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

AIM: 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. METHODS AND RESULTS: We defined the diffuse finely granular nuclear immunostaining pattern as immunopositive for SALL4; this was observed in eight (8.9%) of 90 cHCC-CCs. SALL4 immunopositivity was significantly associated with immunopositivity for α-fetoprotein, glypican 3, and epithelial cell adhesion molecule (EpCAM). There was no relationship between SALL4 immunopositivity and prognosis. We confirmed SALL4 mRNA expression in samples with a punctuate/clumped immunostaining pattern, which showed a significantly lower rate of immunopositivity for EpCAM than those with a diffuse finely granular pattern. CONCLUSIONS: SALL4 immunopositivity is not a prognostic factor in cHCC-CC; however, it is associated with α-fetoprotein, glypican 3 and EpCAM immunopositivity, indicating the mechanism of carcinogenesis. Further study is necessary to interpret the immunostaining pattern for SALL4.

[Multiple pyogenic liver abscesses with the decline in neutrophil phagocytic function: a case report].

A 51-year-old man presenting with fever, weight loss and general fatigue was diagnosed with jaundice and liver tumors and admitted to our hospital for further investigation and treatment. We diagnosed multiple pyogenic liver abscesses, obstructive jaundice, and silent syphilis. The patient was successfully treated with endoscopic biliary stenting, endoscopic nasobiliary drainage, percutaneous transhepatic abscess drainage, and, most effectively, transcatheter regional hepatic arterial infusion with antibiotics. We speculated that the decline in neutrophil phagocytic function may concern to occur the pyogenic liver abscess.

[A case of pancreatic well-differentiated neuroendocrine carcinoma surviving 8 years and 5 months with treatments for multiple liver tumors diagnosed as carcinoid tumor].

The case was a 58-year-old woman who visited our hospital for a thorough examination after multiple liver tumors were found in her at a nearby hospital. By liver tumor biopsy, we diagnosed them as carcinoid. Bone scintigraphy showed an abnormal accumulation in the external left scapula and in both of her hip joints, but the primary lesion was unclear. She died 8 years and 5 months after disease onset from deterioration of liver lesions, inspite of our treatments, such as gemcitabine administration of systemic chemotherapy, transcatheter arterial chemoembolization for liver lesions, and radiation therapy for bone lesions. Pathological anatomy suggested a pancreatic, well-differentiated neuroendocrine carcinoma.

Improved indocyanine green retention after short-term lenvatinib withdrawal in three patients with hepatocellular carcinoma.

Use of lenvatinib, which has a high response rate in advanced hepatocellular carcinoma, sometimes results in tumor shrinkage and resectability of previously unresectable liver cancers. In Asia, including Japan, liver reserve, one of the determinants of resectability, is mainly determined by the indocyanine green (ICG) retention rate. Three patients with advanced liver cancer treated at our institution had very poor ICG retention rates during treatment with lenvatinib. Lenvatinib may reduce blood flow in both cancerous and non-cancerous regions by inhibiting vascular endothelial growth factor. Therefore, accurate determination of liver function likely requires withdrawal of this treatment several days before ICG retention testing.

Activation of the Akt/mammalian target of rapamycin pathway in combined hepatocellular carcinoma and cholangiocarcinoma: significant correlation between p-4E-BP1 expression in cholangiocarcinoma component and prognosis.

The Akt/mammalian target of rapamycin (mTOR) pathway, which plays an important role in regulating cellular functions including proliferation, motility, and invasion, is known to be activated in many cancers. Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) (cHCC-CC) has wide histological diversity characterized by relatively poor prognosis. Because of a lack of investigation into its molecular mechanisms, no effective systemic therapy is currently available for unresectable cHCC-CC tumors. Here, we retrospectively examined the clinicopathological and activation statuses of the Akt/mTOR pathway in 89 cases of cHCC-CC. Expression levels of molecular markers associated with this signaling pathway, including phosphatase and tensin homologue deleted on chromosome 10 (PTEN), phosphorylated Akt (p-Akt), p-mTOR, p-ribosomal protein S6 (p-S6RP), and p-eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (p-4E-BP1), were measured by immunohistochemical staining. In addition, such activation in different cHCC-CC morphological categories was compared by dividing cases into those with HCC (n = 86), CC (n = 78), and intermediate components (n = 60). Comparison of prognosis among these groups revealed that p-4E-BP1 immunopositivity in cHCC-CC cases containing CC a component was a significant risk factor for poorer overall survival (P = 0.041). By evaluating factors in p-4E-BP1 expression in 78 cHCC-CC cases with a CC component, only lymph node metastasis was significantly correlated with positive immunostaining for p-4E-BP1 (P = 0.0222). In conclusion, p-4E-BP1 expression, especially in cHCC-CC cases with a CC component, was a notable Akt/mTOR pathway-related factor associated with poor prognosis. Assessing histological structure and p-4E-BP1 expression in cHCC-CC may be helpful for both predicting prognosis and using molecular targeted therapy.

Elevated non-invasive liver fibrosis markers and risk of liver carcinoma in adult patients after repair of tetralogy of Fallot.

BACKGROUND: Congestive hepatopathy and hepatocellular carcinoma is a serious complication after Fontan procedure. Liver fibrosis due to hepatic congestion could occur also in adult patients after repair of tetralogy of Fallot (rTOF). However, the incidence and severity remain unclear. METHODS: A total of 111 patients with adult congenital heart disease between 2009 and 2016 were enrolled. Liver fibrosis markers and hemodynamic parameters assessed by cardiac magnetic resonance imaging and catheterization were analyzed in 50 rTOF patients having significant pulmonary regurgitation and/or stenosis, 50 Fontan patients and 11 controls. RESULTS: Liver fibrosis markers in patients with rTOF were significantly higher than controls, and tended to be lower than Fontan patients (median, hyaluronic acid: 25.8 vs. 15.9 vs. 40.8, type IV collagen: 129 vs. 113 vs. 166, ng/mL, p < 0.05, respectively). Patients with rTOF showed abnormal hyaluronic acid levels more frequently than controls, and less frequently than Fontan patients (22% vs. 0% vs. 38%, respectively, p < 0.05). Multivariate analyses indicated a positive association of right atrial pressure with type IV-collagen or hyaluronic acid levels (each, p < 0.001, p = 0.003). Abdominal ultrasonography revealed hepatic congestion in 50% of rTOF patients tested. Liver biopsy of the two rTOF patients with highest hyaluronic acid levels showed pathological evidence of moderate and severe (F2 and F3) liver fibrosis and one had combined hepatocellular and cholangiocarcinoma. CONCLUSIONS: We first demonstrated elevated liver fibrosis markers in adult patients with rTOF. These levels may help to predict the progressive liver disease as well as consider the timing of pulmonary valve replacement.

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.

Coexpression of SALL4 with HDAC1 and/or HDAC2 is associated with underexpression of PTEN and poor prognosis in patients with hepatocellular carcinoma.

Spalt-like transcriptional factor 4 (SALL4), a stem marker, is reactivated in several cancers. A previous study has demonstrated that SALL4 interacts with the nucleosome remodeling deacetylase complex, which contains histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2). In this study, we investigated the expression status of SALL4, HDAC1, and HDAC2 and their relationship with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by immunohistochemical analysis of the posthepatectomy specimens of 135 patients with hepatocellular carcinoma who were treated at our hospital. Ninety-two frozen samples were subjected to quantitative reverse-transcription polymerase chain reaction analysis to detect the messenger RNA levels of PTEN. Seventy-six (56%) of 135 patients were positive for SALL4, and this group had a higher prevalence of hepatitis B antigen, a higher value of α-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKAII) and poor histologic differentiation. The 5-year survival rate was significantly lower in the SALL4-positive group. High HDAC1 expression (51%) was correlated with a poor histologic differentiation and a poor prognosis. High HDAC2 expression (46%) was associated with a higher prevalence of hepatitis B antigen positivity, a poor histologic differentiation and higher prevalence of vascular invasion, and a lower 5-year survival rate. Coexpression of SALL4 with HDAC1 and/or HDAC2 was correlated with underexpression of PTEN. Moreover, multivariable analysis revealed that coexpression of SALL4 with HDAC1 and/or HDAC2 was predictive of an unfavorable prognosis. Our data thus suggested that the combination of SALL4, HDAC1, and HDAC2 may provide a potential target for molecular therapy.