The comparative analysis of the clinicopathologic and CT features of hepatitis B virus- positive and negative intrahepatic cholangiocarcinoma patients with different pathological degree differentiation

doi:10.21203/rs.3.rs-3146470/v1

Background hepatitis B is a risk factor for the development of intrahepatic cholangiocarcinoma. The prognosis of HBV-related ICC remains to be further investigated.

AimsTo investigate the clinical, pathological and imaging features of intrahepatic cholangiocarcinoma of hepatitis B virus-positive and -negative patients.

MethodsData from January 31, 2012 to December 31, 2019 of 138 patients were retrospectively analyzed. The patients were divided into hepatitis B virus-positive group (group A[n=66]) and virus-negative group (group B[n=72]), and the patients were divided into well-to-moderately differentiated group and poorly differentiated group according to pathological differentiation degree. The differences in clinical, imaging characteristics and the progression-free survival between groups were statistically analyzed.

Results There were significant differences in gender, age, HBs antibody, HBc antibody, CA125 and AFP between the two groups (P<0.05); tumor distribution site, maximum diameter, plain scan density, blunting of the inferior hepatic angle, peritumoral bile duct dilatation, vascular encasement invasion, intrahepatic bile duct dilatation and abdominal lymphadenopathy between the two groups (P<0.05); There were statistical differences in tumor plain scan density and signs of vascular encasement and invasion between the two groups with well-to-moderately differentiated tumors (P<0.05); there were statistical differences in tumor plain scan density, signs of vascular encasement and lymphadenopathy between the two groups with poorly differentiated tumors (P<0.05). There was no statistical difference in postoperative PFS between the two groups (P>0.05).

Conclusion The clinical and imaging features of ICC of hepatitis B virus-positive and -negative patients are different, and there is little difference in postoperative disease-free survival time.

Health sciences/Oncology/Cancer/Gastrointestinal cancer/Liver cancer

Health sciences/Oncology/Cancer/Cancer imaging

intrahepatic cholangiocarcinoma

imaging

chronic hepatitis B

progression-free survival

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC) and originates from the secondary and above intrahepatic bile ducts due to malignant transformation of biliary epithelial cells [1, 2]. Previous studies have investigated risk factors associated with intrahepatic cholangiocarcinoma, such as intrahepatic bile duct stones and liver fluke related infection [3–6]. In addition, hepatitis B is also a risk factor for the development of ICC [7–10]. The mechanism of hepatitis B virus-induced ICC may be that hepatitis B virus persistent infection on the liver, continuous stimulation of inflammation makes intrahepatic cholangiocytes malignant transformation to form tumors [11]; followed by hepatitis B virus hepatotropic, not easy to infect cholangiocytes, some ICCs are formed by malignant transformation of hepatic stem cells [12, 13].

Zhou and Lee et al found that some clinical and imaging features of hepatitis B-related ICC and hepatitis B-related HCC were similar, such as an earlier age of onset, lesions mostly located in the right lobe of the liver on imaging, and mass type was more common on pathology, while they were quite different from the findings of non-hepatitis B ICC [14, 15]. Serum AFP levels were higher in HBV-related ICC patients than in HBV-negative ICC [16]. Jeong et al [17] also found that patients with HBV-related ICC had a higher degree of cirrhosis, incidence of tumor capsule, and microvascular invasion rate, and their tumors were also poorly differentiated. The surgical principle of HBV-related ICC is similar to that of HBV-related HCC, but because ICC can spread and metastasize intrahepatic and extrahepatic along Glisson sheath and lymphatic vessels, the tumor boundary is unclear, which is more likely to lead to positive resection margins. Some scholars have proposed that HBV-related ICC has less lymph node metastasis rate and better prognosis, and routine lymph node dissection is not recommended [18]. Antiviral therapy (AVT) for HBV-related ICC is also very important. For patients with high viral load, AVT should be given to improve the prognosis of patients at the same time of surgical treatment. However, the impact of hepatitis B virus infection on the prognosis of ICC patients remains controversial. Zhang et al [19]. showed that patients with HBV-related ICC had a better prognosis than HBV-negative ICC patients, and he concluded that HBV infection may protect ICC patients after activating the immune response. In addition, the better prognosis of HBV-related ICC may also be related to the regular follow-up of HBV patients, so that ICC can be detected and treated early. However, some researchers believe that HBV infection has no correlation [20] or negative correlation [21] with the prognosis of ICC. Therefore, the prognosis of HBV-related ICC remains to be further investigated, and the analysis of pathological imaging features of ICC in chronic hepatitis B infection is helpful for clinical decision.

2019 The World Health Organization (WHO) divided ICC into small bile duct type and bold cast type. There are differences in the clinical manifestations of ICC among the above pathological subtypes, but there are not many reports in the literature on the differences between ICC imaging features with or without chronic hepatitis B infection and its pathological differentiation, and postoperative progression-free survival. In this study, ICC was divided into groups according to the presence or absence of chronic hepatitis B infection and different pathological differentiation to investigate the clinical, pathological, imaging features and prognosis of chronic hepatitis B-related intrahepatic cholangiocarcinoma and provide help for accurate clinical diagnosis and treatment.

Patients

This retrospective study was approved by the First Affiliated Hospital of Guangxi Medical University(Ethics approval No. 2022-E431-01)ethics committees, and patient informed consent was waived. From January 1, 2012 to December 31, 2019, the clinical, imaging and pathological data of patients with intrahepatic cholangiocarcinoma who underwent CT examination and hepatectomy in our hospital were retrospectively analyzed.

The main inclusion criteria: (1) All patients underwent radical resection without any prior antitumoral therapies, (2) CT scan was finished within 1 month prior to resection, including plain scan, arterial phase, portal venous phase and equilibrium phase images,(3) Postoperative pathological examination was ICC, (4) a single tumor in liver, (5) complete clinical data. Figure 1 summarizes the flowchart of the research work.

According to American Association for the study of liver diseeases(AASLD) 2018 guidelines for chronic hepatitis B [23] , patients were divided into positive group (group A) and negative group (group B) according to whether they had chronic hepatitis B before treatment.

CT scan

Simens dual-source spiral CT (SOMATOM Definition FLASH, Siemens Healthcare, Forchheim, Germany) was used. All patients underwent CT plain scan and enhanced scan. Before the examination, the patient fasted for 2 hours. The scan parameters were as follows: tube voltage 120kV, tube current 280 mA, rotation time 0.5 s, pitch factor 1.375. The scan was performed supine and ranged from the level of the right diaphragmatic dome to the level of the lower edge of the hepatosplenic region. Contrast-enhanced scanning: nonionic iodine solution was injected as the contrast medium with a high-pressure syringe through the cubital vein at a strength of 300 mg/ml, a dose of 1.5 ml/kg, and a administration rate of 3 ml/s. After the plain scans , three-phase contrast-enhanced scans of the liver were finished, including arterial phase (30 s), portal venous phase (60 s), and equilibrium phase (120 s).

Image feature interpretation

All CT images were independently evaluated by two radiologists (with 5 and 6 years of clinical experience in abdominal MR imaging, respectively), who were blinded with regard to the clinical and histopathological information. In case of any discrepancy, a third abdominal radiologist (with 15 years of experience in abdominal diagnosis) was recruited to resolve.

The following imaging features, were evaluated: (1) Assessment of liver background: liver contour, sharpness of the lower edge of the liver, and esophageal-gastric varices, (2) General characteristics of the tumor: location, shape, size, boundary, and internal density, (Note: tumor size — the maximum diameter of the tumor was measured from the axial, coronal and sagittal views, the density was heterogeneous—there were cystic changes, necrosis, or calcifications in the lesion, and its volume exceeded 1/4 of the mass.) (3) Enhancement characteristics: According to previous study [24-26] the enhancement pattern was divided into four types: arterial phase rim hyperenhancement + internal delayed hypoenhancement (type I), progressive hypoenhancement (type II), arterial phase rim hyperenhancement + central most necrosis (type III), and arterial phase heterogeneous hyperenhancement + portal or delayed phase hypoenhancement (type IV).(4) Accompanying signs: peritumoral bile duct stones, peritumoral bile duct dilatation, shrinkage of the hepatic capsule, overall intrahepatic bile duct dilatation, common bile duct or left and right hepatic duct stones, gallstones or absence of the gallbladder, venous tumor thrombus and venous encasement by the tumor (veins refer to the inferior vena cava, portal vein, hepatic vein and its branches), (5) Abdominal lymph node assessment: size (short diameter >1.0 cm is enlarged), homogeneity of enhancement (Non-homogeneous enhancement including heterogeneous enhancement and ring enhancement).　Some representative cases are shown in Figure 2-5.

Follow-up after surgery

All patients were regularly followed up every 3 months in the outpatient department from discharge until the first occurrence of disease progression or death, whichever came first , the follow-up period ended in December 31, 2022.

Clinical and pathological data evaluation

The analyzed clinical data comprised: (1) General data: gender, age, history of alcohol consumption and history of diabetes, (2) Main clinical symptoms and signs: abdominal pain, abdominal distension, fatigue, anorexia and jaundice.

The analyzed Laboratory parameters comprised: (1) Hepatitis B virological examination: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb), (2) liver fluke infection examination (stool to find liver fluke eggs), (3) Gastrointestinal tumour markers: CEA, CA19-9, CA125, CA153 and AFP, PIVKA-II.

All tumor specimens were obtained by surgical resection and ICC was confirmed by gross microscopic histology, cytological morphology, and immunohistochemistry. According to the fourth edition of the WHO Classification of Tumours of the Digestive System, tumors were divided into well-to-moderately differentiated group and poorly differentiated group(Table 1).

Statistical analysis

All data were analyzed using SPSS 22.0 statistical software. Enumeration data were compared by Chi-square test or Fisher exact test, measurement data were compared by paired t-test or multivariate analysis of variance, and statistical results were analyzed by two-sided test, Kaplan-Meier survival curve was used to evaluate the relationship between postoperative progression-free survival in groups A and B, and Log Rank test was used for comparison between groups, when P <0.05, the difference was statistically significant.

Clinicopathological Characteristics

There were 66 patients in group A, including 42 genderss and 24 females, with an average age of 49.81 ± 8.83 years, 72 patients in group B, including 41 males and 31 females, with an average age of 56.53 ± 11.02 years, the differences in gender and age between the two groups were statistically significant (P <0.05). The odds ratio for gender being associated with chronic hepatitis B positivity was 2.432 (95% CI: 1.113 －5.315).

The proportions of HBs antibody positive and HBc antibody positive in the two groups were 7.6% and 69%, 100% and 78%, respectively, and the difference in HBc antibody was statistically significant (P <0.05). (2) There was no statistically significant difference in the number of positive and negative cases of liver fluke infection (P >0.05). (3) There was statistical difference in serum CA125 and AFP (P <0.05), but there was no statistical difference in CEA, CA19-9 and CA153, PIVKA-II examination results (P >0.05).

The gross pathology of the 138 cases, the texture was hard, the tumor section was mainly gr yelloayishw or grayish white, some scattered bleeding spots were observed, and the boundary of the lesion was mainly infiltrative. There were 67 cases of well-to-moderate differentiation, including 27 cases in group A and 40 cases in group B, and 71 cases of low differentiation, including 39 cases in group A and 32 cases in group B.

Comparison of　imaging between groups A and B

The imaging characteristics of ICC lesions in group A and group B are summarized in Table 2. Group A was mainly distributed in the right lobe and periphery of the liver, and group B was distributed in the left lobe and right lobe, periphery and near the hilum, the lesions in both groups were mainly round in shape, and blurred in border, the lesions were less than 3 cm in diameter in 7 patients (10.6%) and 1 patient (0.01%) in both groups, respectively. There were significant differences in tumor distribution sites and maximum lesion diameters between the two groups (P <0.05), there was no significant difference in tumor shape and boundary (P >0.05).

In both groups, heterogeneous density was predominant on CT scans, slightly lower than peritumoral liver parenchymal density, and there was no statistically significant difference between the two groups (P = 0.054). Lesions in both groups showed predominantly circumferential hyperdensity or isodense hypodensity at the edges in the arterial phase, which was not statistically different (P = 0.171). There was no significant difference in overall enhancement pattern (P = 0.723). Group A showed 31, 18, 7 and 10 cases of type I- IV , respectively, and group B showed 38, 26, 4 and 4 cases of type I-IV, respectively.

Comparison of liver background and accompanying signs between the two groups(Table 3): whether the lower angle of the liver became blunt, peritumoral bile duct dilatation, tumor encasement invading vessels, intrahepatic bile duct dilatation and abdominal lymphadenopathy signs, the difference was statistically significant (P <0.05), liver contour, esophageal/gastric varices, peritumoral bile duct stones, liver capsule shrinkage, vascular tumor thrombus, common bile duct/left and right hepatic duct stones, gallstones/gallbladder absence and abdominal lymph node heterogeneous enhancement and other signs, the difference was not statistically significant (P >0.05). The left lobe of the liver lesions were mainly hepatogastric lymphadenopathy, and the right lobe of the liver lesions were mainly hilar and hepatopancreatic lymphadenopathy.

In addition, for lesions larger than 3 cm in diameter, there were statistically significant differences in peritumoral bile duct dilatation and signs of vascular encasement invasion between groups A and B (P = 0.039).

Comparison of ICC imaging in different pathological differentiation degrees

There were statistically significant differences in tumor plain scan density and signs of vascular encasement invasion between well-to-moderately differentiated groups A and B (P = 0.046, 0.011). Poorly differentiated groups A and B showed statistically significant differences in tumor plain scan density, signs of tumor encasement invading vessels, and lymphadenopathy (P = 0.003, 0.003, 0.001)(Table 4).

Comparative analysis of pathology and imaging of abdominal lymph nodes

A total of 43 cases of lymph node pathology showed metastasis after operation, including 16 cases in group A and 27 cases in group B. Lymph nodes showed heterogeneous enhancement or homogeneous enhancement on CT enhancement.

Postoperative follow-up

Postoperative follow-up ended December 31, 2022. During the follow-up period, there were 78 cases of disease progression, including 44 cases in group A and 34 cases in group B, 43 cases died, including 16 cases in group A and 27 cases in group B, 7 cases had no progression, including 5 cases in group A and 2 cases in group B. There was no significant difference in postoperative progression-free survival time between group A and group B by Log Rank test (P >0.05)(Figure 6).

The incidence of ICC is increasing, while ICC patients with hepatitis B and cirrhosis show atypical imaging findings, which easily affects the diagnosis of ICC. In recent years, many studies have shown that hepatitis B virus infection is statistically associated with ICC [19, 22]. In this study, we investigated the prognostic value of hepatitis virus infection, and we found no significant difference in postoperative tumor progression-free survival between ICC patients with hepatitis and those without hepatitis, however, some clinical, imaging, and pathological characteristics did differ between the two groups.

Our study found that patients in group A had a lower age of predilection and a higher proportion of males, which is similar to other studies [26], and the early age of onset may be related to the early detection of lesions by regular examination of patients. The positive rate of liver fluke infection in this group of patients was 44.6%, and it has been confirmed in the literature that liver fluke infection is associated with ICC [27] .

In terms of tumor markers, AFP was elevated in Group A in a higher proportion, possibly as a result of chronic hepatitis B infection, cirrhosis, or liver cancer [28, 29] ; AFP could also be elevated when ICC originated from liver stem cells or precursor cells [30]. The positive rate of CA125 in group B was higher, which was consistent with the results in the 2021 NCCN Guidelines for the Diagnosis and Treatment of Hepatobiliary Carcinoma [29] ; CA125 is a macromolecular polysaccharide protein, which has good stability in serological levels compared with CA199 and AFP and is not easily interfered by factors of liver, biliary tract inflammation, or cholelithiasis [31] .

In this two groups, the right lobe of liver was the main site of tumor distribution. In group A, the proportion of lesions located in the peripheral part was higher, and the lesion diameter was smaller and the density was uniform, consistent with that reported in the literature [25], presumably because the high rate of reexamination of chronic hepatitis B led to a high rate of early tumor detection. In Group B, the tumor margin was irregular, prone to microvascular invasion, and the prognosis was also poor [32] .

Heterogeneous enhancement in the arterial phase of lesions was higher in group A than in group B. Previous studies have found that ICC enhancement in the setting of chronic hepatitis B and cirrhosis is usually more pronounced than that in the setting without chronic liver disease and cirrhosis [33], and the results of this study are similar. This enhancement feature is similar to HCC in the setting of cirrhosis [34], so ICC is easily misclassified as LR-5/5v in 8/35 patients in the Liver Imaging Reporting and Data System (LI-RADS) [35]. Therefore, it is not enough to diagnose ICC associated with chronic hepatitis B by different enhancement characteristics in the arterial phase alone, which should be combined with more signs. In the overall enhancement pattern, there was no statistically significant difference between the two groups, and ICC was mainly dominated by early rim hyperenhancement + internal delayed hypoenhancement (type I) or progressive hypoenhancement (type II) in both groups, but 8 cases in group A showed heterogeneous hyperenhancement followed by decline, which was similar to the typical HCC "clearance" pattern [29] .

In the accompanying signs, there were 6 cases of peritumoral bile duct stones, 30 cases of peritumoral bile duct dilatation, and 27 cases of overall intrahepatic bile duct dilatation in group A. It was speculated that peritumoral bile duct dilatation was partially caused by bile duct obstruction and partially caused by liver fluke infection. Kim et al reported that risk factors for ICC associated with hepatolithiasis are older age, distal bile duct dilatation in proximal bile duct strictures, liver atrophy, bile duct stones in the left lobe, and postoperative stone recurrence [3] ; in addition, liver fluke infection can also cause cholangitis lesions and then lead to malignant transformation of bile duct epithelial cells. In addition, peritumoral vascular encasement and invasion rather than vascular tumor thrombus formation were more common in group B because ICC heterogeneity and invasiveness were higher than HCC, and tumor thrombus formation occurred only in the late stage because the lesion directly encased and invaded peritumoral vessels to narrow and occlude them in the early stage [36, 37] .

In terms of pathological differentiation, there were differences in plain scan density and signs of vascular encasement invasion between group A and group B; the proportion of lymphadenopathy was higher in poorly differentiated group B, on the one hand because biliary inflammatory lesions stimulated reactive hyperplasia of abdominal lymph nodes more in group B, and on the other hand, the malignancy of ICC may be higher in group B. Comparing the presence or absence of metastases in postoperative pathological lymph nodes with their imaging features, we found that the higher the possibility of metastasis when the lymph node is heterogeneously enhanced.

There was no statistically significant difference in the survival time without postoperative tumor progression between groups A and B, which was similar to Ann 's study results [38]. However, it is not the same as the results reported by two scholars in 2011 and 2017 [39, 40]. Different etiologies and groups may lead to different results, and it is expected to increase the sample size and multicenter data in the future to investigate the effect of chronic hepatitis B on the prognosis of ICC.

Compared with chronic hepatitis B negative ICC patients, chronic hepatitis B positive ICC patients have different clinical, pathological and imaging characteristics, and there is little difference in progression-free survival after surgery. These characteristics may provide help for accurate clinical diagnosis and treatment.

Acknowledgments We thank those who participated in the study, as well as the radiographers, nurses in the Radiology and Oncology department at the first affiliated hospital Guangxi medical University in Nanning, China, for their work, support, and enthusiasm for the study. We thank the key Laboratory of early prevention and treatment for Regional high frequency tumor, ministry of education, Nanning, Guangxi, China, for study management and coordination.

Funding This work was supported by a grant from Guangxi Natural Science Foundation Project, Guangxi, China, 2023GXNSFAA026053. National Natural Science Foundation of China, NSFC81360220, 81260214.

Conflict of interest The authors have no relevant financial or non-financial interests to disclose.

Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xiao-li Huang, Dan Yu, Xin-tao Gu, Jian-sun Li, Jia-qi Chen, Yuan-qiang Zou, Jin-yuan Liao. The first draft of the manuscript was written by Dan Yu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethical standard Research involves human participants. All data was from routine clinical test, and there was no clinical intervention for the participants in the study.

Informed consent All informed consent for the routine clinical tests were obtained from participants. While for the retrospective nature of this study, informed consents for participating in this study was waived by the Institutional Review Board of the First Affiliated Hospital of Guangxi Medical.

Data Availability Statement All data generated or analysed during this study are included in this published article and its supplementary information files.

Ethical Approval This is a retrospective study in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Guangxi Medical (Approve Number: 2022-E431-01) that waived the requirement of an informed consent.

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Table 1 Group A and group B ICC Pathological Differentiation Degree
Pathological differentiation	Group A (n = 66)	Group B (n = 72)	P value
Well-to-moderately differentiated	27 (40.9%)	40 (55.6%)	0.087
Poorly differentiated	39	32
Note: Chi-square test, * means P value is statistically different.

Table 2 Imaging characteristics of ICC lesions in group A and group B
Observed items		Group A (n = 66)	Group B (n = 72)	P value
Tumor site	Left lobe	13	34	0.002*
	Right lobe	43	30
	Left + right lobe	10	8
Tumor location	Peripheral type	52 (78.8%)	42 (58.3%)	0.014
	Juxtahilar type	14	30
Morpho-	Round shape	44	43	0.458
	Irregular shape	22	29
Maximum diameter	<3 cm	7	1	0.039 *
	3-6 cm	24	26
	>6 cm	35	45
Boundary	Clear	33	32	0.413
	Blurring	33	40
Precontrast	Non-uniform density	43	65	0.013 *
	Uniform Density	23	7
Arterial phase	Edge ring high density	38	42	0.171
	Non-uniform high density	10	4
	Equal/Low Density	18	26
Overall enhan- cement pattern	Type I	31	38	0.273
	Type II	18	26
	Type III	7	4
	Type IV	10 (15.2%)	4 (0.05%)
Note: Chi-square test or Fisher 's exact test, * represents that P values are statistically different.

Table 3 Background and accompanying signs of ICC liver in group A and B
Basic Features		Group A (n = 66)	Group B (n = 72)	P value
Liver outline	Smooth	4	2	0.059
	Less smooth	48	64
	Serrated	14	6
Inferior hepatic angle	Dull	59	50	0.006*
	Sharp	7	22
Esophageal and gastric varices	Yes	22	11	0.171
	None	44	61
Peritumoral bile duct stones	Yes	4	7	0.616
	None	62	65
Peritumoral biliary dilatation	Yes	12	36	0.000*
	None	54	36
Shrinkage of hepatic capsule	Yes	32	42	0.276
	None	34	30
Vascular tumor thrombus	Yes	11	12	1.000
	None	55	60
Vessel encasement invasion	Yes	17	46	0.000*
	None	49	26
Dilated intrahepatic ducts	Yes	18	32	0.029 *
	None	48	40
Choledocholithiasis/left and right hepatic duct	Yes	2	3	1.000
	None	64	69
Gallbladder stones/absent gallbladder	Yes	16	9	0.079
	None	50	63
Enlarged lymph nodes	Yes	45	62	0.017 *
	None	21	10
Lymph node heterogeneous enhancement	Yes	16	14	0.610
	None	50	58
Note: Chi-square test or Fisher 's exact test, * means P value is statistically different.

Table 4 Imaging characteristics of ICC lesions in group A and B with different degrees of differentiation
Basic Features		Well-medium differentiated group (n = 27 + 40)		Poorly differentiated group (n = 39 + 32)		P value
Basic Features		Group A	Group B	Group A	Group B	Well-to-moderately differentiated group	Poorly differentiated group
Morpho-	Round shape	17	22	27	21	0.551	0.791
	Irregular shape	10	18	12	11
Maximum diameter	<3 cm	5	2	4	2	0.149	0.057
	3-6 cm	9	14	15	7
	>6 cm	13	24	20	23
Boundary	Clear	10	15	17	9	0.893	0.179
	Blurring	17	25	22	23
Precontrast	Uniform Density	6	6	15	2	0.046*	0.003*
	Non-uniform density	21	34	24	30
Arterial phase	Edge ring high density	15	24	19	18	0.596	0.138
	Non-uniform high density	5	3	5	2
	Equal/Low Density	7	13	15	12
Overall reinforcement pattern	Type I	12	20	19	17	0.796	0.088
	Type II	7	13	11	13
	Type III	3	3	4	1
	Type IV	5	4	5	1
Vascular tumor thrombus	Yes	7	5	6	7	0.512	0.469
	None	22	35	33	25
Vessel encasement invasion	Yes	7	25	10	21	0.011 *	0.003*
	None	20	15	29	11
Enlarged lymph nodes	Yes	21	33	24	29	0.841	0.007
	None	6	7	15	3
Lymph node heterogeneous enhancement	Yes	6	9	10	5	0.894	0.370
	None	21	31	29	27
Note: Chi-square test or Fisher 's exact test, * represents that P values are statistically different.

No competing interests reported.

The comparative analysis of the clinicopathologic and CT features of hepatitis B virus- positive and negative intrahepatic cholangiocarcinoma patients with different pathological degree differentiation

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Abstract

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Introduction

Materials and Methods

Results

Discussion

Conclusions

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Status:

Journal Publication

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