Combined hepatocellular cholangiocarcinoma: A clinicopathological update

Combined hepatocellular-cholangiocarcinoma(cHCC-CCA)is a rare primary liver cancer associated with an appalling prognosis.The diagnosis and manage-ment of this entity have been challenging to physicians,radiologists,surgeons,pathologists,and oncologists alike.The diagnostic and prognostic value of biomarkers such as the immunohistochemical expression of nestin,a progenitor cell marker,have been explored recently.With a better understanding of biology and the clinical course of cHCC-CCA,newer treatment modalities like immune checkpoint inhibitors are being tried to improve the survival of patients with this rare disease.In this review,we give an account of the recent developments in the pathology,diagnostic approach,and management of cHCC-CCA.

Combined hepatocellular-cholangiocarcinoma:An update on epidemiology,classification,diagnosis and management

Background:Combined hepatocellular-cholangiocarcinoma(CHC)is a rare subtype of primary hepatic malignancies,with variably reported incidence between 0.4%–14.2%of primary liver cancer cases.This study aimed to systematically review the epidemiological,clinicopathological,diagnostic and therapeutic data for this rare entity.Data sources:We reviewed the literature of diagnostic approach of CHC with special reference to its clinical,molecular and histopathological characteristics.Additional analysis of the recent literature in order to evaluate the results of surgical and systemic treatment of this entity has been accomplished.Results:The median age at CHC’s diagnosis appears to be between 50 and 75 years.Evaluation of tumor markers[alpha fetoprotein(AFP),carbohydrate antigen 19–9(CA19–9)and carcinoembryonic antigen(CEA)]along with imaging patterns provides better opportunities for CHC’s preoperative diagnosis.Reported clinicopathologic prognostic parameters possibly correlated with increased tumor recurrence and grimmer survival odds include advanced age,tumor size,nodal and distal metastases,vascular and regional organ invasion,multifocality,decreased capsule formation,stem-cell features verification and increased GGT as well as CA19–9 and CEA levels.In case of inoperable or recurrent disease,combinations of cholangiocarcinoma-directed systemic agents display superior results over sorafenib.Liver-directed methods,such as transarterial chemoembolization(TACE),percutaneous ethanol injection(PEI),hepatic arterial infusion chemotherapy(HAIC),radioembolization and ablative therapies,demonstrate inferior efficacy than in cases of hepatocellular carcinoma(HCC)due to CHC’s common hypovascularity.Conclusions:CHC demonstrates an overlapping clinical and biological pattern between its malignant ingredients.Natural history of the disease seems to be determined by the predominant tumor element.Gold standard for diagnosis is histology of surgical specimens.Regarding therapeutic interventions,major hepatectomy is acknowledged as the cornerstone of treatment whereas minor hepatectomy and liver transplantation may be applied in patients with advanced cirrhosis.Despite all therapeutic attempts,prognosis of CHC remains dismal.

Long-term outcomes of combined hepatocellular-cholangiocarcinoma after hepatectomy or liver transplantation: A systematic review and meta-analysis

Background: Combined hepatocellular-cholangiocarcinoma(cHCC-CC) is a rare primary liver malignancy. We conducted a systematic review and meta-analysis to assess the evidence available on the long-term outcomes of cHCC-CC patients after either hepatectomy or liver transplantation(LT). Data Sources: Relevant studies published between January 2000 and January 2018 were identified by searching Pub Med and Embase and reviewed systematically. Data were pooled using a random-effects model. Results: A total of 42 observational studies involving 1691 patients(1390 for partial hepatectomy and 301 for LT) were included in the analysis. The median tumor recurrence and 5-year overall survival(OS) rates were 65%(range 38%–100%) and 29%(range 0–63%) after hepatectomy versus 54%(range 14%–93%) and 41%(range 16%–73%) after LT, respectively. Meta-analysis found no significant difference in OS and tumor recurrence between LT and hepatectomy groups. Conclusion: Hepatectomy rather than LT should be considered as the prior treatment option for cHCC-CC.

Risk factors for combined hepatocellular-cholangiocarcinoma:A hospital-based case-control study

AIM: To identify risk factors contributing to the development of combined hepatocellular-cholangiocarcinoma (CHC) in China.

Contrast-enhanced ultrasound in association with serum biomarkers for differentiating combined hepatocellular-cholangiocarcinoma from hepatocellular carcinoma and intrahepatic cholangiocarcinoma

BACKGROUND Combined hepatocellular-cholangiocarcinoma(CHC)is a rare type of primary liver cancer.Due to its complex histopathological characteristics,the imaging features of CHC can overlap with those of hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC).AIM To investigate the possibility and efficacy of differentiating CHC from HCC and ICC by using contrast-enhanced ultrasound(CEUS)Liver Imaging Reporting and Data System(LI-RADS)and tumor biomarkers.METHODS Between January 2016 and December 2019,patients with histologically confirmed CHC,ICC and HCC with chronic liver disease were enrolled.The diagnostic formula for CHC was as follows:(1)LR-5 or LR-M with elevated alphafetoprotein(AFP)and carbohydrate antigen 19-9(CA19-9);(2)LR-M with elevated AFP and normal CA19-9;or(3)LR-5 with elevated CA19-9 and normal AFP.The sensitivity,specificity,accuracy and area under the receiver operating characteristic curve were calculated to determine the diagnostic value of the criteria.RESULTS After propensity score matching,134 patients(mean age of 51.4±9.4 years,108 men)were enrolled,including 35 CHC,29 ICC and 70 HCC patients.Based on CEUS LI-RADS classification,74.3%(26/35)and 25.7%(9/35)of CHC lesions were assessed as LR-M and LR-5,respectively.The rates of elevated AFP and CA19-9 in CHC patients were 51.4%and 11.4%,respectively,and simultaneous elevations of AFP and CA19-9 were found in 8.6%(3/35)of CHC patients.The sensitivity,specificity,positive predictive value,negative predictive value,accuracy and area under the receiver operating characteristic curve of the aforementioned diagnostic criteria for discriminating CHC from HCC and ICC were 40.0%,89.9%,58.3%,80.9%,76.9%and 0.649,respectively.When considering the reported prevalence of CHC(0.4%-14.2%),the positive predictive value and NPV were revised to 1.6%-39.6%and 90.1%-99.7%,respectively.CONCLUSION CHCs are more likely to be classified as LR-M than LR-5 by CEUS LI-RADS.The combination of the CEUS LI-RADS classification with serum tumor markers shows high specificity but low sensitivity for the diagnosis of CHC.Moreover,CHC could be confidently excluded with high NPV.

Prognostic analysis of patients with combined hepatocellularcholangiocarcinoma after radical resection:A retrospective multicenter cohort study

BACKGROUND Combined hepatocellular-cholangiocarcinoma(cHCC-CCA)is a form of rare primary liver cancer that combines intrahepatic cholangiocarcinoma(ICC)and hepatocellular carcinoma.AIM To investigate overall survival(OS)and recurrence-free survival(RFS)after radical resection in patients with cHCC-CCA,and the clinicopathological factors affecting prognosis in two center hospitals of China.METHODS We reviewed consecutive patients with cHCC-CCA who received radical resection between January 2005 and September 2021 at Peking Union Medical College and the 5th Medical Center of the PLA General Hospital retrospectively.Regular follow-up and clinicopathological characteristics were systematic collected for baseline and prognostic analysis.RESULTS Our study included 95 patients who received radical resection.The majority of these patients were male and 82.7%of these patients were infected with HBV.The mean tumor size was 4.5 cm,and approximately 40%of patients had more than one lesion.The median OS was 26.8(95%CI:18.5-43.0)mo,and the median RFS was 7.27(95%CI:5.83-10.3)mo.Independent predictors of OS were CA19-9≥37 U/mL(HR=8.68,P=0.002),Child-Pugh score>5(HR=5.52,P=0.027),tumor number>1(HR=30.85,P=0.002),tumor size and transarterial chemoembolization(TACE)after surgery(HR=0.2,P=0.005).CONCLUSION The overall postoperative survival of cHCC-CCA patients is poor,and most patients experience relapse within a short period of time after surgery.Preoperative tumor biomarker(CA19-9,alphafetoprotein)levels,tumor size,and Child-Pugh score can significantly affect OS.Adjuvant TACE after surgery prolongs RFS,suggesting that TACE is a possible option for postoperative adjuvant therapy in patients with cHCC-CCA.

Synchronous Double Primary Combined Hepatocellularcholangiocarcinoma and Cholangiolocarcinoma in a Cirrhotic Liver

Both combined hepatocellular-cholangiocarcinoma(cHCCCCA)and cholangiolocarcinoma are rare primary liver cancers.cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells.Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells.According to the 2019 revision of the World Health Organization criteria,a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory.That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA.Consequently,cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct.Herein,we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver.We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma.Furthermore,this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment.The results provide valuable insights into the mechanisms of growth,differentiation,and regulation of liver cancers.

Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is macroscopically classified into three subtypes, mass-forming-type, periductal infiltrating-type, and intraductal growth-type. Each subtype should be preoperatively differentiated to perform the valid surgical resection. Recent researches have revealed the clinical, radiologic, pathobiological characteristics of each subtype. We reviewed recently published studies covering various aspects of intrahepatic cholangiocarcinoma(ICC), focusing especially on the macroscopic subtypes and stem cell features to better understand the pathophysiology of ICC and to establish the valid therapeutic strategy.

Three-in-one incidence of hepatocellular carcinoma,cholangiocellular carcinoma,and neuroendocrine carcinoma:A case report

BACKGROUND Primary hepatic neuroendocrine carcinoma(NEC)is rare,and a combination with hepatocellular carcinoma(HCC)and cholangiocarcinoma(CCA)is extremely rare.To date,only four combination cases have been reported.The present paper describes the fifth patient.CASE SUMMARY A 32-year-old Chinese man with chronic hepatitis B was hospitalized for persistent upper abdominal pain.Abdominal computed tomography(CT)examination revealed a liver mass.The tumor was located in the 7th and 8th segments of the liver,and CT and magnetic resonance imaging findings were consistent with the diagnosis of HCC.Laboratory examinations revealed the following:Alanine aminotransferase,243 U/L;aspartate aminotransferase,167 U/L;alpha-fetoprotein,4519μg/L.Laparoscopic right lobe hepatectomy was performed on the liver mass.Postoperative pathology showed low differentiation HCC plus medium and low differentiation CCA combined with NEC.One month after the surgery,the patient suffered from epigastric pain again.Liver metastasis was detected by CT,and tumor transcatheter arterial chemoembolization was performed.Unfortunately,the liver tumor was progressively increased and enlarged,and after 1 mo,the patient died of liver failure.CONCLUSION This is a rare case,wherein the tumor is highly aggressive,grows rapidly,and metastasizes in a short period.Imaging and laboratory tests can easily misdiagnose or miss such cases;thus,the final diagnosis relies on pathology.

Update on the Diagnosis and Treatment of Combined Hepatocellular Cholangiocarcinoma

Combined hepatocellular-cholangiocarcinoma(cHCC-CCA)is a unique type of liver tumor that contains both hepatocellular carcinoma and cholangiocarcinoma components within a single tumor.The fifth edition of the World Health Organization classification provides a definition and diagnostic criteria for cHCC-CCA.However,the heterogeneous histomorphology and presentation resulting from variation of the proportion of each component poses challenges for clinical diagnosis and treatment.A diagnosis of cHCC-CCA may be suggested by the synchronous elevation of serum tumor markers for hepatocellular carcinoma and cholangiocarcinoma,a mixed enhancement pattern on imaging,and a discrepancy between the elevation of tumor marker and the imaging enhancement pattern.Histopathological examination using hematoxylin and eosin staining is considered the gold standard for diagnosing cHCC-CCA,and comprehensive examination of resection or biopsy specimens is crucial for an accurate diagnosis.Currently,there is no standard treatment for cHCC-CCA,and surgery is the mainstay.Anatomic hepatectomy with lymphadenectomy is among the recommended surgical procedures.The role of liver transplantation in the management of cHCC-CCA is still uncertain.Transarterial chemoembolization may be effective for unresectable cHCC-CCA,particularly for hypervascular tumors.However,the available evidence does not support systemic therapy for advanced cHCC-CCA.The prognosis of cHCC-CCA is generally poor,and there is no established staging system.Further research is needed to better understand the histogenesis and clinical management of cHCC-CCA.This review provides an overview of the current literature on cHCC-CCA with a focus on its clinical characteristics,pathological diagnosis,and management.