Radiation therapy for portal venous invasion by hepatocellular carcinoma

AIM: To clarify the efficacy and safety of three-dimensional conformal radiotherapy (3-D CRT) for this disease and to specify patient subgroups suitable for this treatment. METHODS: Fifty-two patients with HCC received PVI-targeted radiation therapy from January 1995 through December 2003. Portal venous invasion (PVI) was found in the second or lower order branches of the portal vein in 6 patients, in the first branch in 24 patients and in the main trunk in 22 patients. Child classifications of liver function before radiation therapy were A, B, and C for 19, 24 and 2 patients, respectively. All patients received three-dimensional conformal radiotherapy with a total dose ranging from 39 to 60 Gy (57.0 Gy in average). RESULTS: Overall survival rates at 1, 2, 3, 4, and 5 years were 45.1%, 25.3%, 15.2%, 10.1%, and 5.1%, respectively. Univariate analysis revealed that Child status, the number of tumor foci, tumor type, transcatheter arterial embolization (TAE) after radiation therapy were statistically significant prognostic factors. Multivariate analysis showed that the number of tumor foci and TAE after radiation therapy were statistically significant. CONCLUSION: The results of this study strongly suggest the efficacy of 3-D CRT as treatment for PVI in HCC. 3-D CRT is recommended in combination with post-radiation TAE for PVI of HCC with 5 tumor foci or less in the liver and with Child A liver function.     

Development of portal vein invasion and its outcome in hepatocellular carcinoma treated by transcatheter arterial chemo-embolization

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. One serious complication is the invasion of the portal vein. To investigate the new invasion of the portal vein in HCC following treatment by transcatheter arterial chemo-embolization (TACE), 124 patients with HCC were screened by ultrasound, computed tomography and angiography. Fifteen patients were diagnosed with portal vein invasion (PVI) during the initial examination and were excluded from the study. Of the remaining 109 patients, 18 developed PVI. Fourteen were male and four were female. None of these 18 patients completely responded to TACE treatment and all were in recurrence. The median time for appearance of PVI after the first TACE was 212 days. The median interval between PVI and the last negative ultrasound examination was 100 days. Both were correlated with the degree of PVI. The only significant factor affecting the time until the appearance of PVI was the TACE treatment. After the development of PVI, eight patients continued with the TACE treatment, and three of these patients were also treated with portal vein local chemotherapy. The regression of PVI was observed in two patients. The median survival time after the discovery of PVI was 129 days. Factors affecting the survival time were performance state, Pugh classification, sex, the area of tumour invasion and continued treatment.     

Evaluation of newly developed combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma with portal venous invasion: preliminary results

Aim:  Prognosis is extremely poor for advanced hepatocellular carcinoma (HCC) in patients with portal invasion. The present study evaluated the efficacy of combined intra-arterial 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)α-2b in patients with advanced HCC.
Methods:  The subjects comprised nine HCC patients with portal vein thrombosis treated using subcutaneous administration of PEG-IFNα-2b (50–100 µg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1–5 of every week, for 4 weeks). For four patients with hepatitis C virus (HCV) infection, oral administration of ribavirin (400–800 mg/day) was added. At the end of every cycle, response to therapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.
Results:  Partial response (PR) was observed in seven of nine patients, with stable or progressive disease in the remaining two patients. Tumors were resectable in three patients displaying PR after treatment. Tumor markers decreased significantly after therapy. Serum HCV-RNA titers were markedly decreased and became undetectable in all patients with HCV infection. National Cancer Institute–Common Toxicity Criteria: version 3.0 (NCI-CTC) grade 3 thrombocytopenia was seen in one case at the end of treatment, but was resolved with cessation of treatment. Other adverse effects were manageable.
Conclusion:  Combination therapy with intra-arterial 5-FU and systemic PEG-IFNα-2b may be useful as a palliative treatment for patients with advanced HCC. A prospective controlled trial using a larger population of patients with advanced HCC is needed to evaluate this new combination therapy.     

Predictors of microscopic portal vein invasion by hepatocellular carcinoma: Measurement of portal perfusion defect area ratio

Objective:  Microscopic portal vein invasion (PVI) by cancer cells is a poor prognostic factor after hepatic resection for hepatocellular carcinoma (HCC). The aim of this study is to predict PVI preoperatively in patients with HCC.
Methods:  We studied 46 hepatectomized patients who had HCC without any portal venous invasion detected during preoperative radiographic evaluation. We defined the portal perfusion defect area ratio (PPDAR) as the following: the quotient of the maximal portal perfusion defect area, on computed tomography during arterio-portography (CTAP) is divided by the maximal tumor area on magnetic resonance imaging (MRI) or CT.
Results:  The median PPDAR was 1.3 (mean 1.4 ± 1.1; ranged from 0.7 to 5.8). The incidence of PVI was 4.5% in patients with a PPDAR <1.3, 35.7% in those with a PPDAR of 1.3–1.6, 70% in those with a PPDAR ≥1.6 ( P  = 0.0005). When analyzing the preoperative value of different cut-off points for the PPDAR, the lowest P -value by Fisher's exact test was achieved when the PPDAR threshold was 1.6 ( P  = 0.0012). The sensitivity was 58%, and specificity was 91% with this cut-off value. On univariate analyses, factors that significantly correlated with PVI were PPDAR ( P  = 0.0012), serum levels of des-gamma-carboxy prothrombin ( P  = 0.033), and tumor size ( P  = 0.0126). On multivariate analysis, PPDAR was the only significant independent predictor of PVI.
Conclusion:  Our study shows that PPDAR is a new concept, which is useful in predicting PVI and that a value ≥1.6 is predictive of PVI.     

Predictors of hepatic venous trunk invasion and prognostic factors in patients with hepatocellular carcinomas that had come into contact with the trunk of major hepatic veins

Purpose

In this study, we tried to identify the preoperative predictors of hepatic venous trunk invasion and the prognostic factors in patients with hepatocellular carcinoma (HCC) that had come into contact with the trunk of a major hepatic vein over a distance of 1.0?cm or more.

Methods

Forty patients who had such HCCs resected were entered into this study and predictors of hepatic venous trunk invasion and prognostic factors were evaluated by univariate and multivariate analyses.

Results and Conclusions

A combined resection of the HCC and the venous trunk was performed in 29 patients. Hepatic venous trunk invasion was observed in 12 patients, including 2 with inferior vena cava tumor thrombus. A stepwise logistic regression analysis indicated that tumors larger than or equal to 7?cm in diameter and tumors showing a poorly differentiated histological grade were independent predictors of hepatic venous trunk invasion. The survival of patients without venous trunk invasion was significantly better than that for patients with venous trunk invasion (P = 0.048). A univariate analysis revealed that Child–Pugh classification B (P = 0.002), a high des-γ-carboxy prothrombin concentration (≧400?mAU/ml, P = 0.023), a large HCC (≧5.0?cm in diameter, P = 0.002), the presence of portal vein invasion (P < 0.001), the presence of venous trunk invasion (P = 0.048), the presence of intrahepatic metastasis (P < 0.001), and poorly differentiated HCC (P = 0.006) correlated with a worse overall survival after hepatic resection. In a multivariate analysis, however, only the presence of intrahepatic metastasis (P = 0.037, relative risk 8.25) was an independent predictor of poor overall survival.

Conclusions

Large tumors (≥7?cm in diameter) and poorly differentiated HCCs were more likely to be associated with hepatic venous trunk invasion and intrahepatic metastasis was an independent prognostic factor in patients with HCC that had come into contact with the trunk of a major hepatic vein.

     

Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion

Background and Aim:  This study aimed to evaluate the therapeutic efficacy and safety of repeated transarterial chemoembolization (TACE) with additional radiation therapy (RT) in hepatocellular carcinoma (HCC) with portal vein (PV) invasion.
Methods:  We performed survival analysis of consecutive HCC patients with PV invasion according to the treatment modalities after stratification by the degree of PV invasion and liver function retrospectively.
Results:  During 2005, 281 patients were newly diagnosed to have HCC with PV invasion at our institution. Repeated TACE or transarterial chemoinfusion (TACI) was performed in 202 (71.9%) patients and additional RT was performed for PV invasion in 43 of them. A total of 281 patients had a median survival of 5.2 months and a 2-year survival rate (YSR) of 19.2%. Repeated TACE showed significant survival benefits compared with conservative management in patients with PV branch invasion; median survival and 2-YSR was 10.2 vs 2.3 months and 33.7% vs 0% in Child–Pugh A categorized patients and 5.5 vs 1.3 months and 10.3 vs 0% in Child–Pugh B categorized patients, respectively ( P  < 0.001). In patients with PV branch invasion, the survival rate was significantly longer with TACE/TACI plus RT than with TACE/TACI alone both in Child–Pugh A categorized patients (1-YSR: 63.6 vs 35.6%, P  = 0.031) and Child–Pugh B categorized patients (1-YSR: 66.7 vs 7.7%, P  = 0.007). Repeated TACE was well tolerated in our patients, with only one dying within one month after TACE.
Conclusion:  Repeated TACE with additional RT can be performed safely and showed a significant survival benefit in HCC patients with PV branch invasion with conserved liver function.     

Interobserver and intraobserver variability in evaluating vascular invasion in hepatocellular carcinoma

Background and Aim: Hepatocellular carcinoma (HCC) is unique in that the presence of vascular invasion significantly changes tumor stage. Even though searching for vascular invasion is a common practice in surgical pathology, there appears to be a great variation among pathologists in its recognition. This study was designed to assess whether HCC could be accurately staged using vascular invasion as a staging parameter. Methods: The interobserver and intraobserver agreement for vascular invasion was analyzed in 126 liver resections for HCC. Selected slides were circulated twice among six pathologists for independent review using their own criteria. One to three representative images from 26 equivocal cases selected by one of the authors were re‐evaluated by the pathologists. The presence or absence of vascular invasion on each slide or image was recorded as yes or no. The results were analyzed using unweighted kappa statistic analysis for multiple raters. Results: The interobserver agreement was moderate on two slide circulations with kappa values of 0.50 (95% confidence interval 0.45–0.55) and 0.43 (0.38–0.47), respectively. The kappa value dropped significantly to 0.19 (0.09–0.29) on selected images photographed from controversial cases. The intraobserver agreement was moderate, with kappa values ranging from 0.23 to 0.56 (mean = 0.45). Conclusions: Pathologists can reproducibly recognize vascular invasion in many HCC cases but may have difficulty in equivocal cases, which may lead to either understaging or overstaging of the tumors. This may have a significant impact on prognostic assessment and therapeutic decision making. Our observations indicate the need for improved definition for vascular invasion in HCC.     

Prognosis of hepatocellular carcinoma accompanied by microscopic portal vein invasion

AIM： To investigate the prognostic factors in patients with hepatocellular carcinoma （HCC） accompanied by microscopic portal vein invasion （PVI）.
METHODS： Of the 267 patients with HCC undergoing hepatic resection at Aso Iizuka Hospital, 71 had PVI. After excluding 16 patients with HCC that invaded the main trunk and the first and second branches of the portal vein, 55 patients with microscopic PVI were enrolled.
RESULTS： The patients with HCC accompanied by microscopic invasion were divided into two groups： solitary PVI （PVI-S： n = 44）, and multiple PVIs （PVI-M： n = 11）. The number of portal vein branches invaded by tumor thrombi was 5.4 ± 3.8 （2-16） in patients with PVI-M. In cumulative survival, PVI-M was found to be a significantly poor prognostic factor （P = 0.0019）; while PVI-M and non-anatomical resection were significantly poor prognostic factors in disease-free survival （P = 0.0213, and 0.0115, respectively）. In patients with PVI-M, multiple intrahepatic recurrence was more common than in the patients with PVI-S （P = 0.0049）. In patients with PVI-S, non-anatomical resection was a significantly poor prognostic factor in disease-free survival （P = 0.0370）. Operative procedure was not a significant prognostic factor in patients with PVI-M.
CONCLUSION： The presence of PVI-M was a poor prognostic factor in patients with HCC, accompanied by microscopic PVI. Anatomical resection is recommended in these patients with HCC. Patients with HCC and PVI-M may also be good candidates for adjuvant chemotherapy.     

小肝癌MR信号值与微血管侵犯相关性分析

目的分析小肝癌MR信号值与微血管侵犯(microvascular-invasion,MVI)的相关性。方法收集整理2010年12月至2019年1月解放军总医院第五医学中心小肝癌手术切除且于术前1周至1个月内行MR动态增强扫描检查的患者33例,根据病理诊断分为微血管侵犯组和非微血管侵犯组,进一步分为甲胎蛋白(AFP)阳性组和阴性组,测量并计算术前MR图像T1WI、T2WI、DWI序列及动态增强扫描动脉期、门脉期、延迟期病变信号值与相邻肝背景信号值的比值。结果33例患者中微血管侵犯22例,非微血管侵犯组11例;AFP阳性组17例,AFP阴性组16例。AFP阳性病例微血管侵犯与非微血管侵犯组间动脉期强化和延迟期强化信号特征差异有统计学意义(P<0.05),而T1WI序列、T2WI、DWI序列病变信号特征差异无统计学意义(P<0.05);AFP阴性病例T1WI序列、T2WI、DWI序列及动态增强扫描各期病变信号特征差异无统计学意义(P<0.05)。结论微小肝癌MR动态增强扫描病变强化特征可用于预测病变是否存在微血管侵犯。     

Histopathology of portal tracts in livers after transcatheter arterial chemo-embolization therapy for hepatocellular carcinoma

Abstract To study the influence of transcatheter arterial embolization therapy (TAE) on the portal tracts, 32 cases of hepatocellular carcinoma (HCC) with a history of TAE were examined. Portal tract elements are said to be mainly supplied by hepatic arterial blood, as is HCC. The following changes were found: peribile duct fibrosis; biliary epithelial injuries; bile duct necrosis; fibrous thickening of the intima and adventitia of arteries; thrombosis or stenosis of portal vein branches; and fibrosis of portal tract itself. We failed to correlate these histopathologic changes with the frequency of TAE or the interval between TAE therapy and surgery or autopsy. Semi-quantitative assessment disclosed that vessels of the peribiliary vascular plexus (PVP) which are known to be derived from hepatic arterial branches, were considerably decreased. There was little correlation between the degree of reduction of PVP and the observed histopathologic changes of portal tracts. It is suggested that TAE causes adverse effects on the elements of portal tracts and a reduction in the PVP in the vicinity of HCC, but the relationship between them is unclear.     

Signiifcance of pathological positive superior mesenteric/portal venous invasion in pancreatic cancer

BACKGROUND: Pancreaticoduodenectomy with superior mesenteric/portal venous resection for pancreatic ductal ad-enocarcinoma (PDAC) is frequently performed with no added morbidity or mortality in case of tumor abutment to the su-perior mesenteric or portal vein so as to obtain a margin nega-tive resection. True histopathological portal vein invasion is found only in a small subset of such patients. The aim of this review aimed to discuss the signiifcance of histopathological venous invasion in PDAC.
DATA SOURCES: For this review available data was searched from PubMed and analyzed. No randomized trials have been published on this topic.
RESULTS: Existing data on prognostic factors in histopatho-logical venous invasion by PDAC are limited and recent stud-ies indicate worse survival in this subgroup of patients. In addition, venous invasion in PDAC has been associated with large tumors, involved lymph nodes, perineural invasion and R1 resection. The survival of patients with portal venous re-section but without histologic venous invasion is reportedly better than those with histopathological venous invasion;though conlficting studies do exist on the subject. Some stud-ies also relate the depth of venous invasion to prognosis after surgical resection of PDAC.
CONCLUSIONS: Frank/‘histopathological’ invasion of supe-rior mesenteric/portal venous and R1 resection indicate a very poor survival. Such patients may be given the opportunity of beneift of neoadjuvant treatment.     

Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma

Background/Aims: Vascular endothelial growth factor‐C (VEGF‐C) is thought to be an important factor in tumor angiogenesis/lymphangiogenesis, but its role in hepatocellular carcinoma (HCC) has not yet been fully investigated. Methods: We immunohistochemically examined VEGF‐C expression in surgically resected tissues of 90 HCC. Results: In the 78 HCC with a single histological grade, VEGF‐C expression was significantly stronger in poorly differentiated HCC than in well‐ (P = 0.003) or moderately differentiated HCC (P = 0.0002). A ‘nodule‐in‐nodule’ case presented VEGF‐A expression in the well‐differentiated component and VEGF‐C expression in the moderately–poorly differentiated component. According to nodular diameter, VEGF‐C expression was significantly higher in nodules of 3.0 cm or larger (P = 0.0263). Extrahepatic metastases seen in seven cases expressed VEGF‐C. In 20 of the 28 cases who were able to be followed up, the frequency of intrahepatic recurrence tended to be higher and extrahepatic metastasis was significantly higher in the cases who had VEGF‐C expression in the tumor casts of the intrahepatic portal/hepatic vein branches than other cases without the expression (P = 0.0139). Disease‐free survival time tended to be shorter in cases with VEGF‐C expression in tumor casts of the portal/hepatic vein than in those without VEGF‐C expression (P = 0.053; log–rank test). Conclusions: VEGF‐C expression is related to the progression of HCC, and VEGF‐C expression in tumor casts of the intrahepatic portal/hepatic vein is considered to be a factor indicating recurrence/metastasis sites.     

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

BACKGROUND: Four tumor markers for hepatocellular carcinoma(HCC), alpha-fetoprotein(AFP), glypican-3(GPC3), vascular endothelial growth factor(VEGF) and des-gammacarboxy prothrombin(DCP), are closely associated with tumor invasion and patient's survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy.METHODS: A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups: patients with macroscopic vascular invasion(Ma VI +) and those without Ma VI(Ma VI-). The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis.RESULTS: In all patients, tumor size(8 cm) and Ma VI were closely related to HCC recurrence after hepatectomy. For Ma VI+ patients, VEGF(900 pg/m L) was a significant predictor for recurrence(RR=2.421; 95% CI: 1.272-4.606; P=0.007). The 1- and 2-year tumor-free survival rates for Ma VI+ patients with VEGF ≤900 pg/m L versus for those with VEGF 900 pg/m L were 51.5% and 17.6% versus 19.0% and 4.8%(P0.001). For Ma VI- patients, DCP 445 m Au/m L and tumor size 8 cm were two independent risk factors for tumor recurrence(RR=2.307, 95% CI: 1.132-4.703, P=0.021; RR=3.150, 95% CI: 1.392-7.127, P=0.006; respectively). The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 m Au/m L and those with DCP 445 m Au/m L were 90.4% and 70.7% versus 73.2% and 50.5% respectively(P=0.048). The 1-and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and 8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively(P=0.003).CONCLUSIONS: The Ma VI+ patients with VEGF ≤900 pg/m L had a relatively high tumor-free survival than those with VEGF 900 pg/m L. In the Ma VI- patients, DCP 445 m Au/m L and tumor size 8 cm were predictive factors for postoperative recurrence.     

Surgical treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus

The Barcelona Clinic Liver Cancer staging system recommends a tyrosine kinase inhibitor (sorafenib) as standard therapy in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). Sorafenib has been shown to prolong median overall survival (OS) by approximately 3 months in advanced HCC patients with PVTT (8.1 vs. 4.9 months). However, its clinical effectiveness is still controversial and standard treatment with sorafenib is not established in Japan. Surgical resection is considered a potentially curative treatment and provides an acceptable outcome for carefully selected patients. The surgical mortality rate in patients with PVTT who receive surgical resection ranges from 0% to 10%. The median survival time and 1-year OS rate in HCC patients with PVTT who undergo surgical resection have been found to range from 8 to 22 months and 21.7% to 69.6%, respectively. But improvement in therapeutic outcome is difficult with surgical treatment alone. Combination treatment in conjunction with such methods as transarterial chemoembolization, hepatic artery infusion chemotherapy, and radiotherapy has been found to improve the prognosis (median survival time, 11.5–37 months; 1-year OS rate, 46.8–100%). Yet, many problems remain, such as surgical indications and surgical techniques. After resolving these points, a multidisciplinary strategy based on surgical treatment should be established for advanced HCC with PVTT.