocarcinoma associated with hepatolithiasis was an independent prognostic factor in patients with hepatolithiasis who underwent hepatic resection.

Serum Cytokeratin 19 Fragment (CYFRA21-1) as a Prognostic Factor in Intrahepatic Cholangiocarcinoma

BackgroundA high serum cytokeratin 19 fragment (CYFRA21-1) concentration in patients with various cancers is associated with poor prognosis. This study aimed to establish the clinical significance of preoperative serum CYFRA21-1 in patients with intrahepatic cholangiocarcinoma.MethodsCYFRA21-1, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 concentrations were measured in sera from 71 patients with intrahepatic cholangiocarcinoma. The prognostic significance of serum CYFRA21-1 levels was assessed by univariate and multivariate analyses.ResultsAnalysis of the areas under the receiver operator characteristic (ROC) curves clearly showed better discrimination between intrahepatic cholangiocarcinoma and benign liver diseases for CYFRA 21-1 than for CEA or CA 19-9. Based on the maximization of the Youden’s index, the optimal cut-off value was 2.7 ng ml−1 for CYFRA 21-1 (sensitivity, 74.7%; specificity, 92.2%). The serum CYFRA21-1 concentration was related to tumor stage, since the CYFRA21-1 concentrations varied according to tumor size, vascular invasion, and number of tumors. The 3-year recurrence-free survival rates for patients with high and low concentrations of CYFRA21-1 were 25.0% and 76.2%, respectively (log-rank test, p < 0.01). The 3-year overall survival rates for patients with high and low concentrations of CYFRA21-1 were 39.4% and 63.6%, respectively (p = 0.01). On multivariate analysis, a high concentration of CYFRA21-1, nodal metastases, and a microscopic resection margin involvement were independent prognostic factors associated with both tumor recurrence and postoperative death.ConclusionsA high serum CYFRA21-1 concentration is associated with tumor progression and poor postoperative outcomes in patients with intrahepatic cholangiocarcinoma.

Cytokeratin-19 fragments in serum (CYFRA 21-1) as a marker in primary liver cancer

Using an electrochemiluminescence immunoassay, CYFRA 21-1 concentrations were measured in sera from 187 patients with primary liver cancer (164 with hepatocellular carcinoma (HCC) and 23 with intrahepatic cholangiocarcinoma (ICC)) and 87 patients with benign liver diseases. Concentrations of CYFRA 21-1 were significantly higher in patients with ICC (5.0; interquartile range 3.1–10.7 ng ml−1) than in those with benign liver disease (1.4; 1.0–1.9; Mann–Whitney U-test, P<0.0001) or HCC (1.7; 1.1–2.7; Mann–Whitney U-test, P<0.0001). Using cutoff values selected for 95% specificity in the benign group (3.0 ng ml−1), CYFRA 21-1 showed higher sensitivity for ICC (87.0%) than three commonly used markers including α-fetoprotein (17.4%), carcinoembryonic antigen (34.8%), and carbohydrate antigen 19-9 (60.9%). Serum CYFRA 21-1 increased in ICC from stages I/II to IV (Kruskal–Wallis test, P=0.0102). CYFRA 21-1 concentration increased with extent of local invasion, but not nodal status. Serum CYFRA 21-1 represents a useful diagnostic test for ICC that offers high sensitivity. CYFRA 21-1 reflected differences in tumour burden, suggesting applicability to staging and follow-up.

Histologic factors affecting prognosis following hepatectomy for intrahepatic cholangiocarcinoma

Long-term survival following hepatectomy for intrahepatic cholangiocarcinoma has been poor, and specific factors influencing survival are unclear. In a retrospective study we sought to determine prognostic factors related to survival in these patients. In 28 patients who underwent hepatic resection for intrahepatic cholangiocarcinoma, we investigated the relations of several histologic factors to patient survival by univariate and multivariate analyses. No deaths occurred during the first 30 days. Median and mean survival times following hepatectomy were 409 and 935 days, respectively. The respective survival rates at 1, 3, and 5 years were 57%, 27%, and 27%. Resection margin status, intrahepatic metastasis, lymph node involvement, and lymphatic invasion were significant predictors of outcome. In a multivariate analysis using the Cox proportional hazards model, only lymphatic invasion independently predicted survival. Curative resection with clear margins was found to prolong survival after surgery. Hepatectomy for intrahepatic cholangiocarcinoma without lymphatic invasion offers hope for long-term survival.RésuméAlors que la survie à long terme après hépatectomie pour cholangiocarcinome intrahépatique est médiocre, les facteurs spécifiques influençant la survie ne sont pas clairement connus. Dans une étude rétrospective, nous avons essayé de déterminer les facteurs pronostiques en rapport avec la survie chez ces patients. Chez 28 patients ayant eu une résection hépatique pour cholangiocarcinome intrahépatique, nous avons réalisé une analyse uni- et multifactorielle pour étudier les rapports entre plusieurs facteurs histologiques et la survie. Aucune mortalité n’a été enregistrée pendant les 30 premiers jours. La survie médiane et moyenne après hépatectomie ont été, respectivement, de 409 et de 935 jours. Le taux de survie à 1, 3 et 5 ans ont été, respectivement, de 57%, de 27% et de 27%. L’état des marges de résection, les métastases intrahépatiques et l’envahissement ganglionnaire étaient des facteurs pronostiques significatifs. D’après analyse multifactorielle selon Cox, seul l’envahissement ganglionnaire était un facteur indépendant de survie. La résection avec clairance d’une marge de sécurité prolonge la survie. L’hépatectomie pour cholangiocarcinome intrahépatique sans envahissement ganglionnaire offre un espoir de survie à long terme.es|ResumenAunque la supervivencia a largo plazo tras hepatectomía por colangiocarcinoma intrahepático es escasa, no están claros los factores capaces de influir en la misma. En este estudio retrospectivo intentamos determinar los factores pronósticos relacionados con la supervivencia de estos pacientes. En 28 enfermos que sufrieron una resección hepática por colangiocarcinoma intrahepático, investigamos mediante análisis uni y multivariable la relación de diversos hallazgos histológicos con su supervivencia. Ningún paciente falleció en los primeros 30 días. La mediana y la media del tiempo de supervivencia tras hepatectomía fueron 409 y 935 días. La tasa de supervivencia a 1, 3 y 5 años fue 57%, 27% y 27%. Factores predictives significativos para los resultados fueron la infiltración o no de los márgenes de resección, las metástasis intrahepáticas, la afectación de ganglios linfáticos y la invasión linfática. En el análisis multivariante, utilizando el modelo de Cox, sólo la invasión linfática resultó ser un factor predictivo independiente, por lo que a la supervivencia se refiere. Resecciones curativas con limpios márgenes prolongaron la supervivencia tras cirugía. La hepatectomía por colangiocarcinoma intrahepático sin invasión linfática constituye un pronóstico favorable, por lo que a una prolongada supervivencia se refiere.