Combined intraarterial 5-fluorouracil and intramuscular interferon-alpha therapy for advanced hepatocellular carcinoma

We report the case of a 66-year-old man with hepatic cirrhosis and multiple hypervascular tumors in both lobes of the liver as well as tumor thrombi in the portal vein. After unresectable hepatocellular carcinoma was diagnosed, transcatheter arterial embolization was considered to be difficult, because he had major portal vein thrombosis. Conventional ultrasonically-guided local treatments, such as percutaneous ethanol injection therapy and radiofrequency ablation, were also of no value because the tumors were huge and multiple. Ultimately, he was treated with a combination of intraarterial 5-fluorouracil and intramuscular interferon-alpha. After treatment, the multiple tumors became non-enhancing on contrast computed tomography scans and showed a marked decrease in size. There were no serious adverse effects (such as myelosuppression or hepatotoxicity) during treatment or follow-up and the patient is doing well at present. In conclusion, a combination of intraarterial 5-fluorouracil with intramuscular interferon-alpha appears to be useful for the management of advanced hepatocellular carcinoma, especially in patients for whom more aggressive treatment is not acceptable.     

Hepatocellular carcinoma responding to chemotherapy with 5-FU

A 69-year-old man with unresectable hepatocellular carcinoma and portal vein tumor thrombus was treated by chemotherapy with 5-fluorouracil. A dose of 500 mg/day of 5-fluorouracil was continuously administered via a central venous catheter. After 4 months, the alpha-fetoprotein level was decreased from 50,000 ng/mL to 4,760 ng/mL. Computed tomography revealed disappearance of the low-density area in the liver parenchyma, but the portal vein tumor thrombus was not changed. After 6 months, pancytopenia appeared and continuous infusion of 5-fluorouracil was stopped. After 8 months, the patient died of pneumonia, at which time the alpha-fetoprotein level was 12,000 ng/mL. Continuous intravenous infusion of 5-Fluorouracil was effective against unresectable primary hepatocellular carcinoma, but had little influence on portal vein tumor thrombus.     

Complete remission of hepatocellular carcinoma with portal vein tumor thrombus and lymph node metastases by arterial infusion of 5-fluorouracil and interferon-α combination therapy following hepatic resection

We report two cases of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and lymph node (LN) metastases successfully treated by hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic injection of interferon (IFN)-α following hepatic resection for the liver tumor. Complete remission was obtained. Case 1 was a 51-year-old man who had HCC in the right lobe of the liver with PVTT and multiple intrahepatic metastases. He also had abdominal and mediastinal LN metastases. Case 2 was a 53-year-old man who had diffuse-type HCC in the right lobe of the liver with PVTT and intrahepatic metastases. A chest computed tomography scan revealed lymph nodes enlarged to 1.0 cm from the mediastinum to the left supraclavicular space. Both patients underwent the hepatectomy to reduce the tumor volumes and remove the PVTT to relieve portal vein obstruction. Following the surgery, the patients underwent IFN-α/5-FU combination therapy. Three months after this combined therapy, tumor markers (both α-fetoprotein and protein induced by vitamin K absence or antagonist II) returned to the normal range and residual tumors in the liver disappeared. The patients are alive without any recurrence more than 1 year after initial treatment. IFN-α/5-FU combined therapy following hepatic resection is a promising modality for the treatment of advanced HCC with LN metastasis.     

A surgically treated case of hepatocellular carcinoma with extensive lymph node metastases

A 62-year-old man with chronic hepatitis C was found to have a hepatic tumor by ultrasonography. Computed tomography of the liver disclosed a tumor 4 cm in diameter occupying the posterior segment and associated with a portal tumor thrombus and enlargement of hilar and paraaortic lymph nodes. At laparotomy multiple nodal metastases were seen involving hilar, hepatoduodenal, common hepatic arterial, and paraaortic nodes. We performed right hepatic lobectomy and systematic lymph node dissection. Histologic examination of both the main tumor and nodal metastases showed poorly-differentiated hepatocellular carcinoma. Severe postoperative ascites persisted for 1 month. Fifteen months after surgery the patient died of multiple intrahepatic and systemic nodal recurrences. Our experience confirms that surgical treatment of hepatocellular carcinoma with nodal metastases is likely to benefit only a few carefully selected patients, since the prognosis is commonly poor and hepatectomy with lymph node dissection carries the risk of severe complications.     

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-α

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-alpha (PEG-IFN-alpha). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-alpha was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-alpha and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-alpha with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.     

Surgically treated cases of mixed hepatocellular carcinoma and cholangiocarcinoma

The mixed type of combined hepatocellular carcinoma and cholangiocarcinoma is particularly rare. Hepatic resection was performed for two patients with mixed hepatocellular carcinoma and cholangiocarcinoma. In case 1, a 55-year-old Japanese man was found to have a hepatic tumor on ultrasonography. Since ultrasonically-guided needle biopsy revealed that the tumor was poorly differentiated hepatocellular carcinoma, the patient underwent a limited hepatic resection. Histologic and immunohistochemical examination revealed that the tumor had elements of both hepatocellular carcinoma and cholangiocarcinoma. Six months after surgery, the patient died of systemic recurrences. In case 2, a 58-year-old man was found by ultrasonography to have a hepatic tumor occupying the entire right hepatic lobe. Computed tomography revealed that the tumor had a portal tumor thrombus. The diagnosis of hepatocellular carcinoma was made because of a markedly elevated serum alpha-fetoprotein concentration, and a right hepatic lobectomy was performed. Histologic and immunohistochemical examination confirmed that the lesion was mixed hepatocellular and cholangiocellular carcinoma. The patient died of multiple recurrent tumors in the remnant liver 3 months after surgery. Surgical control of mixed hepatocellular carcinoma and cholangiocarcinoma is difficult.     

Application of cystoscope in surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus

Development of portal vein tumor thrombus deteriorates the prognosis of hepatocellular carcinoma, while surgical treatment can offer a promising prognosis for selected patients. However, the possibility of residual lesions in portal vein after conventional thrombectomy is a main risk factor leading to postoperative recurrence. Therefore, ensuring the complete removal of tumor thrombus during operation is critical to improve prognosis. For the first time, we report here one case of hepatocellular carcinoma with portal vein tumor thrombus in which cystoscope was successfully applied as a substitute of intravascular endoscope to visualize the cavity of the portal vein. The patient was a 61-year-old man with a 7-cm tumor in the right lobe of the liver, with tumor thrombus invading the right branch and adjacent to the conjunction of the portal vein. After removal of the tumor, the Olympus CYF-VA2 cystoscope was used to check the portal vein from the opening stump of the right branch of the portal vein. In this case, residual thrombus tissue was found near the opening stump and the conjunction of the portal vein. The residual lesion was carefully retrieved from the stump after retraction of the cystoscope. The procedure was repeated until no residual lesion was found. The whole duration time of thrombectomy was 22.5(15 + 7.5) min. The patient was free from recurrence at 8 months after the procedure. Our work indicated that the cystoscope is a suitable substitute, with a proper size and function to check the portal vein system and ensure the curability of thrombectomy. Although welldesigned clinic trails are still needed, this procedure may further improve the postoperative prognosis of hepatocellular carcinoma with portal vein tumor thrombus.     

Technical note on ALPPS for a patient with ad-vanced hepatocellular carcinoma associated with invasion of the inferior vena cava

Patients with hepatocellular carcinoma have a very short life expectancy if they receive no surgical interven-tion. A relatively new surgical technique termed “Associating Liver Partition and Portal Vein Ligation for Staged Hepa-tectomy” (ALPPS) has been employed for inducing rapid hypertrophy of the future liver remnant for patients waiting for hepatectomy. As portal vein embolization may not result in satisfactory hypertrophy before tumor progression occurs, ALPPS can be an alternative for patients with advanced hepa-tocellular carcinoma. Herein we describe an ALPPS procedure with tumor thrombectomy for a patient who had a small left liver lobe and a large hepatocellular carcinoma involving the whole right liver lobe and the middle hepatic vein and extend-ing into the inferior vena cava. In the ifrst-stage operation, the right portal vein was controlled and divided with a Hemolock. The right hepatic artery was well protected. Hepatic transec-tion was performed with a 1-cm margin from the tumor. The middle hepatic vein trunk was preserved. Ten days afterwards, there was signiifcant hypertrophy of the left lateral section of the liver, and the second-stage operation was conducted. Ex-tended right hepatectomy and tumor thrombectomy were per-formed under sternotomy and total vascular exclusion. The patient had good recovery and was free of disease 10 months after the operation. ALPPS may be a good treatment option even for patients with advanced disease if carried out at high-volume centers.     

Effectiveness of systemic chemotherapy of GEM+CBDCA+5-FU/LV and hepatic arterial infusion of CDDP in a case of advanced, combined hepatocellular-cholangiocarcinoma with multiple lung metastases

This patient is a male in his 30's. He was diagnosed as hepatitis B virus-related huge primary liver cancer, 10cm in diameter, located in segment 4, accompanied with left portal thrombus and multiple lung metastases. Ten months after repeating systemic chemotherapy using gemcitabine (GEM)+carboplatin (CBDCA)+5-FU/leucovorin (LV) and hepatic arterial infusion chemotherapy with cisplatin (CDDP) 4 times, extended left lobectomy with caudate lobe could be successfully performed because of marked reducion of the huge tumor. The pathology revealed almost entirely necrotic changes of the main tumor, and the remaining, viable tumor nests showed combined hepatocellular and cholangiocarcinoma. Systemic chemotherapy was repeatedly given afterwards, which kept the pulmonary metastases stable without growth. The present case suggests that systemic chemotherapy using GEM+CBDCA+5-FU/LV may be useful in the multimodal treatment for the combined hepatocellular and cholangiocarcinoma with distant metastases.     

Arterial, portal, or systemic chemotherapy for patients with hepatic metastasis of colorectal carcinoma

Hepatic metastases from colorectal carcinoma are common and may be resected for cure. The response of liver metastases to systemic chemotherapy is low. In contrast, hepatic arterial chemotherapy produces higher response rates than systemic chemotherapy, but randomized trials have not definitely proved a survival advantage because they allowed cross over. Most adjuvant portal vein chemotherapy studies have shown a survival advantage over the control group, but it is not clear whether this benefit is from the portal vein therapy or from immediate postoperative chemotherapy, since there is rarely a reduction in liver metastases. We describe the results of systemic, hepatic artery infusion, and portal therapy for patients with liver metastases of colorectal carcinoma.     

Alpha-fetoprotein-producing adenocarcinoma in which the metastatic route was determined from calcified lesions

Alpha-fetoprotein (AFP)-producing adenocarcinoma is known for its rapid progression and poor prognosis, and chemotherapy regimens are yet to be standardized. Here we describe the first report of AFP-producing adenocarcinoma with calcification. The metastatic route was visualized from the calcification, and combination chemotherapy was performed. A 77-year-old Japanese man was transferred to our hospital for treatment of liver tumors. Computed tomography (CT) revealed multiple liver tumors with portal vein tumor thrombosis. The tumors were highly attenuated before enhancement, suggesting various degrees of calcification. Serum levels of carcinoembryonic antigen (CEA), AFP, and the proportion of fucosylated AFP were considerably elevated. Gastroduodenoscopy revealed an elevated tumor occupying the duodenal bulb with an ulcerative lesion in the vicinity of the gastroduodenal junction, and biopsy specimens from the duodenum and liver revealed medullary adenocarcinoma with calcification. Three-dimensional reconstruction of CT images clearly showed that the calcified lesions had spread from the gastroduodenal junction to the liver via a route comprising the corresponding local vein, the superior mesenteric vein, and portal vein. The patient was accordingly diagnosed with calcified AFP-producing adenocarcinoma with multiple liver metastases. Combination chemotherapy using TS-1 and cisplatin (CDDP) resulted in a striking response for the initial 4?months in terms of tumor markers and CT findings. This is the first report of AFP-producing adenocarcinoma with calcification. A metastatic route from the primary tumor to the liver was clearly visualized by tracing the calcified lesions. Combination chemotherapy based on 5-fluorouracil and CDDP may have the potential to prolong survival.     

Treatment of portal vein tumor thrombus using ¹²5Iodine seed implantation brachytherapy

We reported two cases of liver metastasis with portal vein tumor thrombus that developed after liver transplantation for hepatocellular carcinoma (HCC). Both the patients were women aged 43 and 55 years, who had liver metastasis and portal vein tumor thrombus formation after liver transplantations for HCC. For the treatment of portal vein tumor thrombus, (125)I seeds were implanted into the hepatic tissue under the guidance of preoperative computed tomography (CT) images with a total radiation dose of 130 Gy. Enhanced spiral CT scan was performed for evaluation of the liver at 12 and 16 wk after treatment. Thereafter, upper abdominal CT examination was performed every 2-3 mo. No severe complications associated with the (125)I seeds were seen in these two patients. The upper abdominal CT images (obtained after 3 and 4 mo of treatment) showed that the thrombosis reactions were complete reaction and restoration of the patency of the partially obstructed portal vein with partial obstruction. In the case with complete obstruction of the portal vein, the thrombosis was resolved completely, but blood flow could not be restored. After this treatment, one of the patients is still alive, while the other died within 6 mo after the treatment due to lung metastasis complicated with lung infection, leading to respiratory failure.     

A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chemotherapy with the novel oral DPD-inhibiting chemotherapeutic drug S-1 and interferon-α

A 54-year-old man was admitted Osaka University Hospital for hepatocellular carcinoma (HCC) with portal vein thrombus and multiple intrahepatic metastases that extended to the bilateral lobes of the liver. He underwent multimodal therapy, including extended left lobectomy followed by intra-arterial 5-fluorourcil (5-FU) infusion chemotherapy combined with subcutaneous interferon-α (IFN-α) to treat the lesions in the residual liver. Seven months after the initial resection, recurrent tumors in the spleen, lung, and residual liver were detected by follow-up examination. We started a new regimen of per oral administration of S-1 and subcutaneous IFN-α injection, because the combined therapy with intra-arterial 5-FU infusion was not considered effective for distant metastases. After two cycles of S-1 and IFN-α, the metastatic tumor in the spleen and the recurrence in the residual liver had disappeared, and the diagnosis was complete remission with no adverse effect; the pulmonary metastasis showed a partial response, and was finally resected. This patient is still alive with no recurrence 32 months after initial hepatic resection. This outcome suggests that combination therapy with S-1 and IFN-α may be a promising treatment modality against advanced HCC with distant metastasis.     

Frequency and significance of tumor thrombi in esophageal varices in hepatocellular carcinoma associated with cirrhosis

Histological examination of the wall of the stomach and esophagus in patients with hepatocellular carcinoma associated with cirrhosis demonstrated intravariceal tumor thrombi in 13 (23.6%) of 55 cases studied. There were distant hematogenous metastases in 31 of them, of whom 12 (38.7%) had variceal tumor thrombi. Tumor thrombi were of varying sizes, and tumor cells appeared either intact, degenerated or necrotic. In seven cases, there was a firm adhesion of thrombi onto the vascular wall suggesting possible mural infiltration, but no extravascular metastases were noted grossly. These findings suggest a possibility of metastasis of hepatocellular carcinoma to the stomach and esophagus via the portal vein. It is also suggested that the degree of varices is not increased by tumor thrombus formation per se, and that both varices and tumor thrombi are due to extensive hepatofugal collateral circulation. Considering that 12 of 13 cases of intravariceal tumor thrombi had lung metastases, a portal vein-varices-lung route is possible for lung metastasis beside the established route through the hepatic vein in hepatocellular carcinoma.     

Complete remission of a case of hepatocellular carcinoma with tumor invasion in inferior vena cava and with pulmonary metastasis successfully treated with repeated arterial infusion chemotherapy

We report the case of a patient having hepatocellular carcinoma with tumor invasion to the inferior vena cava and with multiple pulmonary metastases who was treated with repeated one-shot administration of epirubicin, cisplatin, and mitomycin C by hepatic artery and bronchial artery, which led to complete remission. A 72-year-old woman was diagnosed with infiltrative hepatocellular carcinoma with Vv3, multiple intrahepatic metastases, and multiple pulmonary metastases associated with compensated liver cirrhosis. One-shot infusion of epirubicin, cisplatin, and mitomycin C was performed through proper hepatic artery and bronchial artery for twice at eight weeks of intervals. Pulmonary metastases disappeared and intrahepatic lesions indicated marked shrinkage leaving a scar-like lesion with decreases in tumor markers. After six months and 20 months, tumor markers indicated increasing tendency but no evident recurrence was found by computed tomography or hepatic arteriography. One-shot infusion of the same regimens through proper hepatic artery was performed and tumor markers decreased to normal levels. After 14 months of the last therapy, no evidence of recurrence has been found on image analysis or in tumor markers. This arterial infusion therapy is well tolerated for the patients with compensated liver cirrhosis and might be promising for the effective treatment of advanced hepatocellular carcinoma with pulmonary metastases.     

Successful surgical resection of solid cystic tumor of the pancreas with multiple liver metastases and a tumor thrombus in the portal vein

We report a case of solid cystic tumor of the pancreas with widespread liver metastases and a tumor thrombus in the portal vein. The patient was a 43-year-old woman. She was referred because of an upper abdominal mass and weight loss. Computed tomography disclosed a 10-cm cystic and calcified mass in the body and tail of the pancreas and multiple masses in the liver. She underwent a distal pancreatectomy with splenectomy, extended right lobectomy, and partial resection of the liver. All the tumors were completely resected despite the presence of 20 liver metastases. Histopathological studies showed a tumor thrombus in the intrahepatic portal vein. The patient is well without any signs of recurrence 8 months after the operation. Aggressive surgical resection is considered to yield a good outcome for solid cystic tumor with liver metastases and tumor thrombus of the portal vein.     

Ultrasonographic evaluation of portal blood flow using transhepatic carbon dioxide injection.

BACKGROUND/AIMS: The evaluation of portal blood flow in hepatic mass is important for the diagnosis of hepatocellular carcinoma. We have designed a new method to easily evaluate portal blood flow in hepatic mass using ultrasonography with injection of carbon dioxide into the intrahepatic portal vein by direct puncture with a fine needle. METHODOLOGY: We evaluated 29 masses in the liver of 20 patients ultrasonically with injection of carbon dioxide into the intrahepatic portal vein. RESULTS: Of 29 space-occupying lesions (SOLs), 13 were found to have portal blood flow and 16 were found to have no portal flow by this method. All 15 SOLs which had no portal flow were histologically confirmed to be hepatocellular carcinoma. Of 13 SOLs with portal flow, 5 were confirmed to be hepatocellular carcinoma. For 7 of 9 SOLs in which both this method and arterial portographic computed tomography were performed, the results were in agreement. CONCLUSIONS: Ultrasonographic evaluation of portal blood flow using transhepatic carbon dioxide injection appears to be useful for the evaluation of portal flow in mass and may aid in the diagnosis and management of mass in patients with liver disease.     

Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules: a case report

The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC.     

Resection of hepatocellular carcinoma with tumor thrombus of the portal vein after neoadjuvant regional chemotherapy

We report a successfully managed case of far‐advanced hepatocellular carcinoma (HCC) by intraarterial infusion therapy. A 55‐year‐old man was admitted to our hospital with abdominal pain and subileus. Abdominal ultrasonography, computed tomography, and angiography revealed HCC with obstruction of the main portal vein due to tumor thrombus. Serum levels of α‐fetoprotein (AFP) and protein induced by vitamin K absence or antagonist‐II (PIVKA‐II) were elevated. Neoadjuvant chemotherapy was tried with a course of low‐dose cisplatin (CDDP) +5‐fluorouracil (5‐FU) intrahepatic arterial infusion through the indwelling catheter via the subcutaneous reservoir port. After 7 weeks of administration (total dose CDDP 370 mg/5‐FU 18.5 mg), the main tumor size was effectively reduced. Serum levels of AFP and PIVKA‐II decreased markedly. Adverse effects were tolerated. Following the chemoinfusion therapy, posterior segmentectomy and thrombectomy were performed. Reconstruction of the portal vein was not necessary because we removed the tumor thrombus without resecting the portal vein. The postoperative course was uneventful, and the patient has been doing well more than 2 years after surgery, with no evidence of recurrence or metastasis. Preoperative low–dose CDDP +5‐FU intrahepatic arterial infusion therapy in combination with hepatic resection may be an effective treatment for advanced HCC with portal vein tumor thrombus.