Multiregional analysis of combined hepatocellular-cholangiocarcinoma reveals histologic diversity and molecular clonality.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of liver tumour that exhibits both hepatocytic and biliary differentiation within the same tumour. The histology and genomic alterations of recurrent/metastatic cHCC-CC are poorly understood. We selected six patients with cHCC-CC whose recurrent or metastatic tumours were histologically confirmed. Four patients with classic cHCC-CCs and two with intermediate cell carcinomas (ICs) were included. The clinicopathological features were evaluated, and next-generation sequencing was performed in 17 multiregional and longitudinal tumour samples. The histology of recurrent/metastatic lesions of classic cHCC-CCs was variable: hepatocellular carcinoma (HCC) was observed in one (25.0%) patient, cHCC-CC in one (25.0%) patient, and cholangiocarcinoma (CC) in two (50.0%) patients. Among 13 samples from four classic cHCC-CC patients, the most frequent pathological variants were TP53 (46.2%), TERT promoter (38.5%), ARID1A mutations (23.1%), and MET amplification (30.8%). In the sequencing analysis of each HCC and CC component, three (75.0%) of the four classic cHCC-CCs shared pathogenic variants. A large proportion of mutations, both pathogenic and those of undetermined significance, were shared by each HCC and CC component. Regarding ICs, the ATM mutation was detected in one patient. In conclusion, the histology of recurrent/metastatic cHCC-CCs was heterogeneous. Genomic profiling of classic cHCC-CCs revealed similar genomic alterations to those of HCC. Considerable overlapping genomic alterations in each HCC and CC component were observed, suggesting a monoclonal origin. Genetic alterations in ICs were different from those in either HCC or CC, suggesting the distinct nature of this tumour.

Comprehensive analyses of the clinicopathological features and genomic mutations of combined hepatocellular-cholangiocarcinoma.

AIM: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that has two different tumor phenotypes in a single tumor nodule. The relationship between genetic mutations and clinicopathological features of cHCC-CCA remains to be elucidated. METHODS: Whole-exome sequencing analyses were carried out in 13 primary and 2 recurrent cHCC-CCAs. The whole-exome analyses and clinicopathological information were integrated. RESULTS: TP53 was the most frequently mutated gene in this cohort, followed by BAP1, IDH1/2, and NFE2L2 mutations in multiple cases. All tumors with diameters <3 cm had TP53 mutations. In contrast, six of seven tumors with diameters ≥3 cm did not have TP53 mutations, but all seven tumors had mutations in genes associated with various pathways, including Wnt, RAS/PI3K, and epigenetic modulators. In the signature analysis, the pattern of mutations shown in the TP53 mutation group tended to be more similar to HCC than the TP53 nonmutation group. Mutations in recurrent cHCC-CCA tumors were frequently identical to those in the primary tumor, suggesting that those tumors originated from identical clones of the primary cHCC-CCA tumors. Recurrent and co-occurrent HCC tumors in the same patients with cHCC-CCA had either common or different mutation patterns from the primary cHCC-CCA tumors in each case. CONCLUSIONS: The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone.

Report of the 23rd nationwide follow-up survey of primary liver cancer in Japan (2014-2015).

For the 23rd Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 20 889 newly registered patients and 42 274 previously registered follow-up patients were compiled from 516 institutions over a 2-year period from January 1, 2014 to December 31, 2015. Basic statistics compiled for patients newly registered in the 23rd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 22nd survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non-B non-C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2004 and 2015 whose final outcome was survival or death. The median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, Child-Pugh grade, or albumin-bilirubin grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2015 into five time period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer in the world.

Perioperative and oncologic outcomes of laparoscopic versus open liver resection for combined hepatocellular-cholangiocarcinoma: a propensity score matching analysis.

BACKGROUND: Laparoscopic liver resection (LLR) has now been established as a safe and minimally invasive technique that is deemed feasible for treating hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). However, the role of LLR in treating combined hepatocellular-cholangiocarcinoma (cHCC-CC) patients has been rarely reported. This study aimed to assess the efficacy of LLR when compared with open liver resection (OLR) procedure for patients with cHCC-CC. METHODS: A total of 229 cHCC-CC patients who underwent hepatic resection (34 LLR and 195 OLR patients) from January 2014 to December 2018 in Zhongshan Hospital, Fudan University were enrolled and underwent a 1:2 propensity score matching (PSM) analysis between the LLR and OLR groups to compare perioperative and oncologic outcomes. Overall survival (OS) and recurrence-free survival (RFS) parameters were assessed by the log-rank test and the sensitivity analysis. RESULTS: A total of 34 LLR and 68 OLR patients were included after PSM analysis. The LLR group displayed a shorter postoperative hospital stay (6.61 vs. 8.26 days; p value < 0.001) when compared with the OLR group. No significant differences were observed in the postoperative complications' incidence or a negative surgical margin rate between the two groups (p value = 0.409 and p value = 1.000, respectively). The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory indicators in the LLR group were significantly lower than those in the OLR group on the first and third postoperative days. Additionally, OS and RFS were comparable in both the LLR and OLR groups (p value = 0.700 and p value = 0.780, respectively), and similar results were obtained by conducting a sensitivity analysis. CONCLUSION: LLR can impart less liver function damage, better inflammatory response attenuation contributing to a faster recovery, and parallel oncologic outcomes when compared with OLR. Therefore, LLR can be recommended as a safe and effective therapeutic modality for treating selected cHCC-CC patients, especially for those with small tumors in favorable location.

Radiofrequency ablation versus liver resection and liver transplantation for small combined hepatocellular-cholangiocarcinoma stratified by tumor size.

PURPOSE: Although radiofrequency ablation (RFA) has been proven to provide a good survival benefit for small hepatocellular carcinoma (HCC), there is limited information about RFA for combined hepatocellular-cholangiocarcinoma (cHCC-CC). The purpose of this study was to explore the clinicopathological features of cHCC-CC and the curative effect of RFA in small cHCC-CC without distant metastases compared with liver resection (LR) and liver transplantation (LT). METHODS: Patients with cHCC-CC, intrahepatic cholangiocarcinoma, or HCC were identified in the Surveillance, Epidemiology, and End Results database. RESULTS: cHCC-CC had the highest rate of poor pathological grade and the lowest rate of bone metastases compared with intrahepatic cholangiocarcinoma and HCC (all P < 0.05). In patients with cHCC-CC after surgery, multivariate analysis showed that compared with RFA, LR and LT were independent protective factors for survival (all P < 0.05). But in cHCC-CC stratified by tumor size, for tumor size ≤ 3.0 cm, there was no significant difference among RFA, LR, and LT in univariate survival analysis (P = 0.285). For tumor size 3.0-5.0 cm, multivariate analysis showed that RFA for cHCC-CC yielded worse survival outcomes in comparison with that of LR (hazard ratio [HR]: 7.51, 95% confidence interval [CI]: 2.09-26.94, P = 0.002) and LT (HR: 4.48, 95% CI: 1.20-16.64, P = 0.025). CONCLUSIONS: In patients with cHCC-CC without distant metastases, for tumor size ≤ 3.0 cm, there was no significant survival difference among RFA, LR, and LT. However, for tumor size 3.0-5.0 cm, RFA may provide a worse survival benefit than LT and LR.

Nomogram based on clinical and preoperative CT features for predicting the early recurrence of combined hepatocellular-cholangiocarcinoma: a multicenter study.

PURPOSE: To establish and validate a multiparameter prediction model for early recurrence after radical resection in patients diagnosed with combined hepatocellular-cholangiocarcinoma (cHCC-CC). MATERIALS AND METHODS: This study reviewed the clinical characteristics and preoperative CT images of 143 cHCC-CC patients who underwent radical resection from three institutions. A total of 110 patients from institution 1 were randomly divided into training set (n = 78) and testing set (n = 32) in the ratio of 7-3. Univariate and multivariate logistic regression analysis were used to construct a nomogram prediction model in the training set, which was internally and externally validated in the testing set and the validation set (n = 33) from institutions 2 and 3. The area under the curve (AUC) of receiver operating characteristics (ROC), decision curve analysis (DCA), and calibration analysis were used to evaluate the model's performance. RESULTS: The combined model demonstrated superior predictive performance compared to the clinical model, the CT model, the pathological model and the clinic-CT model in predicting the early postoperative recurrence. The nomogram based on the combined model included AST, ALP, tumor size, tumor margin, arterial phase peritumoral enhancement, and MVI (Microvascular invasion). The model had AUCs of 0.89 (95% CI 0.81-0.96), 0.85 (95% CI 0.70-0.99), and 0.86 (95% CI 0.72-1.00) in the training, testing, and validation sets, respectively, indicating high predictive power. DCA showed that the combined model had good clinical value and correction effect. CONCLUSION: A nomogram incorporating clinical characteristics and preoperative CT features can be utilized to effectively predict the early postoperative recurrence in patients with cHCC-CC.

The significance of the predominant component in combined hepatocellular-cholangiocarcinoma: MRI manifestation and prognostic value.

PURPOSE: To investigate the significance of the predominant component of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in terms of MRI manifestation and its potential prognostic value compared to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: A total of 300 patients with chronic liver disease from two centers were retrospectively enrolled, including 100 surgically proven cases of cHCC-CC, HCC, and ICC each. Univariate and multivariate regression analyses were performed to identify independent predictors for distinguishing HCC-predominant cHCC-CC and ICC-predominant cHCC-CC from HCC and ICC, respectively. Diagnostic models were constructed based on the independent features. Recurrence-free survival (RFS) was estimated and compared between groups. RESULTS: The predominant component was an independent predictor for RFS in cHCC-CC (hazard ratio = 1.957, P = 0.044). The presence of targetoid appearance (odds ratio(OR) = 10.907, P = 0.001), lack of enhancing capsule (OR = 0.072, P = 0.001) and arterial peritumoral enhancement (OR = 0.091, P = 0.003) were independent predictors suggestive of HCC-predominant cHCC-CC over HCC; their combination yielded an area under the curve of 0.756. No significant differences were observed in RFS between HCC-predominant cHCC-CC and HCC (P = 0.864). Male gender (OR = 4.049, P = 0.015), higher alpha fetoprotein (OR = 16.789, P < 0.001) and normal carbohydrate antigen 19-9 (OR = 0.343, P = 0.036) levels, presence of enhancing capsule (OR = 7.819, P < 0.001) and hemorrhage (OR = 23.526, P = 0.004), and lack of targetoid appearance (OR = 0.129, P = 0.005) and liver surface retraction (OR = 0.190, P = 0.021) were independent predictors suggestive of ICC-predominant cHCC-CC over ICC; their combination yielded an area under the curve value of 0.898. ICC-predominant cHCC-CC exhibited poorer survival with shorter RFS than ICC (P = 0.009). CONCLUSION: The predominant histopathological component is closely related to the imaging manifestation of cHCC-CC; and more importantly, it plays a significant prognostic role, which may alter the RFS prognosis of cHCC-CC.

[Advances in imaging diagnosis of mixed-type liver cancer].

Mixed-type liver cancer is a rare kind of primary malignant liver tumor with risk factors similar to those of hepatocellular carcinoma and intrahepatic cholangiocarcinoma, although treatment methods and prognosis differ. An early imaging diagnosis is helpful in adopting appropriate treatment strategies for mixed-type liver cancer. Since mixed-type liver cancer contains different proportions of hepatocellular carcinoma and cholangiocarcinoma in the same lesion, imaging manifestations may vary. This paper reviews the recent literature reports, imaging characteristics, and the latest imaging diagnostic techniques in relation to the imaging diagnosis of mixed-type liver cancer.

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs. METHODS: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling. RESULTS: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies. CONCLUSION: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. LAY SUMMARY: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

DCE-MRI based radiomics nomogram for preoperatively differentiating combined hepatocellular-cholangiocarcinoma from mass-forming intrahepatic cholangiocarcinoma.

OBJECTIVE: To establish a radiomics nomogram based on dynamic contrast-enhanced (DCE) MR images to preoperatively differentiate combined hepatocellular-cholangiocarcinoma (cHCC-CC) from mass-forming intrahepatic cholangiocarcinoma (IMCC). METHODS: A total of 151 training cohort patients (45 cHCC-CC and 106 IMCC) and 65 validation cohort patients (19 cHCC-CC and 46 IMCC) were enrolled. Findings of clinical characteristics and MR features were analyzed. Radiomics features were extracted from the DCE-MR images. A radiomics signature was built based on radiomics features by the least absolute shrinkage and selection operator algorithm. Univariate and multivariate analyses were used to identify the significant clinicoradiological variables and construct a clinical model. The radiomics signature and significant clinicoradiological variables were then incorporated into the radiomics nomogram by multivariate logistic regression analysis. Performance of the radiomics nomogram, radiomics signature, and clinical model was assessed by receiver operating characteristic and area under the curve (AUC) was compared. RESULTS: Eleven radiomics features were selected to develop the radiomics signature. The radiomics nomogram integrating the alpha fetoprotein, background liver disease (cirrhosis or chronic hepatitis), and radiomics signature showed favorable calibration and discrimination performance with an AUC value of 0.945 in training cohort and 0.897 in validation cohort. The AUCs for the radiomics signature and clinical model were 0.848 and 0.856 in training cohort and 0.792 and 0.809 in validation cohort, respectively. The radiomics nomogram outperformed both the radiomics signature and clinical model alone (p < 0.05). CONCLUSION: The radiomics nomogram based on DCE-MRI may provide an effective and noninvasive tool to differentiate cHCC-CC from IMCC, which could help guide treatment strategies. KEY POINTS: • The radiomics signature based on dynamic contrast-enhanced magnetic resonance imaging is useful to preoperatively differentiate cHCC-CC from IMCC. • The radiomics nomogram showed the best performance in both training and validation cohorts for differentiating cHCC-CC from IMCC.

Report of the 22nd nationwide follow-up Survey of Primary Liver Cancer in Japan (2012-2013).

In the 22nd Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 21 155 newly registered patients and 43 041 previously registered follow-up patients were compiled from 538 institutions over a 2-year period from January 1, 2012 to December 31, 2013. Basic statistics compiled for patients newly registered in the 22nd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathologic diagnosis, recurrence status and autopsy findings. Compared with the previous 21st survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, more patients with non-B non-C HCC, smaller tumor diameter and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2002 and 2013 whose final outcome was survival or death. Median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter or Child-Pugh grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2013 into five time period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer worldwide.

Differentiation between combined hepatocellular carcinoma and hepatocellular carcinoma: comparison of diagnostic performance between ultrasomics-based model and CEUS LI-RADS v2017.

BACKGROUND: The imaging findings of combined hepatocellular cholangiocarcinoma (CHC) may be similar to those of hepatocellular carcinoma (HCC). CEUS LI-RADS may not perform well in distinguishing CHC from HCC. Studies have shown that radiomics has an excellent imaging analysis ability. This study aimed to establish and confirm an ultrasomics model for differentiating CHC from HCC. METHODS: Between 2004 and 2016, we retrospectively identified 53 eligible CHC patients and randomly included 106 eligible HCC patients with a ratio of HCC:CHC = 2:1, all of whom were categorized according to Contrast-Enhanced (CE) ultrasonography (US) Liver Imaging Reporting and Data System (LI-RADS) version 2017. The model based on ultrasomics features of CE US was developed in 74 HCC and 37 CHC and confirmed in 32 HCC and 16 CHC. The diagnostic performance of the LI-RADS or ultrasomics model was assessed by the area under the curve (AUC), accuracy, sensitivity and specificity. RESULTS: In the entire and validation cohorts, 67.0% and 81.3% of HCC cases were correctly assigned to LR-5 or LR-TIV contiguous with LR-5, and 73.6% and 87.5% of CHC cases were assigned to LR-M correctly. Up to 33.0% of HCC and 26.4% of CHC were misclassified by CE US LI-RADS. A total of 90.6% of HCC as well as 87.5% of CHC correctly diagnosed by the ultrasomics model in the validation cohort. The AUC, accuracy, sensitivity of the ultrasomics model were higher though without significant difference than those of CE US LI-RADS in the validation cohort. CONCLUSION: The proposed ultrasomics model showed higher ability though the difference was not significantly different for differentiating CHC from HCC, which may be helpful in clinical diagnosis.

Development and validation of nomogram to predict very early recurrence of combined hepatocellular-cholangiocarcinoma after hepatic resection: a multi-institutional study.

BACKGROUND AND OBJECTIVES: Combined hepatocellular cholangiocarcinoma (cHCC) has a high incidence of early recurrence. The objective of this study is to construct a model predicting very early recurrence (VER) (i.e., recurrence within 6 months after surgery) of cHCC. METHODS: One hundred thirty-one consecutive patients from Eastern Hepatobiliary Surgery Hospital served as a development cohort to construct a nomogram predicting VER by using multi-variable logistic regression analysis. The model was internally and externally validated in a validation cohort of 90 patients from Mengchao Hepatobiliary Hospital using the C concordance statistic, calibration analysis, and decision curve analysis (DCA). RESULTS: The VER nomogram contains microvascular invasion (MiVI), macrovascular invasion (MaVI), and CA19-9 > 25 mAU/mL. The model shows good discrimination with C-indexes of 0.77 (95% CI: 0.69-0.85) and 0.76 (95% CI: 0.66-0.86) in the development cohort and validation cohort respectively. Decision curve analysis demonstrated that the model is clinically useful and the calibration of our model was favorable. Our model stratified patients into two different risk groups, which exhibited significantly different VER. CONCLUSIONS: Our model demonstrated favorable performance in predicting VER in cHCC patients.

Combined hepatocellular-cholangiocarcinoma: An update.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a tumour that exhibits both hepatocytic and biliary differentiation. Classical risk factors for hepatocellular carcinoma (HCC) seem to also predispose patients to the development of cHCC-CCA. The pathological definition of cHCC-CCA has significantly evolved over time. The last 2019 WHO classification highlighted that the diagnosis of cHCC-CCA should be primarily based on morphology using routine stainings, with additional immunostaining used to refine the identification of subtypes. Among them, "intermediate cell carcinoma" is recognised as a specific subtype, while "cholangiolocellular carcinoma" is now considered a subtype of iCCA. Increasing molecular evidence supports the clonal nature of cHCC-CCA and parallels its biphenotypic histological appearance, with genetic alterations that are classically observed in HCC and/or iCCA. That said, the morphological diagnosis of cHCC-CCA is still challenging for radiologists and pathologists, especially on biopsy specimens. Identification of cHCC-CCA's cell of origin remains an area of active research. Its prognosis is generally worse than that of HCC, and similar to that of iCCA. Resection with lymph node dissection is unfortunately the only curative option for patients with cHCC-CCA. Thus, there remains an urgent need to develop specific therapeutic strategies for this unique clinical entity.

Comparing the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma with those of other primary liver cancers by use of the updated World Health Organization classification.

AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon hepatic malignancy with a poor outcome. The 2019 World Health Organization (WHO) classification modified the definition and discarded the subtypes with stem cell features. However, the differences among cHCC-CCA, hepatocellular carcinoma (HCC), HCC with stem cell/progenitor features (HCCscf) and intrahepatic cholangiocarcinoma (iCCA) remain undetermined. The aim of this study was to investigate the characteristics of cHCC-CCA in comparison with those of other primary liver cancers by utilising the updated WHO classification. METHODS AND RESULTS: We retrospectively analysed 64 cHCC-CCA patients and 55 HCCscf patients from December 2007 to May 2018. Propensity score matching was conducted to compare these with HCC and iCCA patients. Clinicopathological characteristics, event-free survival and overall survival were evaluated with multivariate Cox proportional hazard regression. During a median follow-up of 55.9 months, cHCC-CCA patients had significantly poorer survival than HCCscf patients, and survival intermediate between that of HCC patients and that of iCCA patients. Hepatitis B virus (HBV) infection and high levels of tumour-infiltrating lymphocytes (TILs) were associated with favourable survival in cHCC-CCA patients. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease and low levels of TILs were significant negative prognostic factors in cHCC-CCA patients. After being pooled with other primary liver cancers, cHCC-CCA and iCCA resulted in the worse survival. CONCLUSIONS: cHCC-CCA patients have survival intermediate between that of HCC patients and iCCA patients, and HBV infection and high levels of TILs predict favourable survival. Our study provides clinical correlations for the new 2019 WHO classification.

Combined Hepatocellular-Cholangiocarcinoma: Magnetic Resonance Imaging Features and Prognosis According to Risk Factors for Hepatocellular Carcinoma.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) can develop in patients with and without risk factors for hepatocellular carcinoma (HCC). PURPOSE: To compare the clinical and magnetic resonance imaging (MRI) characteristics of cHCC-CCA in patients with and without risk factors for HCC, and to assess the influence of risk factors on patient prognosis. STUDY TYPE: Retrospective. POPULATION: A total of 152 patients with surgically confirmed cHCC-CCA. FIELD STRENGTH/SEQUENCE: 1.5-T and 3-T/T1-weighted dual gradient-echo in- and opposed-phase, T2-weighted turbo-spin-echo, diffusion-weighted single-shot spin-echo echo-planar, and T1-weighted three-dimensional gradient-echo contrast-enhanced sequences. ASSESSMENT: MRI features according to the Liver Imaging Reporting and Data System (LI-RADS) and pathologic findings based on revised classification were compared between patients with and without risk factors for HCC. Overall survival (OS) and recurrence-free survival (RFS) were also compared between the two groups, and factors associated with survival were evaluated. STATISTICAL TESTS: The clinico-pathologic and MRI features of the two groups were compared using Student's t-tests, Mann-Whitney U-tests, and chi-square tests. OS and RFS were evaluated by the Kaplan-Meier method, and factors associated with survival were evaluated by Cox proportional hazard model. RESULTS: cHCC-CCA in patients with risk factors were more frequently classified as LI-RADS category 4 or 5 (LR-4/5; probably or definitely HCC) (48.7%), whereas those without risk factors were more frequently classified as category M (LR-M; probably malignant, not specific for HCC) (63.6%). RFS and OS did not differ significantly according to risk factors (P = 0.63 and 0.83). Multivariable analysis showed that pathologic tumor type (hazard ratio 2.02; P < 0.05) and LI-RADS category (hazard ratio 2.19; P < 0.05) were significantly associated with RFS and OS, respectively. DATA CONCLUSION: Although MRI features of cHCC-CCA differed significantly between patients with and without risk factors for HCC, postsurgical prognosis did not. LI-RADS category and pathologic tumor type were independently correlated with postsurgical prognosis in patients with cHCC-CCA. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Clinical outcomes of systemic therapy in patients with unresectable or metastatic combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA. METHODS: Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated. RESULTS: Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS. CONCLUSIONS: The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.

Clinicopathologic and MRI features of combined hepatocellular-cholangiocarcinoma in patients with or without cirrhosis.

BACKGROUND AND AIMS: Differences in combined hepatocellular-cholangiocarcinomas (cHCC-CCAs) arising in high-risk patients with or without liver cirrhosis have not been elucidated. This study aimed to compare the clinicopathologic and imaging characteristics of cHCC-CCAs in patients with or without cirrhosis and to determine the prognostic factors for recurrence-free survival (RFS) after curative resections of single cHCC-CCAs. METHODS: This retrospective study included 113 patients with surgically resected single cHCC-CCAs who underwent preoperative magnetic resonance imaging from January 2008 to December 2019 at two tertiary referral centres. Clinical, pathologic and imaging features of tumours were compared in high-risk patients with or without cirrhosis. Imaging features were assessed using the Liver Imaging Reporting and Data System (LI-RADS) version 2018. RFS and associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis and log-rank test. RESULTS: cHCC-CCAs arising from cirrhotic livers had a smaller mean tumour size (2.9 cm vs. 4.5 cm; P < .001) and were more frequently categorized as LR-5 or 4 (41.2% vs. 20.0%; P = .024) than those arising from non-cirrhotic livers. In multivariable analysis, a tumour size of > 3 cm (hazard ratio [HR], 2.081; 95% confidence interval [CI], 1.180-3.668; P = .011) and the LR-M category (HR, 2.302; 95% CI, 1.198-4.424; P = .012) were independent predictors associated with worse RFS. CONCLUSIONS: The tumour size and distribution of LI-RADS categories of cHCC-CCAs differed in high-risk patients with or without cirrhosis. And LR-M category was a worse prognosis predictor after curative resections than LR-5 or 4 category.

Report of the 21st Nationwide Follow-up Survey of Primary Liver Cancer in Japan (2010-2011).

In the 21st Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 22,134 new patients and 41,956 previously followed patients were compiled from 546 institutions over a 2-year period from 1 January 2010 to 31 December 2011. Basic statistics compiled for patients newly registered in the 21st survey were cause of death, medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 20th survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non-B non-C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy and with radiofrequency ablation. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 1998 and 2011 whose final outcome was survival or death (excluding unknown). Cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, and Child-Pugh grade) and by treatment type (hepatectomy, local ablation therapy, transcatheter arterial chemoembolization, and hepatic arterial infusion chemotherapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2011 into four time-period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer.

Combined hepatocellular-cholangiocarcinoma and its mimickers: Diagnostic pitfalls in surgical pathology.

BACKGROUND: The diagnosis of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) requires histomorphological detection of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). However, these primary liver cancers (PLCs) have a wide variety of microscopic appearances resulting in difficulties and uncertainties in cHCC-CCA's diagnosis. This study aims to perform a clinicopathologic analysis on the diagnosis of PLCs at a tertiary referral hospital in Thailand using traditional morphologic studies. METHODS: A 5-year retrospective analysis of pathologically diagnosed PLCs was conducted. Pathological features and clinical characteristics of cHCC-CCA and other PLCs with the histopathologic resemblance to cHCC-CCA were studied. The pathological diagnosis was rendered based on histomorphological context rather than immunoreactivity. A literature review containing diagnostic pitfalls of cHCC-CCA was carried out. RESULTS: PLCs from a total of 295 patients were retrieved, and cHCC-CCA accounted for 1.4% (n = 4) of the malignancies. Histomorphological evaluation is the most reliable diagnostic modality for cHCC-CCA. Extremely uncommon variants of iCCA (i.e., mucinous iCCA and adenosquamous iCCA) and iCCA arising with hepatocellular nodular lesions (i.e., iCCA with nodular regenerative hyperplasia (NRH), and iCCA in cirrhosis) could have a histomorphologic resemblance to that of cHCC-CCA. CONCLUSIONS: Although there has been an exceedingly high incidence of iCCA in Thailand, such a commonness is not valid for cHCC-CCA in our series. Rare forms of iCCA could have a morphologic resemblance to that of cHCC-CCA. Regardless of the differentiation and immunophenotype, iCCA without a distinct HCC component should never be diagnosed as cHCC-CCA.