Huanlin Wang

New Pathologic Stratification of Microvascular Invasion in Hepatocellular Carcinoma: Predicting Prognosis After Living-donor Liver Transplantation.

Background Vascular invasion of hepatocellular carcinoma (HCC) has a high incidence of recurrence after liver transplantation. Patients with microvascular invasion (MVI) show a high tumor grade; however, some show a good prognosis. This retrospective study aimed to investigate whether the degree of MVI affects prognosis after living-donor liver transplantation. Methods A total of 142 patients with HCC who had undergone living-donor liver transplantation were histologically evaluated about the number of invaded vessels and the maximum number of invading carcinoma cells. Patients with MVI were classified into two subgroups: high MVI group (n = 38), which showed more than 50 carcinoma cells in the vessels, with multiple invaded vessels; and low MVI group (n = 17), which showed MVI, but not high MVI. Results Analysis of recurrence-free survival showed that high MVI group had significantly poorer outcomes than the other groups (P < 0.001). High MVI group had significantly higher &agr;-fetoprotein levels, des-&ggr;-carboxy prothrombin levels, number of tumors, a larger tumor size, and a higher percentage of poorly differentiated HCC than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.030). Among patients exceeding the Milan criteria (n = 61), high MVI group had significantly poorer outcomes than the other groups for recurrence-free survival (P = 0.003). Patients in high MVI group had significantly higher des-&ggr;-carboxy prothrombin levels and a larger tumor size than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.014). Conclusion In living-donor liver transplantation for HCC, high MVI is a novel pathologic marker for predicting prognosis.

Mass-forming intrahepatic cholangiocarcinoma: Enhancement patterns in the arterial phase of dynamic hepatic CT - Correlation with clinicopathological findings.

AbstractObjectivesTo evaluate the relationship between the enhancement pattern of intrahepatic cholangiocarcinomas (ICCs) in the hepatic arterial phase (HAP) of dynamic hepatic CT and the clinicopathological findings with special reference to the perihilar type and the peripheral type.MethodsForty-seven patients with pathologically proven ICCs were enrolled. Based on the enhancement pattern in the HAP, the lesions were classified into three groups: a hypovascular group (n=13), rim-enhancement group (n=18), and hypervascular group (n=16). The clinicopathological findings were compared among the three groups.ResultsPerihilar-type ICCs were significantly more frequently observed in the hypovascular group than in the rim-enhancement and hypervascular groups (p=0.006 and p <0.001, respectively). Lymphatic invasion, perineural invasion, and biliary invasion were significantly more frequent in the hypovascular group than the rim- enhancement group (p=0.001, p=0.025 and p=0.029, respectively) or hypervascular group (p <0.001, p <0.001 and p=0.025, respectively). Patients with hypovascular lesions showed significantly poorer disease-free survival than patients with rim-enhancing or hypervascular lesions (p=0.001 and p=0.001, respectively). Hypovascularity was an independent preoperative prognostic factor for disease-free survival (p<0.001).ConclusionsHypovascular ICCs in the HAP tend to be of perihilar type and to have more malignant potential than other ICCs.Key Points• Hypovascular ICCs have greater malignant potential than rim-enhancing and hypervascular ICCs. • Hypovascular ICCs show a higher frequency of perihilar-type ICCs. • Perihilar-type ICCs do not always display distal ductal wall thickening.

Pathological analysis of opened round ligaments as venous patch grafts in living donor liver transplantation

Although the round ligament, including the umbilical vein, could be used as a venous graft in living donor liver transplantation (LDLT), no studies have determined its appropriate use on the basis of pathological findings. We prospectively examined 19 LDLT cases in which the donors round ligament was procured and used as a venous graft. The round ligaments were categorized into 3 types based on the CD31 immunohistochemistry of tissue cross‐sections: (I) canalized umbilical veins (n = 7 or 36.8%), (II) capillary umbilical vessels (n = 4 or 21.1%), and (III) occluded umbilical veins (n = 8 or 42.1%). After dilatation and incision, the round ligaments provided patch grafts that were 5.8 ± 0.4 cm long and 1.8 ± 1.2 cm wide. However, histological studies showed the absence of fine intimal layers on the dilated round ligaments after mechanical maneuvers. The ligaments were used to cuff the venous orifices in 15 patients (left lobe, n = 8; right lobe, n = 7) and were used as venous bridges in 4 patients (left lobe, n = 2; right lobe, n = 2). We detected no thrombosis at the implant sites after LDLT. Our pathological findings indicate that opened round ligaments can be used safely as venous patch grafts in LDLT. Liver Transpl 19:1245–1251, 2013.

Spalt-like transcription factor 4 immunopositivity is associated with epithelial cell adhesion molecule expression in combined hepatocellular carcinoma and cholangiocarcinoma

Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) (cHCC‐CC) is a rare biphasic liver cancer. Recent studies have demonstrated that cHCC‐CC originates from hepatic progenitor cells (HPCs). Spalt‐like transcription factor 4 (SALL4) is a marker for a progenitor subclass of HCC with an aggressive phenotype. However, little has been revealed about SALL4 expression in cHCC‐CC. The aims of this study were to report SALL4 immunopositivity and the results of clinicopathological analysis in cHCC‐CC, and to examine the two different nuclear immunostaining patterns for SALL4.

Education and imaging. Hepatology: Rare Stevens-Johnson syndrome and vanishing bile duct syndrome induced by acetaminophen, requiring liver transplantation.

A 40-year-old female with Steven Johnson syndrome (SJS) related to acetaminophen was admitted to a local hospital for steroid pulse and immunoglobulin therapy in November 2013. Although this led to resolution of her conjunctivitis and a maculopapular rash on her neck and arms, she developed progressive obstructive jaundice with signs of liver failure. Laboratory results revealed leucocytosis (WCC = 20,580/μL), alkaline phosphatase = 895 U/L, GGT = 64 U/L, AST = 63 U/L, ALT = 17 U/L, albumin = 1.8 g/dl, total serum bilirubin level = 27.9 mg/dl (direct bilirubin = 21.0 mg/dl), normal IgG4 and INR = 1.28. There was marked intrahepatic biliary dilatation, but normal common bile duct, on CT scan and MRCP (Fig. 1a). Her liver and biliary tract was normal on CT scan in the preceding 3 months (Fig 1b). MELD score was 18 points and Child-Pugh score was 10. She was transferred to our university hospital for consideration of a living-donor liver transplantation (LDLT), after the case was discussed with the Liver Transplantation Subcommittee. The left lobe was donated from her 53-year-old husband. Given blood type (AB+) of the donor was incompatible, the patient received rituximab treatment to decrease anti-blood-type antibodies. She underwent successful LDLT with duct to duct, left hepatico— common hepaticostomy. She received with tacrolimus with mycophenolate mofetil and steroids for postoperative immunosuppression. The histological examination of the explanted liver revealed vanishing bile duct syndrome (VBDS), with severe cholestasis and necrosis of hepatocyte. Cytokeratin 19 (the marker of bile duct) stains of resected liver were negative in the portal tract and small bile duct disappeared (Fig. 2). She discharged home 68 days after LT with no evidence of recurrence of VBDS. Drugs such as anti-inflammatory drugs (NSAIDs), antibiotics, tricyclic anti-depressants, neuroleptics and carbamazepine have been reported to cause SJS and VBDS. Here, we report a rare case of acetaminophen induced SJS, VBDS and liver failure, requiring LDLT. Although the mechanism of biliary epithelial cell injury and interlobular duct loss in VBDS is not well understood, drug-induced bile duct damage is often extensive and can induced irreversible ductpenia. In most cases, the treatment involves withdrawal of the offending drug, supportive care, and immunosuppressants. In rare cases, despites these measure, progressive liver failure occur and require liver transplantation, as illustrated in our case.

Hepatology: Rare Stevens-Johnson syndrome and vanishing bile duct syndrome induced by acetaminophen, requiring liver transplantation

A 40-year-old female with Steven Johnson syndrome (SJS) related to acetaminophen was admitted to a local hospital for steroid pulse and immunoglobulin therapy in November 2013. Although this led to resolution of her conjunctivitis and a maculopapular rash on her neck and arms, she developed progressive obstructive jaundice with signs of liver failure. Laboratory results revealed leucocytosis (WCC = 20,580/μL), alkaline phosphatase = 895 U/L, GGT = 64 U/L, AST = 63 U/L, ALT = 17 U/L, albumin = 1.8 g/dl, total serum bilirubin level = 27.9 mg/dl (direct bilirubin = 21.0 mg/dl), normal IgG4 and INR = 1.28. There was marked intrahepatic biliary dilatation, but normal common bile duct, on CT scan and MRCP (Fig. 1a). Her liver and biliary tract was normal on CT scan in the preceding 3 months (Fig 1b). MELD score was 18 points and Child-Pugh score was 10. She was transferred to our university hospital for consideration of a living-donor liver transplantation (LDLT), after the case was discussed with the Liver Transplantation Subcommittee. The left lobe was donated from her 53-year-old husband. Given blood type (AB+) of the donor was incompatible, the patient received rituximab treatment to decrease anti-blood-type antibodies. She underwent successful LDLT with duct to duct, left hepatico— common hepaticostomy. She received with tacrolimus with mycophenolate mofetil and steroids for postoperative immunosuppression. The histological examination of the explanted liver revealed vanishing bile duct syndrome (VBDS), with severe cholestasis and necrosis of hepatocyte. Cytokeratin 19 (the marker of bile duct) stains of resected liver were negative in the portal tract and small bile duct disappeared (Fig. 2). She discharged home 68 days after LT with no evidence of recurrence of VBDS. Drugs such as anti-inflammatory drugs (NSAIDs), antibiotics, tricyclic anti-depressants, neuroleptics and carbamazepine have been reported to cause SJS and VBDS. Here, we report a rare case of acetaminophen induced SJS, VBDS and liver failure, requiring LDLT. Although the mechanism of biliary epithelial cell injury and interlobular duct loss in VBDS is not well understood, drug-induced bile duct damage is often extensive and can induced irreversible ductpenia. In most cases, the treatment involves withdrawal of the offending drug, supportive care, and immunosuppressants. In rare cases, despites these measure, progressive liver failure occur and require liver transplantation, as illustrated in our case.

Liver transplantation for cryptogenic liver failure caused by diffuse hepatic angiosarcoma: case report

BackgroundPrimary hepatic angiosarcoma is a non-epithelial malignancy derived from sinusoidal endothelial cells, accounting for approximately 1.8% of primary hepatic malignancies. Diagnosis of primary hepatic angiosarcoma is complicated by difficulties in the qualitative radiological assessment of these tumors. Prognosis is very poor due to local recurrence and distant metastasis after liver resection or liver transplantation (LT).Case presentationThis case report describes two patients with primary hepatic angiosarcoma who were diagnosed by histopathological examination of the explanted liver after LT. One patient had undergone living donor LT, and the other had undergone deceased donor LT. Neither showed evidence of malignancy on the pre-operative imaging tests.ConclusionsHepatic angiosarcoma has a very high relapse rate after LT. Pre-transplant liver biopsy may be necessary to distinguish diffuse hepatic angiosarcoma from tumors of other origin in patients with cryptogenic liver failure.

Combined primary hepatic neuroendocrine carcinoma and hepatocellular carcinoma with aggressive biological behavior (adverse clinical course): A case report

Combined primary hepatic neuroendocrine carcinoma (PHNEC) and hepatocellular carcinoma (HCC) is a very rare malignant hepatic tumor. Its prognosis and histological features are uncertain. Here we report the case of such a tumor in a 70-year-old male Japanese patient with adverse prognosis. The patient underwent a right hepatic lobectomy for a tumor mass that measured 11×10cm in diameter located in the right lobe of the liver, treated with transcatheter arterial chemoembolization (TACE) and percutaneous transhepatic portal vein embolization (PTPE) therapy five weeks before the operation. Histologically, the hepatic tumor was composed of predominantly HCC and admixed with a small part of neuroendocrine carcinoma (NEC). The NEC component was distributed as a collision-type tumor separated by fibrous bands from HCC and the combined-type tumor, focally intermingling with HCC. One month after the surgery, metastasis to abdominal lymph nodes and the lumbar vertebra was detected. Although the additional treatments of systematic chemotherapy and radiation therapy were performed, the patient died 3 months after the initial surgery.

The changes in treatment strategies in ABOi living donor liver transplantation for acute liver failure

INTRODUCTION Living donor liver transplantation (LDLT) using ABO-incompatible (ABOi) graft for acute liver failure (ALF) is a developing treatment modality. METHODS We reviewed the changes in our treatment strategies in applying ABOi LDLT for FH over our fourteen years of experience. RESULTS Five patients with ALF received LDLT in adults using ABOi grafts, with different but gradually renewed protocols. The etiologies for acute liver failure included autoimmune hepatitis (n=3) and unknown (n=2). The desensitization protocol for ABOi barrier included Case #1; local infusion (portal vein)+plasma exchange (PE), Case #2; local infusion (hepatic artery)+rituximab+PE, Case #3 and #4; rituximab+PE, and Case #5; rituximab+PE under high-flow continuous hemodiafiltration. Local infusion was abandoned since Case #3, because Case #1 had portal vein thrombosis resulting in graft necrosis and Case #2 had hepatic artery dissection. The patients (Case #2 and #3), who received rituximab within 7 days before LDLT, experienced antibody-mediated rejection. Thus, the most recent protocol for ABOi-LDLT is that rituximab is given 2 weeks before LDLT, followed by high-flow continuous hemodiafiltration to obstacle hepatic encephalopathy until LDLT. The four patients except Case #1 are doing well with good graft function over 3.8±3.7 years. CONCLUSION Rituximab-based ABOi-LDLT, most-recently under high-flow hemodiafiltration for treating encephalopathy, is a feasible option for applying LDLT for ALF.

Liver‐enriched transcription factor expression relates to chronic hepatic failure in humans

The mechanisms by which the liver fails in end‐stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver‐enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer‐binding protein (CEBP)α, and CEBPβ. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho‐ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p‐ERM], phospho‐myosin light chain [p‐MLC], low‐density lipoprotein receptor‐related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child‐Pugh classification, Model for End‐Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4α expression was down‐regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4α expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho‐associated protein kinase pathways, which have been implicated in the regulation of HNF4α, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4α and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582‐594)