Invasion of bile duct system by hepatocellular carcinoma (HCC) is rare, and its clinical characteristics and impact on prognosis of patient were not well defined. The first case of HCC patient presenting with “obstructive jaundice” was reported in 1947 as a consequence of tumor invasion and thrombosis in bile duct [
Most of these studies included only patients with obstructive jaundice due to biliary tumor thrombi. However, microscopic invasion of peripheral bile ducts in liver by HCC is being investigated as unique biological characteristic by surgeons and pathologists, which might have certain impacts on prognosis of patients after surgical treatment [
From January 2007 to January 2010, data of 413 cases of HCC undergoing curative liver resection (defined as resection of all the detectable tumors in liver with negative surgical margin) for HCC in our institute was retrospectively collected. The diagnosis of HCC was made by computed tomography (CT) scan, ultrasonography, magnetic resonance image (MRI), and/or angiography preoperatively and confirmed by histopathological examination of the resected specimen postoperatively.
BDI was suspected when tumors located adjacently, or dilation of bile duct and the branches was detected. If necessary, certain invasive examination (percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiography (ERCP)) or magnetic resonance cholangiopancreatography (MRCP) was used to confirm invasion of main branches of bile ducts or the common hepatic duct, evaluate stricture extent of bile duct, and also used for bile drainage before surgery. Among them, 35 cases (35/413, 8.5%) were diagnosed as HCC with BDI macroscopically and microscopically including 14 patients with bile duct thrombi. Particularly, HCC of seven patients was found microscopic invasion of peripheral bile duct by pathological examination postoperatively but no invasion of first-order branch of bile duct or common hepatic duct. Two separate pathologists were in agreement with the pathological diagnosis of all cases. We compared the clinical characteristics of HCC with BDI (B+ group,
Liver resection was the treatment of patients with HCC when available based on the general condition, tumor status, preoperative liver function, and the future remnant liver parenchymal. Hepatectomies included anatomic resection (subsegmentectomy, segmentectomy, and lobectomy) and nonanatomic resection. The invaded bile duct was resected with the entire tumors, and biliary-enteric anastomosis was performed if appropriate. All the cases were definitively diagnosed finally by paraffin pathological examination of the specimen.
Laboratory test was documented at the admission before surgery. Clinical, pathological, and surgical variables were compared between B+ and B− groups who underwent curative surgery at the same time period. Tumor size, number, tumor cell differentiation, capsule formation, and surgical margin were determined finally with pathological examination. Operation time was defined as the time period from incision of skin to closure of wound. Intraoperative blood transfusion volume indicated the volume of transfused packed erythrocytes in the operation. Postoperative morbidity includes the complications related to the hepatic surgery, for example, ascites, pleural effusion, chest infection, intra-abdominal abscess, intra-abdominal or upper gastrointestinal bleeding, bile leakage and wound infection, and so forth.
Data were expressed as mean ± SD for numerical variables or percentages for nominal variables. Mann-Whitney
The average age of B+ group was 51.3 years (range 41–77), comprised of 24 men and 11 women. 28 patients were classified as B1 including two patients with invasion of peripheral bile duct and first-order branches of bile duct, and 7 were classified as B2. Totally, 17 patients of B1 (60.7%) were presented with jaundice on admission. Abdominal pain was the most common symptom of the patients (21/35, 60%). 26 of B1 (93%) patients with HCC were diagnosed BDI by CT, MRCP, ERCP, or PTC preoperatively. The rest three of B1 and all of B2 were diagnosed intraoperatively by laparotomy and/or postoperative pathological examination. Partial hepatectomy was performed in 13 of B1 and all of B2. 10 patients of B1 underwent preoperative biliary decompression by PTC or ERCP. The entire tumors and invaded bile duct were removed, and choledochojejunostomy was also performed in ten of B1. The rest five patients of B1 underwent partial hepatectomy and thrombectomy and T tube drainage. Surgical complications occurred in 9 patients (25.7%), including bleeding (
The clinical characteristics of B+ and B− groups were compared and shown in Table
Preoperative clinical variables of HCC patients with and without bile duct invasion.
Clinical parameters | Bile duct invasion |
|
|||
---|---|---|---|---|---|
Yes ( |
No ( | ||||
Number or mean | % or SE | Number or mean | % or SE | ||
Age (y) | 51.3 | 2.0 | 50.2 | 0.6 | 0.571 |
Gender | |||||
Male/female | 24/11 | 68.6/31.4 | 309/69 | 81.7/18.3 | 0.073 |
Virus status | |||||
HBV/HCV/none | 26/0/9 | 74.3/0/25.7 | 286/7/85 | 75.7/1.9/22.5 | 0.669 |
Child-Pugh classification | |||||
A/B | 25/10 | 71.4/28.6 | 276/102 | 73.0/27.0 | 0.839 |
Liver cirrhosis | 25 | 71.4 | 247 | 65.3 | 0.577 |
Hemoglobin (g/L) | 130.5 | 4.9 | 128.8 | 1.7 | 0.752 |
Platelet count (×109/L) | 122.1 | 6.6 | 113.9 | 3.2 | 0.439 |
TBIL (umol/L) | 54.0 | 19.0 | 22.5 | 1.7 |
|
ALT (U/L) | 83.9 | 22.9 | 62.5 | 3.4 | 0.102 |
AST (U/L) | 83.5 | 22.9 | 61.6 | 3.0 | 0.070 |
ALB (g/L) | 38.3 | 0.9 | 38.9 | 0.3 | 0.485 |
PT (s) | 13.2 | 0.4 | 13.5 | 0.1 | 0.360 |
AFP (ng/mL) | 5770.7 | 2424.0 | 4071.2 | 1022.5 | 0.622 |
HCC: hepatocellular carcinoma; SE: standard error; HBV: hepatitis B virus; HCV: hepatitis C virus; AFP: alpha-fetoprotein; TBIL: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALB: albumin; PT: prothrombin time.
The bold value means “
The pathological and surgical variables between the two groups were compared and shown in Table
Pathological and surgical parameters of HCC patients with and without bile duct invasion.
Tumor status parameters | Bile duct invasion |
|
|||
---|---|---|---|---|---|
Yes ( |
No ( | ||||
Number or mean | % or SE | Number or mean | % or SE | ||
Tumor number | |||||
Single/multiple | 20/15 | 57.1/42.9 | 297/81 | 78.6/21.4 |
|
Maximal tumor size | |||||
≤5 cm/>5 cm | 11/24 | 31.4/68.6 | 216/162 | 57.1/42.9 |
|
Capsule formation | |||||
Present/absent | 11/24 | 31.4/68.6 | 116/262 | 30.7/69.3 | 1.000 |
Portal vein invasion | |||||
Positive/negative | 10/25 | 28.6/71.4 | 38/340 | 10.1/89.9 |
|
Cellular differentiation | |||||
Well/moderately/poorly | 3/22/10 | 8.6/62.9/28.5 | 25/252/101 | 6.1/64.2/29.7 | 0.864 |
Surgical mode | |||||
Nonanatomic/anatomic | 26/9 | 74.3/26.7 | 239/139 | 63.2/36.8 | 0.215 |
Surgical margin | |||||
<1 cm/≥1 cm | 23/12 | 65.7/34.3 | 175/203 | 46.3/53.7 |
|
Intraoperative blood transfusion (mL) | 602.9 | 87.4 | 658.7 | 23.4 | 0.493 |
Operation time (h) | 5.6 | 1.2 | 4.2 | 0.5 | 0.128 |
Postoperative morbidity | |||||
Presence/absence | 9/26 | 25.7/74.3 | 135/243 | 35.7/64.3 | 0.235 |
Hospital stay (d) | 24.6 | 1.6 | 23.6 | 0.8 | 0.683 |
HCC: hepatocellular carcinoma; SE: standard error.
The bold value means “
To July 2012, the median followup of all patients was 24 months (3–65 ms). Kaplan-Meier curves for overall survival of B+ and B− groups were plotted in Figure
Kaplan-Meier curves of overall survival of hepatocellular carcinoma patients with bile duct invasion (B+ group,
Kaplan-Meier curves for overall survival of B−, B1, and B2 were plotted and shown in Figure
Kaplan-Meier curves of overall survival of the 35 patients with bile duct invasion according to different type of bile duct invasion. B1, central type; B2, peripheral type.
Next, to investigate risk factors affecting prognosis of HCC patients after surgical treatment, we enrolled 20 potential variables including BDI and analyzed by univariate analysis (Table
Univariate analysis of risk factors for prognosis of HCC after surgical resection.
Variables |
|
Median survival (m) |
|
---|---|---|---|
Age (≤40/>40 yr) | 96/317 | 28.4/30.6 | 0.475 |
Gender (male/female) | 333/80 | 30.4/28.3 | 0.423 |
Virus status | |||
HBV/HCV/none | 312/7/94 | 32.0/30.2/29.5 | 0.210 |
Child-Pugh classification | |||
A/B | 301/112 | 33.6/30.0 | 0.456 |
Liver cirrhosis (+/−) | 272/141 | 29.3/31.4 | 0.512 |
Hemoglobin (<110/≥110 g/L) | 62/351 | 32.7/34.3 | 0.666 |
Platelet count (×109/L) (<100/≥100) | 194/219 | 33.1/27.3 |
|
ALT (≤40/>40 U/L) | 195/218 | 33.5/27.4 |
|
AST (≤40/>40 U/L) | 139/274 | 37.9/26.3 |
|
TBIL (≤17.1/>17.1 umol/L) | 228/185 | 29.6/30.4 | 0.870 |
Albumin(<35/≥35 g/L) | 320/93 | 31.3/27.0 | 0.153 |
PT (<14/≥14 s) | 278/135 | 29.6/31.0 | 0.580 |
AFP (<20/≥20 ng/mL) | 118/295 | 37.3/27.2 |
|
Tumor size (<5/≥5 cm) | 227/186 | 37.2/21.4 |
|
tumor number (1/≥2) | 317/96 | 33.3/19.2 |
|
Capsule formation (+/−) | 286/127 | 33.7/21.8 |
|
Bile duct invasion (B−/B1/B2) | 378/28/7 | 31.1/14.6/39.0 |
|
Portal vein invasion (+/−) | 48/365 | 14.6/32.2 |
|
Surgical margin (<1/≥1 cm) | 198/215 | 31.9/28.7 | 0.153 |
Blood transfusion (≤600/>600 mL) | 196/217 | 36.7/24.4 |
|
Hepatocellular carcinoma; HBV: hepatitis B virus, AFP: alpha-fetoprotein, TBIL: total bilirubin, ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALB: albumin; PT: prothrombin time.
The bold value means “
Multivariate analysis of risk factors for prognosis of HCC after surgical resection.
Variables | Hazard ratio | 95% CI |
|
---|---|---|---|
Tumor size (≥5 cm) | 1.7 | 1.3–2.2 | <0.001 |
Tumor number (≥2) | 1.6 | 1.2–2.1 | <0.001 |
Capsule absence | 2.0 | 1.5–2.6 | <0.001 |
Bile duct invasion (B1) | 1.3 | 1.1–1.7 | 0.015 |
Portal vein invasion | 1.5 | 1.1–2.2 | 0.015 |
Blood transfusion (>600 mL) | 1.7 | 1.3–2.2 | <0.001 |
ALT (>40 U/L) | 0.9 | 0.7–1.2 | 0.851 |
AST (>40 U/L) | 1.7 | 1.3–2.3 | <0.001 |
Platelet count (×109/L) (<100) | 0.9 | 0.7–1.2 | 0.428 |
AFP (≥20 ng/mL) | 1.6 | 1.2–2.1 | 0.002 |
HBV: hepatitis B virus; HCC: hepatocellular carcinoma; ALT: alanine aminotransferase; AST: aspartate aminotransferase; PT: prothrombin time; AFP: alpha-fetoprotein.
HCC with BDI is a rare event, and little is known about this type of HCC. This type of HCC was firstly recognized as “icteric type” of HCC, since patients complained of “jaundice” because of obstruction of bile duct by tumor thrombi [
However, there is not yet a consensus regarding the impacts of bile duct thrombi or BDI on patient’s survival after curative surgery, and whether BDI is an independent risk factor worsening prognosis of HCC patients after surgical treatment remains unknown. As summarized in Table
Summary of the previous reports of surgical outcome of HCC with bile duct invasion.
Authors | Year | Number of HCC patients with bile duct invasion (percentage) | Overall survival |
---|---|---|---|
Satoh et al. [ |
2000 | 17 (2.5%) | Similar to HCC without bile duct thrombus ( |
Shiomi et al. [ |
2001 | 17 (12.9%) | Similar to HCC without bile duct thrombus ( |
Yeh et al. [ |
2004 | 17 (3.0%) | Worse than HCC without bile duct thrombus ( |
Qin et al. [ |
2004 | 34 (0.8%) | NA |
Ikenaga et al. [ |
2009 | 15 (5.5%) | Worse than HCC without bile duct invasion ( |
Yu et al. [ |
2011 | 20 (3.0%) | Worse than HCC without bile duct thrombus ( |
Our series | 35 (8.5%) | Worse than HCC without bile duct invasion ( |
Most previous studies focused on only HCC with bile duct thrombi [
Next, we also compared clinical, pathological, and surgical variables that might differentiate HCC with BDI from those without. Patients with BDI presented with higher preoperative bilirubin level, which might be a result of biliary tract invasion. Tumors with multiple and large lesions were predominantly observed in patients with BDI. And portal vein invasion was more frequently identified in patients with BDI. These differences suggested HCC with BDI had more aggressive biological behavior and was associated with late stage of cancer, which accounted for poorer prognosis of the patients even after surgical treatment. Since portal vein and bile duct are surrounded by the same Glissonian sheath, tumors can easily invade both of them [
Although limited by a retrospective study, the results of the present study suggest that BDI was associated with more advanced tumor stage, and central BDI was an independent risk factor affecting the prognosis of patients with HCC. Curative surgery with complete removal of tumors and invaded bile duct supplies the only hope for long-term survival of patients.
The authors declare that there is no conflict of interests regarding the publication of this paper.