Introduction
Intrahepatic cholangiocarcinoma (ICC) originates from the secondary or smaller branches of the intrahepatic bile ducts. ICC presents predominantly with mass lesions of the liver, and accounts for 5–10 per cent of all cholangiocarcinomas. It is a rare malignancy, with the exception of certain regions (in south‐east Asia) with well known predisposing epidemiological factors. However, the recent increase in its incidence and mortality rate in several other geographical regions of the world has warranted a revisiting of the pathogenesis and therapeutic modalities.
Liver resection is the only curative treatment for patients with ICC. However, the majority of patients present with advanced unresectable disease, which precludes a potentially curative approach. Moreover, the recurrence rate is high, reported to be 60 per cent or above; management of recurrent ICC is challenging and may include resection or ablation. The survival benefit of adjuvant therapies is unclear, and is currently under clinical investigation.
In the present cohort study of patients undergoing liver resection for ICC, the determinants of outcome were further characterized, with particular focus on revisiting the biological and surgical determinants of recurrence. The role of available modalities for managing recurrent disease was also evaluated.
Methods
From a prospectively processed database of all patients undergoing liver resection at the Department of General, Abdominal and Transplant Surgery at the University Hospital of Heidelberg, all consecutive entries for patients who were referred and underwent liver resection for a new liver mass lesion between December 2001 and December 2015 were reviewed. Demographic, radiological, clinical, operative, surgical pathological and follow‐up data for all patients with a final surgical pathological diagnosis of ICC were collected. The ethics committee of the Faculty of Medicine at the Ruprecht‐Karls University of Heidelberg approved this retrospective study (S‐754/2018).
Preoperative investigation
Evaluation of the patients included physical examination, blood tests for complete blood count and differentiation, biochemistry, liver function tests, coagulation studies, hepatitis serology, and the tumour markers alpha‐fetoprotein, carcinoembryonic antigen and carbohydrate antigen (CA) 19‐9. Contrast‐enhanced triple‐phase helical CT or MRI, or both (when necessary), were used in all patients to locate the lesion, the level of biliary obstruction, and the presence of lymphadenopathy. Magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiopancreatography and, more recently, [18F]fluoro‐2‐deoxy‐d‐glucose‐PET, especially for detection of recurrence, were employed if necessary.
Perioperative care and surgical technique
The institutional standards of hepatobiliary surgery have been published elsewhere. Briefly, after laparotomy through a reversed L‐shaped incision, all patients underwent a thorough abdominal exploration to rule out metastatic disease, intraoperative ultrasonography of the liver and assessment of lymph nodes (LNs) of the hepatoduodenal ligament, retropancreatic and coeliac regions. Portal triad clamping (Pringle manoeuvre) was used when necessary. The extent of resection was defined for each patient according to the number, size and location of the lesion. The Brisbane 2000 nomenclature for liver anatomy and surgery was used to describe the liver resections. Transection of the liver parenchyma was performed under low central venous pressure (2–5 mmHg). The standard procedure for the parenchymal dissection was stapler hepatectomy. En bloc resection of segment 1 (caudate lobectomy) and the resection (and reconstruction) of major vessels was done when necessary to achieve tumour clearance. Lymphadenectomy was performed in patients with lymphadenopathy. In patients without lymphadenopathy, LN sampling with frozen section was performed. Locoregional lymphadenectomy from the hepatoduodenal ligament, coeliac or posterior pancreatoduodenal regions was performed only in patients with positive findings on frozen‐section examination. Excision of the extrahepatic bile duct and reconstruction of bilioenteric continuity through a Roux‐en‐Y hepaticojejunostomy was performed if the biliary confluence was included in the resection. Argon‐beam coagulation and topical sealants were used liberally to stop bleeding at the resection surface. Abdominal drains were placed routinely. Transfusion of blood products was performed according to an established algorithm. Postoperative biliary complications were graded according to the system of the International Study Group of Liver Surgery.
Pathological diagnosis
The diagnosis was confirmed in all patients by reviewing the clinical and histopathological data. Tumours were typed, graded and staged according to the eighth edition of the AJCC/UICC classification of malignant tumours. Tumours that could not be classified confidently according to the TNM classification were excluded. Patients with histological subtypes other than adenocarcinoma were excluded. Patients with unusual histological adenocarcinoma subtypes, such as papillary or mucinous adenocarcinoma and combined hepatocellular carcinoma/cholangiocarcinoma, were also excluded.
Additional immunohistological staining was performed in patients with untypical tumour histomorphology or in those with other known malignancies. Only patients with either a typical histomorphology or a typical immunohistochemistry for ICC (CK7, CK20 and CDX2) were included in the study. Adenocarcinomas of other origin in the medical record were accepted as primary to the liver only if they expressed CK7 with no expression of CK20, CDX2, or other markers of the known primary tumour..
Statistical analysis
All variables that were potentially related to outcome were categorized into three main groups of preoperative, surgical pathological, and postoperative determinants of survival. IBM SPSS® Statistics version 25.0 for Windows® (IBM, Armonk, New York, USA) was used for statistical analysis. Data are presented as mean(s.d.) unless indicated otherwise. Overall survival (OS) was determined from the date of surgery to last follow‐up or death, whichever occurred first. Disease‐free survival (DFS) was calculated from the date of surgery to the date of recurrence, or to the date of death or last follow‐up. Receiver operating characteristic (ROC) curve analysis was used to determine cut‐off values for age, preoperative CA19‐9 level, preoperative total bilirubin level, and median tumour diameter for prediction of poor survival using Youden's J statistic. Survival rates were analysed with the Kaplan–Meier method, and differences were compared using the log rank test. Patients with a local R2 status after the primary resection were omitted from the DFS analysis. The influence of prognostic factors on outcome was assessed by means of Cox proportional hazard regression analysis, giving hazard ratios (HRs) and 95 per cent confidence intervals. Variables with P < 0·100 in the univariable analysis were included in the multivariable analysis. An effect was considered statistically significant at P < 0·050.
Results
A total of 190 patients underwent liver resection for ICC. Demographic, preoperative, surgical and pathological data of patients undergoing liver resection are shown in Table . The only relevant predisposing factor identified in the past medical history of the patients was primary sclerosing cholangitis in nine patients (4·7 per cent). Nineteen patients (10·2 per cent) had undergone neoadjuvant chemotherapy with gemcitabine or 5‐fluorouracil and/or transarterial chemoembolization. The most frequent surgical approach entailed the resection of three or fewer segments, in 49 patients (25·8 per cent). Locoregional lymphadenectomy was performed in 91 of 189 patients (48·1 per cent) (median 2 (range 1–45) LNs).
Demographic, preoperative, surgical and pathological data of patients with intrahepatic cholangiocarcinoma| No. of patients (n = 190) | |
| Age at diagnosis (years) | 63 (24–86) |
| Sex ratio (F : M) | 83 : 107 |
| Primary sclerosing cholangitis | 9 (4·7) |
| Presenting signs/symptoms | |
| Jaundice | 41 of 187 (21·9) |
| Pain | 69 of 163 (42·3) |
| Weight loss ≥ 5 kg | 37 (19·5) |
| Carbohydrate antigen 19‐9 level (units/ml) | 32 (1–41 567) |
| Bilirubin level (mg/dl) | 0·8 (0·2–22·7) |
| Preoperative biliary drainage | 17 (9·0) |
| Neoadjuvant chemotherapy/TACE | 19 of 187 (10·2) |
| PVE | 4 (2·1) |
| Surgical procedure | |
| Extended right hepatectomy | 34 (17·9) |
| Extended left hepatectomy | 21 (11·1) |
| Right hemihepatectomy | 41 (21·6) |
| Left hemihepatectomy | 45 (23·7) |
| Resection of ≤ 3 segments | 49 (25·8) |
| Segment 1 resection | 70 of 188 (37·2) |
| Bilioenteric anastomosis | 58 (30·5) |
| Lymphadenectomy | 91 of 189 (48·1) |
| (Partial) resection of major vessels | 55 (28·9) |
| Tumour diameter (cm) | 5·8 (0·2–21·0) |
| Surgical margins | n = 181 |
| R0 | 117 (64·6) |
| R1 | 59 (32·6) |
| R2 | 5 (2·8) |
| Tumour grade | n = 176 |
| G1 | 19 (10·8) |
| G2 | 101 (57·4) |
| G3 | 53 (30·1) |
| G4 | 3 (1·7) |
| T category | n = 182 |
| T1 | 53 (29·1) |
| T2 | 68 (37·4) |
| T3 | 45 (24·7) |
| T4 | 16 (8·8) |
| N category | |
| Nx | 63 (33·2) |
| N0 | 75 (39·5) |
| N1 | 52 (27·4) |
A clear resection margin (R0) was achieved in 117 (64·6 per cent) of 181 patients. Although not significantly different, patients with a positive resection margin (R1–2) had a larger tumour size than those with a clear margin (7 versus 6·1 cm respectively; P = 0·078). In addition, the rate of T3–4 status (46 versus 26·5 per cent; P = 0·012) and extended hepatectomy (42 versus 22·2 per cent; P = 0·006) was significantly higher in patients with an R1–2 resection margin than in those with a clear margin. Thirty of 188 patients (16·0 per cent) underwent relaparotomy for postoperative complications. The most common indication for relaparotomy was grade C bile leakage, in 15 patients (7·9 per cent). Median hospital stay was 14 (range 2–92) days. Thirteen patients (6·8 per cent) died within 30 days of surgery.
Adjuvant chemotherapy was performed in 57 of 187 patients (30·5 per cent). The protocol included gemcitabine in 27 patients, gemcitabine plus platinum in 18, FOLFOX‐3 (leucovorin, 5‐fluorouracil and oxaliplatin) in three and other protocols in nine patients. Twenty‐five of 187 patients (13·4 per cent) underwent adjuvant external‐beam radiotherapy (median dose 45 Gy). Median follow‐up was 19 (range 1–170) months.
Survival analysis
The 1‐, 3‐ and 5‐year OS rates were 74·8, 56·6 and 37·9 per cent respectively. In the multivariable analysis for OS, age 65 years or over (HR 2·18, 95 per cent c.i. 1·18 to 4·03; P = 0·012), median tumour diameter of 5 cm or more (HR 2·87, 1·37 to 6·00; P = 0·005), preoperative biliary drainage (HR 2·65, 1·13 to 6·20; P = 0·025) and local R1–2 status (HR 1·90, 1·02 to 3·53; P = 0·043) were independent determinants of poor OS (Table S1, supporting information).
In the multivariable analysis of DFS, independent predictive factors of poor DFS were median tumour diameter of 5 cm or greater (HR 1·71, 95 per cent c.i. 1·09 to 2·68; P = 0·020) and high‐grade (G3–4) tumour (HR 1·63, 1·04 to 2·55; P = 0·034) (Table S2, supporting information). Histological evidence of a positive tumour margin (local status R1) was the only surgical variable independently to predict significantly decreased DFS (HR 1·70, 1·09 to 2·65; P = 0·020). Fig. depicts the Kaplan–Meier plots according to independent predictors of DFS.
Enlarge this image.Kaplan–Meier plots analysis of 2‐year disease‐free survivalPatients with: a tumour diameter of 5 cm or more versus those with tumour diameter of less than 5 cm; b R0 versus R1 resection margin; and c patients with low‐grade (G1–2) versus high‐grade (G3–4) tumour. The five patients with a local R2 status after primary resection were omitted from DFS analysis; data for tumour size, R status and tumour grade were not available for six, nine and 14 patients respectively. a P = 0·001, b P = 0·010, c P < 0·001 (log rank test).
Recurrent intrahepatic cholangiocarcinoma
Recurrence was diagnosed in 87 of the 190 patients (45·8 per cent) during a median follow‐up of 10 (range 1–85) months. Fifty‐four patients had only an intrahepatic recurrence. Eighteen were diagnosed with only extrahepatic metastases on lymph nodes (6 patients), bone (3), mesenteric vessels (3), lung (2), peritoneum (2) or pancreas (2). Fifteen patients had both intrahepatic recurrence and extrahepatic metastases on lungs (7), lymph nodes (7) and peritoneum (1). The mean(s.d.) time to recurrence was 10(11) months, with a mean survival time after the documentation of recurrence of 16(17) months. Intervention‐associated survival after recurrence is shown in Table .
Intervention‐associated survival after recurrence| Type of intervention after recurrence | No. of patients (n = 87) | Time to recurrence (months) | Survival (months) |
| Exploration | 31 (36) | 11(9) (7, 15) | 22(21) (14, 29) |
| Resection | 25 | 11(8) (8, 15) | 25(22) (16, 34) |
| Liver resection | 20 | 11(9) (7, 15) | 24(24) (13, 36) |
| Lymph node dissection | 5 | 10(5) (3, 17) | 28(10) (15, 40) |
| Chemotherapy | 41 of 64 (64) | 9(11) (6, 12) | 13(14) (9, 18) |
| Gemcitabine monotherapy | 15 of 41 (37) | 10(15) (1, 18) | 15(15) (6, 23) |
| Gemcitabine + platinum | 19 of 41 (46) | 9(8) (6, 13) | 10(13) (4, 17) |
| FOLFOX‐3 | 3 of 41 (7) | 7(6) (1, 22) | 23(10) (1, 47) |
| Other | 4 of 41 (10) | 6(3) (1, 10) | 14(15) (2, 38) |
| Chemoradiotherapy | 15 of 64 (23) | 9(15) (1, 18) | 16(11) (10, 22) |
| RFA | 7 (8) | 7(5) (2, 13) | 21(11) (10, 32) |
| Palliative therapy | 8 of 87 (9) | 18(14) (6, 30) | 2(2) (0, 4) |
Management of recurrent disease
The management of recurrence included (one or a combination of) exploration, chemotherapy, radiotherapy and radiofrequency ablation (RFA) (Table ). There were no differences between different chemotherapeutic protocols used in the setting of recurrence (P = 0·738). Thirty‐one patients had surgery with curative intent for recurrence. Liver resection was performed in 20 patients (11 extra‐anatomical and 9 anatomical resections) and LN dissection in five patients. Six additional patients were deemed to have inoperable disease during surgery and underwent biopsy. Forty‐one patients received chemotherapy alone for recurrence. The chemotherapeutic protocol was gemcitabine monotherapy in 15 patients, gemcitabine plus platinum chemotherapy in 19 and FOLFOX‐3 regimen in three. Combined gemcitabine‐based chemoradiotherapy was also performed in 15 patients. RFA was performed in combination with either surgery (9 patients), chemotherapy/chemoradiotherapy (4) or alone (3).
Repeat liver resection for recurrent intrahepatic cholangiocarcinoma
OS varied significantly between different groups of patients who underwent resection (with or without chemotherapy or chemoradiotherapy), chemoradiotherapy alone, or chemotherapy alone for recurrent disease (P < 0·001) (Fig. ). Anatomical monosegmentectomy was performed in seven patients, non‐anatomical monosegmentectomy in seven, anatomical bisegmentectomy in three, non‐anatomical bisegmentectomy in two, and tumour excision in one patient after recurrence of ICC. Detailed perioperative data for the 20 patients who had repeat liver resection for recurrent ICC are shown in Table .
Enlarge this image.Kaplan–Meier analysis of 2‐year survival after recurrence of intrahepatic cholangiocarcinomaThirty‐one patients had a repeat operation with curative intent for recurrence; liver resection was performed in 20 patients and lymph node dissection in five. Additional chemotherapy/chemoradiotherapy was performed in 21 patients after resection. Chemotherapy alone was received by 41 patients, and chemoradiotherapy alone by 15. Eight patients had standard palliative care only. Radiofrequency ablation (RFA) was performed in combination with either surgery (9 patients), chemotherapy/chemoradiotherapy (4) or alone (3); patients who had only RFA were not included in the survival analysis. Patients undergoing resection had better survival (P < 0·001, log rank test).
| Patient no. | TNM grade | Resection margin | Type of primary liver resection | Adjuvant therapy | Time to recurrence (months) | Location of recurrence (segments) | Type of repeat liver resection | Additional therapy | Follow‐up after recurrence (months) |
| 1 | T3 N0 M0 G2 | R0 | Right EH | No | 3 | 2 + 3 | Non‐anatomical segments | Radiotherapy | 33 |
| 2 | T3 Nx M0 G1 | R0 | Minor (< 3 segments) | Yes | 3 | 2 + 3 | Anatomical segments | Gemcitabine | 11 |
| 3 | T1 N0 M0 G1 | R0 | Left HH | No | 11 | 5 + 7 | Non‐anatomical segments | Gemcitabine + cisplatin | 41 |
| 4 | T3 N1 M0 G3 | R1 | Minor (< 3 segments) | Yes | 5 | 4 | Anatomical segment | Capecitabine | 1 |
| 5 | T2 Nx M0 G3 | R0 | Right HH | No | 10 | 4 | Anatomical segment | FOLFOX‐3 | 76 |
| 6 | T2 N0 M0 G2 | R1 | Left EH | Yes | 5 | 7 | Anatomical segment | – | 19 |
| 7 | T1 N0 M0 G3 | R0 | Right EH | No | 8 | 2 | Non‐anatomical segment | Gemcitabine | 53 |
| 8 | T1 Nx M0 G1 | R0 | Minor (< 3 segments) | No | 5 | 8 | Anatomical segment | – | 85 |
| 9 | T1 Nx M0 G1 | R0 | Minor (< 3 segments) | No | 15 | 2 + 3 | Anatomical segments | Cetuximab + radiotherapy | 21 |
| 10 | T2 N0 M0 G2 | R0 | Left EH | No | 8 | 7 | Anatomical segment | Gemcitabine + cisplatin | 16 |
| 11 | T3 Nx M0 G3 | R1 | Right EH | No | 11 | 2 | Tumour excision | Gemcitabine + cisplatin | 39 |
| 12 | T2 Nx M0 G3 | R0 | Minor (< 3 segments) | No | 7 | 7 + 8 | Anatomical segments | Gemcitabine + cisplatin | 11 |
| 13 | T1 Nx M0 G2 | R0 | Minor (< 3 segments) | No | 6 | 4 | Anatomical segment | Gemcitabine + cisplatin | 3 |
| 14 | T2 N0 M0 G1 | R0 | Right HH | No | 17 | 4 | Non‐anatomical segment | Gemcitabine + radiotherapy | 9 |
| 15 | T1 Nx M0 G1 | R1 | Right EH | No | 40 | 2 | Anatomical segment | Gemcitabine + cisplatin | 23 |
| 16 | T4 N1 M0 G3 | R1 | Left HH | No | 6 | 5 | Non‐anatomical segment | Gemcitabine + cisplatin | 7 |
| 17 | T2 Nx M0 G3 | R0 | Right HH | No | 21 | 4 | Non‐anatomical segment | Capecitabine | 4 |
| 18 | T1 Nx M0 G2 | R1 | Left EH | No | 17 | 6 | Non‐anatomical segment | – | 26 |
| 19 | T3 Nx M0 G2 | R0 | Right HH | Yes | 19 | 4 | Non‐anatomical segment | – | 1 |
| 20 | T1 Nx M0 G2 | R0 | Left HH | No | 12 | 8 | Non‐anatomical segment resection | Gemcitabine + cisplatin | 8 |
Discussion
In this study, several different preoperative, surgical and clinicopathological variables were associated with reduced OS (age 65 years or more, median tumour diameter of 5 cm or greater, preoperative biliary drainage and local R1–2 status) and DFS (median tumour diameter 5 cm or more, high‐grade (G3–4) tumour and local R1 status). In the present cohort, a R0 rate of almost 65 per cent, a recurrence rate of less than 46 per cent, and a 5‐year OS rate of almost 40 per cent were achieved. The high positive resection margin rate in the present study could be explained by the large number of patients with an advanced tumour stage, who were treated in the tertiary institution. In addition, the present study has shown that the cohort of patients having repeat surgery with curative intent, with or without additional therapy, for recurrent ICC has a significantly better outcome than those undergoing chemotherapy or chemoradiotherapy alone.
Despite advances in understanding the pathophysiology of ICC and the emergence of novel therapeutic options, liver resection remains the only chance of cure in patients with ICC, with no significant improvement in survival in recent decades. The management of recurrent ICC has drawn increasing attention recently, with some studies with relatively larger numbers of patients helping to delineate better the role of repeat resection for recurrent ICC. These cohorts, however, lack sufficient numbers of patients to be able to define precisely the role of surgery, as well as that of additional therapy, in recurrent ICC. The present cohort of patients with recurrent ICC undergoing repeat surgery with curative intent was almost as large as that from two recent multi‐institutional studies. Furthermore, the results of the present study are similar to the findings of Si and colleagues, who reported on the largest cohort of patients (72) undergoing repeat liver resection, in which the median OS time was 45·1 months with a 1‐year survival rate of 97 per cent.
A study of patients with ICC from Memorial Sloan‐Kettering Cancer Center in New York reported the presence of multiple hepatic tumours as the only independent predictor of both disease‐free and disease‐specific survival. These authors showed that tumour diameter of 5 cm or less was significantly associated with longer recurrence‐free survival, but this association was lost in the multivariable analysis. It was shown that a median tumour diameter of 5 cm or more could independently predict both poor OS and DFS, in line with the findings from more recent cohorts.
Using SEER (Surveillance, Epidemiology and End Results) data, it has been shown that node positivity is associated with worse survival in patients with cholangiocarcinoma. Ito and co‐workers showed a disease‐specific survival benefit for patients with N0 disease with hilar cholangiocarcinoma in whom a minimum of seven lymph nodes had been removed. Although locoregional lymphadenectomy has been recommended for both extrahepatic cholangiocarcinoma and gallbladder cancer, the clinical benefit of lymphadenectomy in ICC is unknown, and it is not a widely performed component of surgical resection for the condition, especially in Western medical centres. In this study, a statistically prognostic significance for the locoregional lymphadenectomy in ICC could not be proved.
The most important limitation of this study, like that of other similar studies, is the low sample size of the patients with recurrent ICC for whom a definitive therapeutic plan can be devised. Even in more recent, relatively larger, cohorts of patients with recurrent ICC, the number undergoing definitive treatment was still too low to allow any significant conclusion regarding the role of surgery and additional therapy in this setting. A further limitation of this study is the retrospective design, which may result in varied durations of follow‐up, as well as loss to follow‐up. Well designed, larger, international multi‐institutional studies are needed for more precise conclusions to be drawn.
OS and DFS rates following liver resection for ICC remain poor. The recurrence rate is high, especially in the setting of bigger tumours (5 cm or larger), higher grade (G3–4) and local tumour‐positive resection margin (R1 status) despite adjuvant therapy. The approach to recurrent disease is challenging, although patients seem to have survival benefit from repeat surgery. More effective additional strategies are clearly needed, and should be investigated in multicentre clinical trials.
Disclosure
The authors declare no conflict of interest.
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Details
; Büchler, M W 1 ; Mehrabi, A 1
1 Department of General, Visceral and Transplant Surgery, Ruprecht‐Karls University, Heidelberg, Germany; Liver Cancer Centre Heidelberg, Ruprecht‐Karls University, Heidelberg, Germany
2 Department of General, Visceral and Transplant Surgery, Ruprecht‐Karls University, Heidelberg, Germany
3 Institute of Medical Biometry and Informatics, Ruprecht‐Karls University, Heidelberg, Germany
4 Institute of Pathology, Ruprecht‐Karls University, Heidelberg, Germany; Liver Cancer Centre Heidelberg, Ruprecht‐Karls University, Heidelberg, Germany
5 Department of Internal Medicine, Ruprecht‐Karls University, Heidelberg, Germany; Liver Cancer Centre Heidelberg, Ruprecht‐Karls University, Heidelberg, Germany