Correction:Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellularcholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant

Rereading the article“Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant”(DOI:10.5306/wjco.v13.i8.688),published on August 24,we observe,with concern,that figures 3 and 4 are wrong.The authors have attached the correct figures for correction.

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.

Ultrasomics in liver cancer: Developing a radiomics model for differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma using contrast-enhanced ultrasound

BACKGROUND Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)represent the predominant histological types of primary liver cancer,comprising over 99%of cases.Given their differing biological behaviors,prognoses,and treatment strategies,accurately differentiating between HCC and ICC is crucial for effective clinical management.Radiomics,an emerging image processing technology,can automatically extract various quantitative image features that may elude the human eye.Reports on the application of ultrasound(US)-based radiomics methods in distinguishing HCC from ICC are limited.METHODS In our retrospective study,we included a total of 280 patients who were diagnosed with ICC(n=140)and HCC(n=140)between 1999 and 2019.These patients were divided into training(n=224)and testing(n=56)groups for analysis.US images and relevant clinical characteristics were collected.We utilized the XGBoost method to extract and select radiomics features and further employed a random forest algorithm to establish ultrasomics models.We compared the diagnostic performances of these ultrasomics models with that of radiologists.RESULTS Four distinct ultrasomics models were constructed,with the number of selected features varying between models:13 features for the US model;15 for the contrast-enhanced ultrasound(CEUS)model;13 for the combined US+CEUS model;and 21 for the US+CEUS+clinical data model.The US+CEUS+clinical data model yielded the highest area under the receiver operating characteristic curve(AUC)among all models,achieving an AUC of 0.973 in the validation cohort and 0.971 in the test cohort.This performance exceeded even the most experienced radiologist(AUC=0.964).The AUC for the US+CEUS model(training cohort AUC=0.964,test cohort AUC=0.955)was significantly higher than that of the US model alone(training cohort AUC=0.822,test cohort AUC=0.816).This finding underscored the significant benefit of incorporating CEUS information in accurately distin-guishing ICC from HCC.CONCLUSION We developed a radiomics diagnostic model based on CEUS images capable of quickly distinguishing HCC from ICC,which outperformed experienced radiologists.

Propensity-matched analysis of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma and hepatocellular carcinoma undergoing a liver transplant

BACKGROUND Cholangiocarcinoma(CC)is a rare tumor that arises from the epithelium of the bile ducts.It is classified according to anatomic location as intrahepatic,perihilar,and distal.Intrahepatic CC(ICC)is rare in patients with cirrhosis due to causes other than primary sclerosing cholangitis.Mixed hepatocellular carcinoma-CC(HCC-CC)is a rare neoplasm that shows histologic findings of both HCC and ICC within the same tumor mass.Due to the difficulties in arriving at the correct diagnosis,patients eventually undergo liver transplantation(LT)with a presumptive diagnosis of HCC on imaging when,in fact,they have ICC or HCC-CC.AIM To evaluate the outcomes of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma on pathological examination after liver transplant.METHODS Propensity score matching was used to analyze tumor recurrence(TR),overall mortality(OM),and recurrence-free survival(RFS)in LT recipients with pathologically confirmed ICC or HCC-CC matched 1:8 to those with HCC.Progression-free survival and overall mortality rates were computed with the Kaplan-Meier method using Cox regression for comparison.RESULTS Of 475 HCC LT recipients,1.7%had the diagnosis of ICC and 1.5%of HCC-CC on pathological examination of the explant.LT recipients with ICC had higher TR(46%vs 11%;P=0.006),higher OM(63%vs 23%;P=0.002),and lower RFS(38%vs 89%;P=0.002)than those with HCC when matched for pretransplant tumor characteristics,as well as higher TR(46%vs 23%;P=0.083),higher OM(63%vs 35%;P=0.026),and lower RFS(38%vs 59%;P=0.037)when matched for posttransplant tumor characteristics.Two pairings were performed to compare the outcomes of LT recipients with HCC-CC vs HCC.There was no significant difference between the outcomes in either pairing.CONCLUSION Patients with ICC had worse outcomes than patients undergoing LT for HCC.The outcomes of patients with HCC-CC did not differ significantly from those of patients with HCC.

Dynamic contrast enhanced ultrasound in differential diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

BACKGROUND Non-invasive differential diagnosis between hepatocellular carcinoma(HCC)and other liver cancer(i.e.cholangiocarcinoma or metastasis)is highly challenging and definitive diagnosis still relies on histological exam.The patterns of enhancement and wash-out of liver nodules can be used to stratify the risk of malignancy only in cirrhotic patients and HCC frequently shows atypical features.Dynamic contrast-enhanced ultrasound(DCEUS)with standardized software could help to overcome these obstacles,providing functional and quantitative parameters and potentially improving accuracy in the evaluation of tumor perfusion.AIM To explore clinical evidence regarding the application of DCEUS in the differential diagnosis of liver nodules.METHODS A comprehensive literature search of clinical studies was performed to identify the parameters of DCEUS that could relate to histological diagnosis.In accordance with the study protocol,a qualitative and quantitative analysis of the evidence was planned.RESULTS Rise time was significantly higher in HCC patients with a standardized mean difference(SMD)of 0.83(95%CI:0.48-1.18).Similarly,other statistically significant parameters were mean transit time local with a SMD of 0.73(95%CI:0.20-1.27),peak enhancement with a SMD of 0.37(95%CI:0.03-0.70),area wash-in area under the curve with a SMD of 0.47(95%CI:0.13-0.81),wash-out area under the curve with a SMD of 0.55(95%CI:0.21-0.89)and wash-in and wash-out area under the curve with SMD of 0.51(95%CI:0.17-0.85).SMD resulted not significant in fall time and wash-in rate,but the latter presented a trend towards greater values in HCC compared to intrahepatic cholangiocarcinoma.CONCLUSION DCEUS could improve non-invasive diagnosis of HCC,leading to less liver biopsy and early treatment.This quantitative analysis needs to be applied on larger cohorts to confirm these preliminary results.

Neuroendocrine carcinoma of the common hepatic duct coexisting with distal cholangiocarcinoma:A case report and review of literature

BACKGROUND Neuroendocrine carcinoma(NEC)of the extrahepatic bile duct is very rare,and the treatment and prognosis are unclear.Herein,we report the case of a middleaged female with primary large cell NEC(LCNEC)of the common hepatic duct combined with distal cholangiocarcinoma(dCCA).Additionally,after a review of the relevant literature,we summarize and compare mixed neuroendocrine-nonneuroendocrine neoplasm(MiNEN)and pure NEC to provide a reference for selecting the appropriate treatment and predicting the prognosis of this rare disease.CASE SUMMARY A 62-year-old female presented to the hospital due to recurrent abdominal pain for 2 months.Physical examination showed mild tenderness in the upper abdomen and a positive Courvoisier sign.Blood tests showed elevated liver transaminase and carbohydrate antigen 199 levels.Imaging examination revealed node dissection was performed,and hepatic duct tumours were unexpectedly found during surgery.Pathology suggested poorly differentiated LCNEC(approximately 0.5 cm×0.5 cm×0.4 cm),Ki-67(50%),synaptophysin+,and chromogranin A+.dCCA pathology suggested moderately differentiated adenocarcinoma.The patient eventually developed lymph node metastasis in the liver,bone,peritoneum,and abdominal cavity and died 24 months after surgery.Gene sequencing methods were used to compare gene mutations in the two primary bile duct tumours.CONCLUSION The prognosis of MiNEN and pure NEC alone is different,and the selection of treatment options needs to be differentiated.

Liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma:A multicenter study

BACKGROUND Patients with combined hepatocellular carcinoma and cholangiocarcinoma(cHCC-CC)are not traditionally considered eligible for liver transplantation(LT)AIM To compare outcomes between living donor LT(LDLT)patients with hepatocellular carcinoma(HCC)and LT patients with cHCC-CC and to identify risk factors for tumor recurrence and death after LT in cHCC-CC patients.METHODS Data for pathologically diagnosed cHCC-CC patients(n=111)who underwent LT from 2000 to 2018 were collected for a nine-center retrospective review.Patients(n=141)who received LDLT for HCC at Samsung Medical Center from January 2013 to March 2017 were selected as the control group.Seventy patients in two groups,respectively,were selected by 1:1 matching.RESULTS Cumulative disease-free survival(DFS)and overall survival(OS)in the cHCC-CC group were significantly worse than in the HCC group both before and after matching.Extrahepatic recurrence incidence in the cHCC-CC group was higher than that in the HCC group(75.5%vs 33.3%,P<0.001).Multivariate analysis demonstrated that the cHCC-CC group had significantly higher rates of tumor recurrence and death compared to the HCC group.In cHCC-CC subgroup analysis,frequency of locoregional therapies>3,tumor size>3 cm,and lymph node metastasis were predisposing factors for tumor recurrence in multivariate analysis.Only a maximum tumor size>3 cm was a predisposing factor for death.CONCLUSION The poor prognosis of patients diagnosed with cHCC-CC after LT can be predicted based on the explanted liver.Frequent regular surveillance for cHCC-CC patients should be required for early detection of tumor recurrence.

Application value of mixed reality in hepatectomy for hepatocellular carcinoma

BACKGROUND As a new digital holographic imaging technology,mixed reality(MR)technology has unique advantages in determining the liver anatomy and location of tumor lesions.With the popularization of 5 G communication technology,MR shows great potential in preoperative planning and intraoperative navigation,making hepatectomy more accurate and safer.AIM To evaluate the application value of MR technology in hepatectomy for hepatocellular carcinoma(HCC).METHODS The clinical data of 95 patients who underwent open hepatectomy surgery for HCC between June 2018 and October 2020 at our hospital were analyzed retrospectively.We selected 95 patients with HCC according to the inclusion criteria and exclusion criteria.In 38 patients,hepatectomy was assisted by MR(Group A),and an additional 57 patients underwent traditional hepatectomy without MR(Group B).The perioperative outcomes of the two groups were collected and compared to evaluate the application value of MR in hepatectomy for patients with HCC.RESULTS We summarized the technical process of MR-assisted hepatectomy in the treatment of HCC.Compared to traditional hepatectomy in Group B,MR-assisted hepatectomy in Group A yielded a shorter operation time(202.86±46.02 min vs 229.52±57.13 min,P=0.003),less volume of bleeding(329.29±97.31 mL vs 398.23±159.61 mL,P=0.028),and shorter obstructive time of the portal vein(17.71±4.16 min vs 21.58±5.24 min,P=0.019).Group A had lower alanine aminotransferas and higher albumin values on the third day after the operation(119.74±29.08 U/L vs 135.53±36.68 U/L,P=0.029 and 33.60±3.21 g/L vs 31.80±3.51 g/L,P=0.014,respectively).The total postoperative complications and hospitalization days in Group A were significantly less than those in Group B[14(37.84%)vs 35(60.34%),P=0.032 and 12.05±4.04 d vs 13.78±4.13 d,P=0.049,respectively].CONCLUSION MR has some application value in three-dimensional visualization of the liver,surgical planning,and intraoperative navigation during hepatectomy,and it significantly improves the perioperative outcomes of hepatectomy for HCC.

Liver transplantation in patients with incidental hepatocellular carcinoma/cholangiocarcinoma and intrahepatic cholangiocarcinoma： a single-center experience

BACKGROUND： Reports of fiver transplantation （LT） in patients with mixed hepatocellular carcinoma/cholangiocarcinoma （HCC/CC） and intrahepatic cholangiocarcinoma （ICC） are modest and have been mostly retrospective after pathological categorization in the setting of presumed HCC. Some studies suggest that patients undergoing LT with small and unifocal ICC or mixed HCC/CC can achieve about 40%-60% 5-year post-transplant survival. The study aimed to report our experience in patients undergoing LT with explant pathology revealing HCC/CC and ICC. METHODS： From a prospectively maintained database, we performed cohort analysis. We identified 13 patients who underwent LT with explant pathology revealing HCC/CC or ICC. RESULTS： The observed recurrence rate post-LT was 31% （4/13） and overall survival was 85%, 51%, and 51% at 1, 3 and 5 years, respectively. Disease-free survival was 68%, 51%, and 41% at 1, 3 and 5 years, respectively. In our cohort, four patients would have qualified for exception points based on updated HCC Organ Procurement and Transplantation Network imaging guidelines. CONCLUSIONS： Lesions which lack complete imaging characteristics of HCC may warrant pre-LT biopsy to fully elucidate their pathology. Identified patients with early HCC/CC or ICC may benefit from LT if unresectable. Additionally, incorporating adjunctive perioperative therapies such as in the case of patients undergoing LT with hilar cholangiocarcinoma may improve outcomes but this warrants further investigation.

Differentiation of intrahepatic cholangiocarcinoma from hepatocellular carcinoma in high-risk patients: a predictive model using contrast-enhanced ultrasound

AIM To develop a contrast-enhanced ultrasound(CEUS)predictive model for distinguishing intrahepatic cholangiocarcinoma(ICC) from hepatocellular carcinoma(HCC) in high-risk patients.METHODS This retrospective study consisted of 88 consecutive high-risk patients with ICC and 88 high-risk patients with HCC selected by propensity score matching between May 2004 and July 2016. Patients were assigned to two groups, namely, a training set and validation set, at a 1:1 ratio. A CEUS score for diagnosing ICC was generated based on significant CEUS features. Then, a nomogram based on the CEUS score was developed, integrating the clinical data. The performance of the nomogram was then validated and compared with that of the LR-M of the CEUS Liver Imaging Reporting and Data System(LI-RADS).RESULTS The most useful CEUS features for ICC were as follows: rim enhancement(64.5%), early washout(91.9%), intratumoral vein(58.1%), obscure boundary of intratumoral non-enhanced area(64.5%), and marked washout(61.3%, all P < 0.05). In the validation set, the area under the curve(AUC) of the CEUS score(AUC = 0.953) for differentiation between ICC and HCC was improved compared to the LI-RADS(AUC = 0.742)(P < 0.001). When clinical data were added, the CEUS score nomogram was superior to the LI-RADS nomogram(AUC: 0.973 vs 0.916, P = 0.036, Net Reclassification Improvement: 0.077, Integrated Discrimination Index: 0.152). Subgroup analysis demonstrated that the CEUS score model was notably improved compared to the LIRADS in tumors smaller than 5.0 cm(P < 0.05) but not improved in tumors smaller than 3.0 cm(P > 0.05).CONCLUSION The CEUS predictive model for differentiation between ICC and HCC in high-risk patients had improved discrimination and clinical usefulness compared to the CEUS LIRADS.

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(5HC).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.

Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery

BACKGROUND： Combined hepatocellular carcinoma and cholangiocarcinoma （cHCC-CC） is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma （HCC） and cholangiocarcinoma （CC）. Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. METHODS： The dinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. Cancer staging was performed according to the AJCC Cancer Staging Manual （6th ed.）. Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. RESULTS： Significant differences were observed in clinico- pathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease- free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC;but significantly poorer than those with HCC. In subanalysis of patients with stage Ⅱ, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. CONCLUSION： Patients with cHCC-CC showed similar dinico- pathological features as those with HCC or CC, and patients with cHCC-CC or CC had a poorer prognosis compared with those with HCC, especially at matched stage Ⅱ.

Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare subtype of primary liver cancer, and clinicopathological features of cHCC-CC have seldom been reported in detail. This study was undertaken to explore the diagnosis and clinicopathological characteristics of cHCC-CC in comparison with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), respectively. METHODS: The clinical data from 15 patients with cHCC-CC, 132 patients with HCC and 44 patients with CC who had undergone hepatic resection were analyzed retrospectively. Clinicopathological characteristics of cHCC-CC, HCC and CC such as hepatitis B viral infection, serum hepatitis C virus (HCV) antibody, serum alpha-fetoprotein (AFP) level, cirrhosis, vascular invasion, lymph node metastasis, surgical procedure and adjuvant treatment were also analyzed. Follow up was carried out in the patients, and their 1-, 3-, and 5-year survival rates were calculated. RESULTS: Two patients with cHCC-CC were correctly diagnosed by enhanced CT before operation, the other 13 patients were diagnosed by histology and immunohistochemistry after operation. Radical (8/15) and conservative hepatectomy (7/15) for cHCC-CC was similar to that for HCC and CC (P > 0.05). Pathologically cHCC-CC showed more significantly vascular invasion and lymph node metastasis than HCC (P < 0.05), and a similarity to CC (P > 0.05). Hepatitis B viral infection, serum HCV antibody, cirrhosis, and serum AFP level of cHCC-CC patients were similar to those of HCC patients (P > 0.05) but different from CC patients (P < 0.05). The cumulative 1-, 3-, and 5-year survival rates in patients with cHCC-CC were poorer than in patients with HCC or CC (P < 0.05). CONCLUSIONS: Patients with cHCC-CC are seldom diagnosed before operation. The progression of cHCC-CC is more rapid than that of HCC or CC. Survival rate of patients with cHCC-CC after hepatic resection is poorer than that of patients with HCC or CC.

Clinicopathological analysis of 14 patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND:Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary hepatic carcinoma,and its prognosis is poor.This study was undertaken to investigate the prognosis and the clinicopathological characteristics of cHCC-CC,including their possible cellular origin.METHODS:Among 852 patients with a primary hepatic carcinoma who underwent hepatectomy from January 1998 to April 2008 at our hospital,cHCC-CC was identified in 14 patients The clinicopathological characteristics of the 14 patients were analyzed retrospectively.The expression of the liver stem cell markers (c-kit,CD90,CD133 and CK19) in the tumor tissue was detected by immunohistochemistry,and the Kaplan-Meier method was used to evaluate survival.RESULTS:Among the 14 patients,9 presented with abdominal pain,3 with anorexia and debilitation,and the remaining two patients were asymptomatic.The mean age was 53.6±3.0 (range 38-74) years.Among the included patients,11 had an elevated serum alpha-fetoprotein level,13 were infected with hepatitis B virus,9 had vascular invasion and 1 had lymph node metastasis The average diameter of the tumors was 9.9±1.1 (range 5.0-16.0) cm.The median overall survival time was 7.9±1.0 months In addition,the presence of the liver stem cell markers,c-kit CD90,CD133 and CK19 was 71.4%,85.7%,92.9% and 78.6% respectively.All four markers were simultaneously expressed in eight cases.CONCLUSIONS:cHCC-CC has aggressive characteristics and the prognosis is extremely dismal.The high expression of liver stem cell markers in the tumor tissue suggests that these tumors may derive from liver stem cells.

Can contrast enhanced ultrasound differentiate intrahepatic cholangiocarcinoma from hepatocellular carcinoma?

BACKGROUND Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(ICC)differ in treatment and prognosis,warranting an effective differential diagnosis between them.The LR-M category in the contrast-enhanced ultrasound(CEUS)liver imaging reporting and data system(LI-RADS)was set up for lesions that are malignant but not specific to HCC.However,a substantial number of HCC cases in this category elevated the diagnostic challenge.AIM To investigate the possibility and efficacy of differentiating ICC from HCC classified in the LR-M category according to the CEUS LI-RADS.METHODS Patients with complete CEUS records together with pathologically confirmed ICC and LR-M HCC(HCC classified in the CEUS LI-RADS LR-M category)between January 2015 and October 2018 were included in this retrospective study.Each ICC was assigned a category as per the CEUS LI-RADS.The enhancement pattern,washout timing,and washout degree between the ICC and LR-M HCC were compared using theχ2 test.Logistic regression analysis was used for prediction of ICC.Receiver operating characteristic(ROC)curve analysis was used to investigate the possibility of LR-M criteria and serum tumor markers in differentiating ICC from LR-M HCC.RESULTS A total of 228 nodules(99 ICCs and 129 LR-M HCCs)in 228 patients were included.The mean sizes of ICC and LR-M HCC were 6.3±2.8 cm and 5.5±3.5 cm,respectively(P=0.03).Peripheral rim-like arterial phase hyperenhancement(APHE)was detected in 50.5%(50/99)of ICCs vs 16.3%(21/129)of LR-M HCCs(P<0.001).Early washout was found in 93.4%(93/99)of ICCs vs 96.1%(124/129)of LR-M HCCs(P>0.05).Marked washout was observed in 23.2%(23/99)of ICCs and 7.8%(10/129)of LR-M HCCs(P=0.002),while this feature did not show up alone either in ICC or LR-M HCC.Homogeneous hyperenhancement was detected in 15.2%(15/99)of ICCs and 37.2%(48/129)of LR-M HCCs(P<0.001).The logistic regression showed that rim APHE,carbohydrate antigen 19-9(CA 19-9),and alpha fetoprotein(AFP)had significant correlations with ICC(r=1.251,3.074,and-2.767,respectively;P<0.01).Rim APHE presented the best enhancement pattern for diagnosing ICC,with an area under the ROC curve(AUC)of 0.70,sensitivity of 70.4%,and specificity of 68.8%.When rim hyperenhancement was coupled with elevated CA 19-9 and normal AFP,the AUC and sensitivity improved to 0.82 and 100%,respectively,with specificity decreasing to 63.9%.CONCLUSION Rim APHE is a key predictor for differentiating ICC from LR-M HCC.Rim APHE plus elevated CA 19-9 and normal AFP is a strong predictor of ICC rather than LR-M HCC.Early washout and marked washout have limited value for the differentiation between the two entities.

Histopathological characteristics of needle core biopsy and surgical specimens from patients with solitary hepatocellular carcinoma or intrahepatic cholangiocarcinoma

BACKGROUND Pathological manifestations of hepatic tumours are often associated with prognosis. Although surgical specimens(SS) can provide more information,currently, pre-treatment needle core biopsy(NCB) is increasingly showing important value in understanding the nature of liver tumors and even in diagnosis and treatment decisions. However, the concordance of the clinicopathological characteristics and immunohistochemical(IHC) staining between NCB and SS from patients with hepatic tumours were less concerned.AIM To introduce a more accurate method for interpreting the IHC staining results in order to improve the diagnostic value of hepatic malignancy in NCB samples.METHOD A total of 208 patients who underwent both preoperative NCB and surgical resection for hepatocellular carcinoma(HCC) or intrahepatic cholangiocarcinomaRESULTS Morphologically, the presence of compact tumour nests or a cord-like structure in NCB was considered the primary cause of misdiagnosis of HCC from ICC. The kappa statistic showed a moderate agreement in histomorphology(k = 0.504) and histological grade(k = 0.488) between NCB and SS of the tumours. A 4-tier(+++,++, +, and-) scoring scheme that emphasized the focal neoplastic cell immunoreactivity of tumour cells revealed perfect concordance of CK19, GPC3 and HepPar1 between NCB and SS(k = 0.717; k = 0.768; k = 0.633). Furthermore,with the aid of a binary classification derived from the 4-tier score, a high concordance was achieved in interpreting the IHC staining of the three markers between NCB and final SS(k = 0.931; k = 0.907; k = 0.803), increasing the accuracy of NCB diagnosis C(k = 0.987; area under the curve = 0.997, 95%CI: 0.990-1.000; P< 0.001).CONCLUSION These findings imply that reasonable interpretation of IHC results in NCB is vital for improving the accuracy of tumour diagnosis. The simplified binary classification provides an easy and applicable approach.

Prostate-specific membrane antigen expression in hepatocellular carcinoma,cholangiocarcinoma,and liver cirrhosis

BACKGROUND Primary liver cancer includes three subtypes:Hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(CCA),and combined hepatocellular carcinoma.Patients with primary liver cancer experienced poor prognosis and high mortality,so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer.Prostate-specific membrane antigen(PSMA)expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently,but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIM To study the expression of PSMA in HCC,CCA,and liver cirrhosis.METHODS A total of 446 formalin-fixed paraffin-embedded(FFPE)liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital.Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens(213 HCC,203 CCA,and 30 liver cirrhosis).The tumor compartment and the associated neovascular endothelium were separately analyzed.PSMA expression was examined by two certified pathologists,and the final results were presented in a 4-point scoring system(0-3 points).Correlation between PSMA expression and clinicopathological information was also assessed.RESULTS PSMA was expressed primarily in the neovascular endothelium associated with tumors.The positive rate of PSMA staining in HCC was significantly higher than that in CCA(86.8%vs 79.3%;P=0.001)but was only 6.6%in liver cirrhosis(P=0.000).HCC cases had more 3-score PSMA staining than CCA had(89/213,41.8%vs 35/203,17.2%;P=0.001).PSMA expression correlated positively with the stage and grade of HCC and CCA.In both liver cancer subtypes,there were more PSMA+cases in stages III–V diseases than in stages I and II.High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage.There was no significant association of PSMA expression with sex,age,region,α-fetoprotein,hepatitis B surface antigen,or tumor size in both tumor subtypes.CONCLUSION Neovascular PSMA may be a promising marker to differentiate HCC from liver cirrhosis and a prognostic marker for anti-tumor angiogenesis therapy for HCC.

Do the existing staging systems for primary liver cancer apply to combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma?

Background:The incidence of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma(cHCC-ICC)is relatively low,and the knowledge about the prognosis of cHCC-ICC remains obscure.In the study,we aimed to screen existing primary liver cancer staging systems and shed light on the prognosis and risk factors for cHCC-ICC.Methods:We retrospectively reviewed 206 cHCC-ICC patients who received curative surgical resection from April 1999 to March 2017.The correlation of survival measures with the histological types or with tumor staging systems was determined and predictive values of tumor staging systems with cHCC-ICC prognosis were compared.Results:The histological type was not associated with overall survival(OS)(P=0.338)or disease-free survival(DFS)(P=0.843)of patients after curative surgical resection.BCLC,TNM for HCC,and TNM for ICC stages correlated with both OS and DFS in cHCC-ICC(all P<0.05).The predictive values of TNM for HCC and TNM for ICC stages were similar in terms of predicting postoperative OS(P=0.798)and DFS(P=0.191)in cHCC-ICC.TNM for HCC was superior to BCLC for predicting postoperative OS(P=0.022)in cHCC-ICC.Conclusion:The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-ICC prognosis.

Combined hepatocellular carcinoma and cholangiocarcinoma:a case report and review of the literature

BACKGROUND: combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is a rare histopathologic form of primary liver cancer. We report a case of cHCC-CC and review the literature. METHOD: The clinicopathological features of a 61-year-old male were retrospectively analyzed. RESULTS: Hepatocellular carcinoma (HCC) was preoperatively considered on the basis of clinical findings resembling those associated with HCC. Hepatectomy was therefore performed. Microscopically, the specimen displayed histological features of cHCC-CC. The patient has remained alive after follow-up for 3 months without evidence of recurrence and metastasis. CONCLUSION: It is difficult to make a correct preoperative diagnosis of cHCC-CC and hepatic resection is the treatment of choice.

Comprehensive radiomics nomogram for predicting survival of patients with combined hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND Combined hepatocellular carcinoma(HCC)and cholangiocarcinoma(cHCCCCA)is defined as a single nodule showing differentiation into HCC and intrahepatic cholangiocarcinoma and has a poor prognosis.AIM To develop a radiomics nomogram for predicting post-resection survival of patients with cHCC-CCA.METHODS Patients with pathologically diagnosed cHCC-CCA were randomly divided into training and validation sets.Radiomics features were extracted from portal venous phase computed tomography(CT)images using the least absolute shrinkage and selection operator Cox regression and random forest analysis.A nomogram integrating the radiomics score and clinical factors was developed using univariate analysis and multivariate Cox regression.Nomogram performance was assessed in terms of the C-index as well as calibration,decision,and survival curves.RESULTS CT and clinical data of 118 patients were included in the study.The radiomics score,vascular invasion,anatomical resection,total bilirubin level,and satellite lesions were found to be independent predictors of overall survival(OS)and were therefore included in an integrative nomogram.The nomogram was more strongly associated with OS(hazard ratio:8.155,95%confidence interval:4.498-14.785,P<0.001)than a model based on the radiomics score or only clinical factors.The area under the curve values for 1-year and 3-year OS in the training set were 0.878 and 0.875,respectively.Patients stratified as being at high risk of poor prognosis showed a significantly shorter median OS than those stratified as being at low risk(6.1 vs 81.6 mo,P<0.001).CONCLUSION This nomogram may predict survival of cHCC-CCA patients after hepatectomy and therefore help identify those more likely to benefit from surgery.