Clinicopathological features and recurrence patterns of combined hepatocellular-cholangiocarcinoma.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a primary liver carcinoma with both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) components. We examined the clinicopathological characteristics and recurrence patterns of cHCC-CCA. Because of the rarity of cHCC-CCA, its etiology, clinicopathological features, and prognosis in comparison with other primary liver carcinoma remain unknown. Its recurrence pattern and sites in particular also need to be elucidated. METHODS: All patients who underwent hepatectomy for primary liver malignancies between 2005 and 2015 were retrospectively included in this study. RESULTS: Eight hundred and ninety-four hepatectomies were performed. Nineteen cases of cHCC-CCA (2.1%) in 16 patients were enrolled. Three patients underwent re-hepatectomy. The background of hepatitis viruses and tumor marker patterns of cHCC-CCA were similar to those of HCC and dissimilar to those of intrahepatic CCA (iCCA). Biliary invasion was common in cHCC-CCA and iCCA. The 5-year overall survival values of the cHCC-CCA, HCC, and iCCA patients were 44.7%, 56.6%, and 38.5%, respectively. The 5-year recurrence-free survival values of the cHCC-CCA, HCC, and iCCA patients were 12.2%, 28.7%, and 32.9%, respectively. The liver was the most common recurrence site. Unlike HCC, however, the lymph node was the second-most common recurrence site in both cHCC-CCA and iCCA. Pathological samples of the recurrent lesions were obtained in six patients, and four had cHCC-CCA recurrence pathologically. CONCLUSION: cHCC-CCA had a mixture of characteristics of HCC and iCCA. Many cases of cHCC-CCA remained cHCC-CCA pathologically even after recurrence.

Combined hepatocellular-cholangiocarcinoma: a population level analysis of incidence and mortality trends.

BACKGROUND: The purpose of this study was to explore trends in incidence, incidence-based (IB) mortality, and survival for combined hepatocellular-cholangiocarcinoma (cHCC-CC) utilizing a population-based database to attract people's attention to this disease. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to investigate the incidence and IB mortality for cHCC-CC from 2000 to 2014. Trends in age-adjusted incidence and IB mortality were characterized by the Joinpoint Regression program. The Kaplan-Meier method and log-rank test were utilized to implement survival analyses. Cox regression was utilized to estimate independent predictors of mortality. RESULTS: The incidence of cHCC-CC was 0.26 per 1,000,000 individuals in 2000 and 0.59 per 1,000,000 individuals in 2014, with an annual percent change (APC) (i.e., the extent of increase in incidence) of 3.84% (95% confidence interval [CI] 1.7-6.1; P < 0.05). The IB mortality also displayed a sustained increase (APC was 4.59%, 95% CI 1.9-7.4; P < 0.05). Compared to patients not undergoing surgery, patients undergoing surgical treatment experienced a significant increase in median survival (3 vs. 28 months; P < 0.001). However, the median survival decreased in patients with tumor size > 5 cm (20 vs. 9 months; P < 0.001). Based on univariate Cox regression analysis, African-American race, distant stage, regionalized stage, tumor size ≥ 5 cm, and no surgery were risk factors for death. CONCLUSIONS: We identified an overall steady increase in the incidence of cHCC-CC, which indicates that primary prevention strategies for cHCC-CC have not improved much in recent years and that cHCC-CC needs to be taken seriously.

Positive expression of Midkine predicts early recurrence and poor prognosis of initially resectable combined hepatocellular cholangiocarcinoma.

BACKGROUND: Post-surgical prognosis is usually poor for combined hepatocellular cholangiocarcinoma (CHCC-CC), a rare primary liver cancer. Although midkine (MK) is a prognostic biomarker for several known cancers, it is not known whether it can be used as such in resectable CHCC-CC. This study examined whether MK expression can predict recurrence and survival in patients with resectable CHCC-CC. METHODS: We retrospectively enrolled 52 patients with resectable CHCC-CC who had received curative hepatic resections. MK expression was assessed in post-surgical immunohistochemical studies of specimens in paraffin blocks. Clinical outcomes were analyzed from medical records. RESULTS: Two-year disease-free and three-year overall survival rates were 42.1% and 44.6%. MK was expressed in 30 patients. Univariate analysis showed patients positively expressing MK had a significantly poorer 2-year disease free and three-year overall survival. Multivariate analysis found positive MK expression independently predicted recurrence. CONCLUSIONS: Positive expression of MK predicts poor prognosis in patients with resectable CHCC-CC.

Pediatric combined hepatocellular-cholangiocarcinoma (cHCC-CC) with neuroendocrine features: distinguishing genetic alterations detected by chromosomal microarray.

BACKGROUND: Liver tumors exhibiting hepatocellular, cholangiocarcinoma, and neuroendocrine features are extremely rare, with only five cases reported in the literature. CASE PRESENTATION: We present an unusual case of a combined hepatocellular-cholangiocarcinoma (cHCC-CC) with neuroendocrine features in a pediatric patient. A 16-year-old presented with abdominal pain and a 21.0 cm mass in the right hepatic lobe with extension into the left lobe. Histology showed a poorly differentiated tumor with a solid, tubuloglandular, and microcystic architecture. Immunohistochemistry results were negative for hepatic markers, positive for markers of biliary differentiation, and positive for neuroendocrine differentiation. The neoplasm was reviewed at several institutions with differing diagnoses. Single nucleotide polymorphism (SNP) chromosomal microarray (CMA) showed large deletions within chromosomes 6q and 13q in both the hepatocellular-like areas and the cholangiocarcinoma-like areas, with additional large deletions in the cholangiocarcinoma-like areas, supporting origin from hepatocellular carcinoma. The final diagnosis was a cHCC-CC with neuroendocrine features. CONCLUSIONS: Diagnosis of cHCC-CCs relies predominately on histomorphology, as per the 2018 International Consensus Group on the nomenclature of cHCC-CC. These findings in this case support that the pathological classification of these lesions be based on molecular data, which could better direct treatment. Further classification of cHCC-CCs and determination of their clinicopathological relevance will require more interobserver consistency and continued molecular profiling of these lesions.

Ataxia-telangiectasia and combined hepatocellular-cholangiocarcinoma: A case report.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disease characterized by ataxia, cutaneous and ocular telangiectasia, impaired immunity with susceptibility to sino-pulmonary infections, radiation sensitivity, and cancers particularly of hemato-lymphoid origin. Liver function tests abnormalities and elevated alfa feto-protein have been reported in A-T; however, there is no reported case of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in literature. These tumors should be treated in similar fashion as in general population; however, reduction of chemotherapy dose might be helpful in decreasing chemo-toxicity.

Surgical Strategies for Combined Hepatocellular-Cholangiocarcinoma (cHCC-CC).

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a tumor entity presenting features of hepatocellular and cholangiocellular epithelial differentiation. Due to the likeness between cHCC-CC, HCC and CC, accurate pretherapeutical diagnosis is challenging and advanced stages are prevalent. Radical oncological surgery is the only curative therapeutical option in patients with cHCC-CC. To reach this goal a profound understanding of this rare liver tumor is crucial. Factors such as clinicopathological characteristics, growth patterns and biological behavior are of central importance. To explore onco-surgical strategies and aspects for complete resection of cHCC-CC and to answer important key questions, an extensive review of the literature was conducted to answer the following questions: What are the best surgical options? Is there a significance for nonanatomical resections? Is there a prognostic value of concomitant lymphadenectomy? What about multimodal concepts in local advanced cHCC-CC? The role of minimally invasive liver surgery (MILS) including the role of robotic liver surgery for cHCC-CC will be discussed. While liver transplantation (LT) is standard for patients with unresectable HCC, the role of LT in cHCC-CC patients is still controversial. How can patients with high risk for early tumor recurrence be identified to avoid aggressive surgical treatment without clinical benefit? The comprehensive understanding of this challenging liver tumor will help to improve future treatment options for these patients.

Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma.

Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options.

MRI-based radiomics distinguish different pathological types of hepatocellular carcinoma.

OBJECT: To distinguish combined hepatocellular cholangiocarcinoma (cHCC-CC), hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) before operation using MRI radiomics. METHOD: This study retrospectively analyzed 196 liver cancers: 33 cHCC-CC, 88 HCC and 75 CC. They had confirmed by pathological analysis in the Affiliated Hospital of Hebei University. MRI lesions were manually segmented by a radiologist.1316 features were extracted from MRI lesions by Pyradiomics. Useful features were retained through two-level feature selection to establish a classification model. Receiver operating characteristic (ROC), area under curve (AUC) and F1-score were used to evaluate the performance of the model. RESULTS: Compared with low-order image features, the performance of the model based on high-order features was improved by about 10%. The model showed better performance in identifying HCC tumors during the delay phase (AUC = 0.91, sensitivity = 0.88, specificity = 0.89, accuracy = 0.89, F1-Score = 0.88). CONCLUSION: The classification ability of cHCC-CC, HCC and CC can be further improved by extracting MRI high-order features and using a two-level feature selection method.

Diagnostic Performance of LI-RADS Version 2018 for Primary Liver Cancer in Patients With Liver Cirrhosis on Enhanced MRI.

Purpose: The study evaluated the diagnostic performance of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 for differentiating hepatocellular carcinoma (HCC) from primary liver cancer in patients with liver cirrhosis based on the updated 2019 WHO classification. Materials and Methods: From 2016 to 2021, 300 patients with surgically confirmed primary liver cancer (PLC) and liver cirrhosis based on the updated 2019 WHO classification were eligible for this retrospective study (100 cases in each of three groups including HCC, ICC, and cHCC-CCA). Two radiologists were blinded to the final diagnosis and independently assigned an LI-RADS category to each liver nodule. The diagnostic performances of the LR-5 category (definitely HCC), and the LR-M category (probably or definitely malignant, but not specific for HCC) were calculated in overall and small observations (<20 mm). Comparisons between groups of categorical variables were performed by one-way analysis of variance and the Chi-squared or Fisher's exact test. Results: The mean age of 300 patients (226 men and 74 women) was 57.40 ± 11.05 years. The sensitivity and specificity of the LR-5 category for differentiating HCCs from other primary liver cancers were 81% (81 of 100) and 82% (164 of 200), respectively. The LR-M category had a sensitivity of 63% (126 of 200) for diagnosing non-HCCs (ICCs and cHCC-CCAs), with a specificity of 90% (90 of 100). The LR-5 category had a sensitivity of 82.5% (33 of 40) for diagnosing HCCs in small observations (<20 mm) with a specificity of 76.6% (59 of 77). On the contrary, LR-M demonstrated slightly higher specificity (93.8%) and sensitivity (73.8%) for diagnosing non-HCCs with tumor size <20 mm. Conclusion: The LR-5 category as well as the LR-M category of Liver Imaging Reporting and Data System (LI-RADS) version 2018 can effectively distinguish hepatocellular carcinoma from other primary hepatic malignancies in patients with liver cirrhosis, especially for small observations (<20 mm).

Patients' prognosis of intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma after resection.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) and intrahepatic cholangiocarcinoma (ICC) are classified into one category, but comparison of prognosis of the two carcinomas remains controversial. The aim of the current study was to investigate surgical outcomes for patients with ICC or cHCC-CC who underwent resection in order to elucidate whether the classification of ICC and cHCC-CC is justified. Subjects were 61 patients with ICC and 29 patients with cHCC-CC who underwent liver resection from 2001 to 2017. Clinic-pathological data from the two groups were compared. Tumor number and vascular invasion were independent risk factors for recurrence-free survival (RFS) in both groups (P < .001 for both). Of note, for patients with ICC, tumor cut-off size of 5 cm showed statistical significance in median RFS (>5 cm vs ≤5 cm, 0.5 years vs 4.0 years, P = .003). For patients with cHCC-CC, tumor cut-off size of 2 cm showed statistical significance in median RFS (>2 cm vs ≤2 cm, 0.6 years vs 2.6 years, P = .038). The median RFS of patients with cHCC-CC was 0.9 years (95% confidence interval: 0.3-1.6), which was poorer than that of patients with ICC (1.3 years, 0.5-2.1) (P = .028); the rate of RFS at 5 years was 0% and 37.7% respectively. Our study supports the concept of classifying ICC and cHCC-CC into different categories because of a significant difference in RFS between the two.

Liver transplantation and combined hepatocellular-cholangiocarcinoma: Feasibility and outcomes.

INTRODUCTION: Combined hepatocellular-cholangiocarcinoma (CHC or cHCC-CC) is a rare primary liver tumor displaying histological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Most patients are not suitable for surgery because of the advanced stage of the disease at the moment of diagnosis. We decided to review the literature in order to identify the outcomes after liver transplantation for CHC and to clarify which is the most appropriate treatment. MATERIAL AND METHODS: A systematic literature search was performed. Studies reporting outcomes of liver transplantation (LT) for CHC and studies comparing oncologic outcomes after LT versus liver resection (LR) for CHC were included in this review. RESULTS: The mean 5-y Disease Free Survival (DFS) reported in literature is 45.4%, while the mean 5-y overall survival (OS) is 41.8%, analyzing a cohort of 418 cases. The mean DSF in our series after LT was 7.97 months, while the mean OS was 11.7 months. CONCLUSIONS: LT should be avoided for the treatment of CHC, in order to allocate organs for more appropriate diseases. Moreover, surgical resections, and in particular major hepatectomies, seem to be associated with acceptable outcomes. An accurate preoperative management is needed, and the use of PET-CT when differential diagnosis is difficult should be considered.

Living donor liver transplantation for hepatocellular carcinoma at the University of Tokyo Hospital.

BACKGROUND: Living donor liver transplantation (LDLT) is an established treatment not only for those with end-stage liver disease but for those with hepatocellular carcinoma (HCC) developing in cirrhotic liver. The aim of this study was to present a single-center experience of LDLT for HCC at the University of Tokyo Hospital, Japan. METHODS: Among 573 liver transplant recipients from January 1996 until the end of 2015, 139 patients have been indicated LDLT for the treatment of HCC, and were the subjects of the present study. We use the expanded criteria for HCC as follows; the number of tumor should be five or less, and the maximum diameter of the tumor should be 5 cm or less, without the distant metastasis nor the vascular invasion (Tokyo criteria, 5-5 rule). We also focused on the identification of the incidental intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma/cholangiocarcinoma (cHCC-CC) in liver explants. RESULTS: The overall 1-, 5-, and 10-year recurrence-free and patient survival rates were 95%, 91%, and 91%, 91%, and 80%, 78%, respectively. The 1-, 3-, and 5-year cumulative recurrence rate was 5%, 6%, and 6% for within Milan, 0%, 8%, and 8% for beyond Milan/within Tokyo, and 33%, 50%, and 50% for beyond Tokyo, respectively, demonstrating the significantly impaired outcome of those beyond Tokyo criteria (P<0.001). The high alpha-fetoprotein (AFP) value (≥400 ng/mL), the high des-gamma-carboxy prothrombin (DCP) value (≥200 mAU/mL) and beyond the Tokyo criteria were proved to be significant predictors for the HCC recurrence, but the size or the type of the partial graft was not associated. Incidental ICC and cHCC-CC were found in one and two patients, respectively, with the size of less than 2 cm in all cases. ICC was not detected in preoperative evaluation but cHCC-CCs were misdiagnosed as HCC preoperatively. All three patients were alive without recurrence with a follow-up period of 2 to 14 years. CONCLUSIONS: The present results of our institution seem acceptable in terms of the recurrence-free and patient survival. The issues of the expansion of indication, living donor vs. deceased donor for HCC, and liver transplantation (LT) for cholangiocarcinoma are still left to be investigated in future studies.

Circulating Tumor DNA Analysis for Liver Cancers and Its Usefulness as a Liquid Biopsy.

BACKGROUND & AIMS: Circulating tumor DNA (ctDNA) carrying tumor-specific sequence alterations has been found in the cell-free fraction of blood. Liver cancer tumor specimens are difficult to obtain, and noninvasive methods are required to assess cancer progression and characterize underlying genomic features. METHODS: We analyzed 46 patients with hepatocellular carcinoma who underwent hepatectomy or liver transplantation and for whom whole-genome sequencing data was available. We designed personalized assays targeting somatic rearrangements of each tumor to quantify serum ctDNA. Exome sequencing was performed using cell-free DNA paired primary tumor tissue DNA from a patient with recurrent liver cancer after transcatheter arterial chemoembolization (TACE). RESULTS: We successfully detected ctDNA from 100 µL of serum samples in 7 of the 46 patients before surgery, increasing with disease progression. The cumulative incidence of recurrence and extrahepatic metastasis in the ctDNA-positive group were statistically significantly worse than in the ctDNA-negative group (P = .0102 and .0386, respectively). Multivariate analysis identified ctDNA (OR 6.10; 95% CI, 1.11-33.33, P = .038) as an independent predictor of microscopic vascular invasion of the portal vein (VP). We identified 45 nonsynonymous somatic mutations in cell-free DNA after TACE and 71 nonsynonymous somatic mutations in primary tumor tissue by exome sequencing. We identified 25 common mutations in both samples, and 83% of mutations identified in the primary tumor could be detected in the cell-free DNA. CONCLUSIONS: The presence of ctDNA reflects tumor progression, and detection of ctDNA can predict VP and recurrence, especially extrahepatic metastasis within 2 years. Our study demonstrated the usefulness of ctDNA detection and sequencing analysis of cell-free DNA for personalized treatment of liver cancer.

A case of primary biliary cirrhosis that complicated with combined hepatocellular and cholangiocellular carcinoma.

Primary biliary cirrhosis (PBC) is frequently complicated with hepatocellular carcinoma (HCC), but complication with combined hepatocellular and cholangiocellular carcinoma (cHCC-CC) or cholangiocellular carcinoma (CCC) has not been reported. Here, we describe a case of PBC in which cHCC-CC occurred. The patient was a 70-year-old man who had developed jaundice at 62 years old. He was diagnosed with PBC based on a liver biopsy and blood tests. In August 2006, blood tests showed elevated alpha-fetoprotein, and a liver tumor in the right lobe and a metastatic lymphadenopathy in the back near to the head of the pancreas were detected by abdominal contrast-enhanced CT. A (18)F-fluorodeoxyglucose-PET scan showed accumulation of the tracer in the tumor and in a lymph node at the back of the pancreas. The tumor and lymph node were removed, and the tumor was diagnosed pathologically as cHCC-CC based on the presence of features of HCC and CCC. This case is the first to show that a patient with PBC can develop cHCC-CC. This is of interest, since cHCC-CC may originate in hepatic stem cells or hepatic precursor cells. This case also suggests that cHCC-CC should be included as a differential diagnosis for a liver tumor complicated with PBC.