Combined hepatocellular and cholangiocarcinoma originating from the same clone: a pathomolecular evidence-based study.

BACKGROUND: Combined hepatocellular and cholangiocarcinoma (CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC); however, its cellular origin remains unclear. The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC. METHODS: The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC (SHC). Loss of heterozygosity (LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC. Expression of hepatocyte markers [hepatocyte paraffin 1 (Hep Par 1) and glypican 3 (GPC3)] and cholangiocyte markers [cytokeratin (CK)7 and 19] in tumor tissues was examined by immuno histochemical analysis. RESULTS: In the 16 CHC specimens, the difference in LOH patterns between HCC and ICC was less than 30%, suggesting the same clonal origin of HCC and ICC. Consistent with this finding, immunohistochemical analysis revealed that hepatocyte markers (Hep Par 1 and GPC3) and cholangiocyte markers (CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9% of CHC specimens, suggesting that the two components shared a similar phenotype with hepatic progenitor cells (HPCs). On the contrary, in all 10 SHC cases, the difference in LOH patterns between the HCC and ICC components was greater than 30%, suggesting different clonal origins of HCC and ICC. Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC (P < 0.05). CONCLUSIONS: Our results suggest that the HCC and ICC components of CHC may originate from the same clone, having the potential for dual-directional differentiation similar to HPCs. CHC tended to exhibit the biological behaviors of both HCC and ICC, which may enhance the infiltrative capacity of tumor cells, leading to poor clinical outcomes for patients with CHC.

Unique genetic alterations and clinicopathological features of hepatocellular adenoma in Chinese population.

Hepatocellular adenoma (HCA) is a benign hepatocyte-derived tumor commonly seen in reproductive-aged women with long-term use of oral contraceptives (OCs) in European and North American countries. Accordingly, HCA is currently classified into four molecular subtypes as adopted by the World Health Organization. The present study was firstly to characterize and determine the genetic alterations and clinicopathological features of the largest series of HCAs in China. We reviewed 189 patients with HCA who underwent hepatectomies at our liver center from January 1984 to January 2012, among which 36 HCAs were randomly selected for the sequencing of HNF1α, ß-catenin and gp130 genes, and 60 HCAs were randomly selected for detecting microsatellite instability (MSI). Compared with Western studies, our data showed distinctive findings including male (69.8%) and overweight/obese (50.3%) predominance. Only 3.5% of female patients had a documented history of OCs use for 2-4 years. All 36 sequenced HCAs showed HNF1α mutations (72% missense, 28% synonymous), 2 hotspot polymorphisms of HNF1α (I27L: rs1169288 and S487N: rs2464196) were seen in 17 (47%) and 10 (27.8%) cases, respectively, and a novel single nucleotide polymorphism site (rs1169304) in intron 9 of HNF1α was detected in 32 (88%) cases, but no ß-catenin or gp130 gene mutation was detected, and no nuclear ß-catenin staining was detected by immunohistochemistry. The frequency of MSI was 75% for D12S1398 (HNF1α inactivated pathway) and 78.5% for D6S1064 (HIPPO signaling pathway) in 34 overweight/obese patients with HCA. Our results firstly indicate that patients with HCA in China frequently occur in male overweigh and obese adult population, lack an association with OCs use and exhibit unique genetic alterations. Taken together, these observations suggest that alternative pathogenetic pathways involve in HCA tumorigenesis in Chinese patients.

Hepatic carcinosarcoma: evidence of polyclonal origin based on microsatellite analysis.

AIMS: Hepatic carcinosarcoma (HCS) is an aggressive tumor for which a consensus regarding the clonal origin has not yet been reached. The aim of the study was to identify the origin of the hepatocellular carcinoma (HCC) and sarcoma components in HCS. METHODS: We chose microsatellite technique containing loss of heterozygosity (LOH) and microsatellite instability (MSI) on three HCS patients who underwent curative resection confirmed by pathological examination. Tumors were firstly analyzed for Hep Par 1, CK18, CD10, CD117, SMA and vimentin expression by immunohistochemistry. LOH and MSI were then investigated. The incidence rate of LOH/MSI in all nine MS was calculated as the fractional allelic loss (FAL) index, which was internationally recognized standard. A FAL<30% was representative of a monoclonal origin and a FAL≥30% indicated a polyclonal origin. RESULTS: All patients were positive for HBsAg. Microscopic examination showed HCS containing two different cell types: a fibrosarcoma component with spindle cells and an HCC population of cells with a trabecular pattern. In the HCC tumor portions, Hep Par 1, CK18, CD10 were expressed while vimentin was not. In contrast, the spindle cell populations were positive for vimentin and negative for Hep Par 1, CK18, CD10. The highest frequencies of LOH and MSI were at the D16S505 (2/3; 66.7%), D17S831 (2/3; 66.7%) and D17S938 MS (2/3; 66.7%). The FALs for the three cases of HCS were 50% (4/8), 55.6% (5/9) and 33.3% (3/9), suggesting a polyclonal origin. CONCLUSIONS: Immunohistochemistry and analysis of LOH and MSI strongly demonstrated that the three HCS samples were consistent with a polyclonal origin for all three cases.

[Clinicopathological and survival features of primary hepatic lymphoma: an analysis of 35 cases].

OBJECTIVE: To evaluate the clinicopathological features and prognosis of primary hepatic lymphoma (PHL). METHODS: Thirty-five patients with PHL who underwent surgical resection and were confirmed by pathology in our hospital from 1982 to 2012 were re-evaluated for clinicopathological data, including their symptoms, radiological features, recurrence interval, histopathological properties and prognosis. RESULTS: Of the 35 patients, 25 were men (71.4%) and 10 were women (28.6%), with an average age of 52.6 years old (range, 17-79 years). Presented symptoms were epigastric phymatosis, abdominal pain and low-grade fever. In the present study, 21 (60.0%) patients were positive for HBsAg, 1(2.9%) patient was positive for anti-HCV, 3 patients were positive for AFP, 12 patients and 2 patients were complicated by cirrhosis and hepatocellular carcinoma, respectively. Pathologically, 35 PHL were classified into 19 DLBCL (54.3%), 13 T cell-lymphoma (37.1%), and 3 MALT lymphoma (8.6%). Patients with DCBCL showed better postoperative survival than patients with T cell-lymphoma (31.7 ± 3.2) months vs. (22.9 ± 2.2) months (P < 0.05). CONCLUSIONS: Hepatitis B virus (HBV) infection may contribute to the pathogenesis of Chinese patients with PHL. Surgical resection followed by comprehensive therapy is the first-line option for PHL. The prognosis of patients with PHL is associated with PHL subtypes.

SUOX is a promising diagnostic and prognostic biomarker for hepatocellular carcinoma.

BACKGROUND & AIMS: To investigate diagnostic and prognostic values of sulfite oxidase (SUOX) in patients with hepatocellular carcinoma (HCC) who underwent curative resection. METHODS: We investigated immunohistochemically the expression dynamics of SUOX, aldo-ketoreductase family 1 member B10 (AKR1B10) and CD34 at different stages of HCC. The differential diagnostic performance of three markers or their combinations in high-grade dysplastic nodules (HGDNs) and well-differentiated small HCC (WD-sHCC) were investigated by logistic regression models and validated in an independent testing set. Overall survival (OS) and time to recurrence (TTR) were evaluated in 300 patients with HCC as the testing cohort, and validated in 198 patients with HCC. RESULTS: SUOX was decreased and AKR1B10 and CD34 were increased with the stepwise progression of hepatocarcinogenesis. For differential diagnosis of WD-sHCC from HGDNs, the sensitivity and specificity of the SUOX+AKR1B10+CD34 combination for WD-sHCC detection were 93.8% and 95.2%, respectively, and overall accuracy was much higher than any of the three individual markers and two marker combinations. In addition, SUOX, but not AKR1B10 and CD34, was an independent prognostic factor for OS and TTR, and showed better correlation with OS and TTR if combined with serum α-fetoprotein (AFP) for both the testing and validation cohorts. CONCLUSIONS: SUOX+AKR1B10+CD34 combination could make a substantial contribution to hepatic immunopathological diagnosis to distinguish WD-sHCC from HGDNs. Meanwhile, SUOX combined with serum AFP may predict postoperative outcome and tumor recurrence risk.