Clinicopathological characteristics and prognosis of combined hepatocellular cholangiocarcinoma.

There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification.

Li Y ，He D ，Lu ZJ ，Gu XF ，Liu XY ，Chen M ，Tu YX ，Zhou Y ，Owen G ，Zhang X ，Jiang D ... -  《BMC CANCER》

Expression of fibroblast growth factor receptor 2 (FGFR2) in combined hepatocellular-cholangiocarcinoma and intrahepatic cholangiocarcinoma: clinicopathological study.

Genetic alterations including fusions in fibroblast growth factor receptor 2 (FGFR2) are detected in 10-20% of intrahepatic cholangiocarcinoma (iCCA), and FGFR2 inhibitors are effective for the treatment of iCCA. We examined a prevalence of FGFR2 genetic alterations and their clinicopathological significance in combined hepatocellular-cholangiocarcinoma (cHCC-CCA). FGFR2 expression, which is a surrogate marker for FGFR2 genetic alterations, was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 35 with small duct-type iCCA, 30 with large duct-type iCCA, and 35 with hepatocellular carcinoma (HCC). FGFR2 genetic alterations were detected by reverse transcription-PCR and direct sequence. An association of FGFR2 expression with clinicopathological features was investigated in cHCC-CCAs. FGFR2 expression was detected in significantly more patients with cHCC-CCA (21.3%) and small duct-type iCCA (25.7%), compared to those with large duct-type iCCA (3.3%) and HCC (0%) (p < 0.05). FGFR2-positive cHCC-CCAs were significantly smaller size (p < 0.05), with more predominant cholangiolocarcinoma component (p < 0.01) and less nestin expression (p < 0.05). Genetic alterations of ARID1A and BAP1 and multiple genes were significantly more frequent in FGFR2-positive cHCC-CCAs (p < 0.05). 5'/3' imbalance in FGFR2 genes indicating exon18-truncated FGFR2 was significantly more frequently detected in FGFR2-positive cHCC-CCAs and small duct iCCAs, compared to FGFR2-negative ones (p < 0.05). FGFR2::BICC fusion was detected in a case of cHCC-CCAs. FGFR2 genetic alterations may be prevalent in cHCC-CCAs as well as small duct-type iCCAs, which suggest cHCC-CCAs may also be a possible therapeutic target of FGFR2 inhibitors.

Sasaki M ，Sato Y ，Nakanuma Y 《-》

Is nestin a diagnostic marker for combined hepatocellular-cholangiocarcinoma?

The type IV intermediate filament, nestin, may be a candidate diagnostic marker for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Therefore, the significance of nestin as a diagnostic marker for cHCC-CCA categorized by the World Health Organization (WHO) 2019 classification and its relationship with clinicopathological features were examined in the present study. Nestin expression was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 22 with small duct-type intrahepatic cholangiocarcinoma (iCCA), 20 with large duct-type iCCA and 35 with hepatocellular carcinoma (HCC). Nestin expression and its relationship with clinicopathological features and genetic alterations were investigated in cHCC-CCA. Nestin expression was detected in significantly more patients with cHCC-CCA (66.7%) than in those with large duct-type iCCA (5%) (P < 0.01), HCC (2.9%) (P < 0.01) and small duct-type iCCA (40.9%) (P < 0.05). Nestin expression was partly associated with neural cell adhesion molecule (NCAM) and vimentin expression. Nestin expression was also observed in significantly more patients with small duct-type iCCA than in those with large duct-type iCCA and HCC (P < 0.01). Nestin-positive cHCC-CCA was characterized by a smaller tumour size, the more frequent presence of cholangiolocellular carcinoma (CLC) components, a higher rate of p53 overexpression and a higher rate of multiple genetic alterations (P < 0.05). Furthermore, p53 overexpression was associated with a higher histological grade and multiple genetic alterations (P < 0.05) in nestin-positive cHCC-CCA. Nestin may be a useful diagnostic marker for a specific subgroup of cHCC-CCA and small duct-type iCCA associated with CLC components, p53 mutations and multiple genetic alterations, which are related to stemness and multipotent differentiation.

Sasaki M ，Sato Y ，Nakanuma Y 《-》

YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role.

Van Haele M ，Moya IM ，Karaman R ，Rens G ，Snoeck J ，Govaere O ，Nevens F ，Verslype C ，Topal B ，Monbaliu D ，Halder G ，Roskams T ... -  《-》

The clinical characteristics and prognostic factors of combined Hepatocellular Carcinoma and Cholangiocarcinoma, Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma after Surgical Resection: A propensity score matching analysis.

Background: Clinical characteristics and prognosis among combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (cHCC-CC) with HCC and intrahepatic cholangiocarcinoma (ICC) were inconsistent in previous studies. The aim of this study was to compare postoperative prognosis among cHCC-CC, HCC and ICC, and investigated the prognostic risk factor of cHCC-CC after surgical resection. Methods: A total of 1041 eligible patients with pathological diagnosis of cHCC-CC (n=135), HCC (n=698) and ICC (n=208) were enrolled in this study. Univariate and multivariate Cox analysis were applied for assessing important risk factors. cHCC-CC were further 1:1 matched with HCC and ICC on important clinical risk factors. Survival curves of matched and unmatched cohorts were depicted by Kaplan-Meier method with log-rank test. Results: Patients with cHCC-CC had similar rate of sex, age and cirrhosis with HCC (p<0.05) and comparable incidence of hepatitis B or C with ICC (p=0.197). Patients of cHCC-CC had intermediate prognosis between HCC and ICC, with median overall survival (OS) time of cHCC-CC, HCC and ICC of 20.5 months, 35.7 months and 11.6 months (p<0.001). In matched cohorts, the OS of cHCC-CC were worse than HCC (p<0.001) but comparable with ICC (p=0.06), while the disease-free survival (DFS) of cHCC-CC was worse than HCC but better than ICC (p<0.05). And lymph node infiltration and postoperative transarterial chemoembolization (TACE) were independent risk factors of cHCC-CC associated with prognosis. Conclusion: The long term survival of cHCC-CC was worse than HCC but comparable with ICC when matched on albumin level, tumor size, lymph node infiltration, tumor stage and margin. Presence of lymph node infiltration and no postoperative TACE were associated with poor prognosis of cHCC-CC.

Tang Y ，Wang L ，Teng F ，Zhang T ，Zhao Y ，Chen Z ... -  《-》