Central Bile Duct Carcinoma (Klatskin Tumor)
Central bile duct carcinoma, also known as perihilar cholangiocarcinoma or Klatskin tumor after its first describer, belongs to the group of cholangiocellular carcinomas (CCC; [1,2]). CCCs arise from the epithelial cells of the intra- and extrahepatic bile ducts, and thus intra- and extrahepatic CCCs are distinguished. Intrahepatic CCCs originate from the small bile ducts or the large ducts of the right or left bile duct system proximal to the bifurcation. Extrahepatic CCCs begin with the bifurcation.
Regardless of their origin (intra- or extrahepatic), bile duct carcinomas that infiltrate the central bile duct fork are referred to as perihilar CCCs. 50% of all CCCs are perihilar, 40% distal extrahepatic, and 10% intrahepatic tumors [3]. The majority of tumors are adenocarcinomas (90%), with the remaining tumors being predominantly squamous cell carcinomas.
Perihilar CCCs are classified according to their anatomical pattern of involvement using the Bismuth-Corlette classification [4]. However, the classification only refers to the longitudinal extent of manifestation in the bile duct system, whereas vascular and parenchymal infiltrations are not considered. The longitudinal extent is not sufficient for assessing resectability or prognosis, so this can only be assessed in combination with contrast-enhanced cross-sectional imaging (CT / MRI).
Perihilar/Klatskin Tumors: Classification according to Bismuth-Corlette
| Type | Description |
|---|---|
| I | Tumor affects the common hepatic duct, but not the hepatic bifurcation |
| II | Tumor additionally affects the hepatic bifurcation |
IIIa IIIb | Tumor affects hepatic bifurcation + right main branch Tumor affects hepatic bifurcation + left main branch |
| IV | Tumor affects hepatic bifurcation + both main branches |
CCCs are rare, with an incidence of 1 to 2 cases per 100,000 inhabitants. The incidence of extrahepatic CCCs has decreased in recent years, while that of intrahepatic CCCs seems to be increasing [5]. The growth pattern of carcinomas can occur longitudinally along the bile ducts, but also vertically. The pattern is usually diffuse, but discontinuous growth has also been described ("skip lesions"). An R0 resection is significantly complicated by the observation of lymphatic vessel invasion as well as perineural growth [6].
Risk factors for the development of a CCC include recurrent cholangitis (cholelithiasis, primary sclerosing cholangitis), bile duct cysts, chronic hepatitis B and C, as well as chemicals (e.g., dioxins, nitrosamines) and medications (e.g., isoniazid, methyldopa), with primary sclerosing cholangitis and bile duct cysts being the most common triggers [7]. In Asia, parasitic infections also play a role in carcinogenesis (Opisthorchis viverrini, Clonorchis sinensis).
Diagnostics
Even when cholangiocarcinoma is suspected, an interdisciplinary coordinated diagnostic approach is required depending on the therapeutic goal. This coordination should occur early in a tumor board presentation, even in the case of suspicion.
The diagnostic steps have already been outlined in the "Perioperative Management" section of the teaching contribution, so only a brief overview is provided here:
| Examination | Notes |
|---|---|
| Physical examination | |
| Laboratory |
|
| CT thorax, abdomen with contrast |
|
| MRI abdomen (possibly with contrast) |
|
| Ultrasound abdomen |
|
| EUS, endosonography |
|
| ERCP + brush cytology/fine needle aspiration |
|
| MRCP, magnetic resonance cholangiopancreatography |
|
| Staging laparoscopy with histology/cytology |
|
| LiMAx, liver elastography |
|
| Liver volumetry |
|
| PET-CT |
|
MRCP is better suited to describe the extent of the tumor than ERCP, but tends to "understage" [8]. MRCP should be performed before relieving cholestasis (ERCP/PTCD [percutaneous transhepatic cholangiodrainage]) due to a consequent collapse of the duct system.
A PET-CT has been evaluated by several groups, but does not provide significant additional information for most patients [9].
The triphasic high-resolution CT allows a good assessment of the individual anatomy and possible hilar vascular infiltrations in the portal venous and arterial system. It can also serve for virtual surgical planning (liver vascularization -> resection strategy, relatively accurate volumetry of the residual liver [10]).
Preoperative Decompression of the Bile Ducts
ERCP with stent placement and PTCD are available for decompressing obstructed bile ducts. The advantage of ERCP is the possibility of biopsy (although rarely successful). Disadvantages include bacterial contamination up to the intrahepatic bile ducts with increased rates of infectious complications as well as potential tumor cell dissemination during intraoperative stent removal. Tumor cell dissemination in the sense of implantations or increased occurrence of liver metastases has also been postulated for PTCD [11].
Whether drainage of the bile duct system is useful is controversially discussed [3, 12 – 15]. Under cholestasis, liver dysfunction increases, which is responsible for increased postoperative morbidity and mortality [4, 11]. Stents should be avoided in principle, but are often unavoidable for this reason. The necessary imaging to clarify resectability should be completed before stent placement. A stent in place complicates the intraoperative assessment of resectability.
Assessment of Resectability
Since the intraductal longitudinal extent of the tumor cannot be reliably assessed preoperatively by any method, the assessment of resectability and the planning of an appropriate resection strategy are problematic. Even the combination of different diagnostic measures often leads to an overestimation of the proximal extent, so that the actual resectability can only be determined by operative exploration. This means that a tumor classified as Bismuth IV is not inoperable from the outset [7, 16]. Even locoregional lymph node involvement does not constitute a contraindication to resection [9, 10]. For perihilar bile duct carcinomas, a high exploration rate must therefore be accepted despite extensive preoperative diagnostics [8, 11, 17].
Diagnostic laparoscopy is routinely performed by many groups to exclude liver metastases and peritoneal carcinomatosis, but is not suitable for assessing resectability [5, 10, 18].
Criteria of Unresectability
In addition to general contraindications, distant metastases, malignant ascites, and advanced liver diseases, particularly advanced primary sclerosing cholangitis, are contraindications to surgery. Local tumor infiltration can also lead to inoperability, e.g., in bilateral vascular infiltration or infiltration of the main arterial trunk or extensive tumor invasion in the bile duct system unilaterally with simultaneous atrophy or vascular occlusion contralaterally. In cases where both branches of the portal vein are involved or the bile duct is affected contralateral to portal vein invasion, resection is excluded [19, 20, 21].
Locoregional lymph node involvement (hilus, celiac trunk) does not constitute a contraindication to resection [9, 10]. If the residual liver volume is insufficient with the risk of small-for-size syndrome and inadequate regeneration of the residual liver, ipsilateral portal vein embolization can be performed to induce hypertrophy of the contralateral segments, especially if the critical threshold of 25-30% residual liver is undershot [11, 22].
Assessment of Future Residual Liver
In healthy liver parenchyma, the residual liver after resection (FLR, future liver remnant) should be > 25 - 30%, in a damaged organ > 40% [23]. Therefore, a CT volumetric analysis should be routinely performed before extensive liver resections. A disadvantage of CT volumetry is the lack of consideration of individual patient characteristics, and the technique is prone to errors [24]. Therefore, liver function capacity should also be determined (e.g., LiMAx test, indocyanine green (ICG) elimination test). The combination with virtual resection allows the calculation of liver residual function and thus improves postoperative outcomes [25].
Liver Conditioning
Several techniques are available for inducing hypertrophy of the future residual liver in staged liver resections, including surgical portal vein ligation (PVL), radiological portal vein embolization (PVE), and the combination of portal vein closure and in-situ split (ALPPS, "associating liver partition with portal vein ligation").
A meta-analysis shows that ALPPS is associated with stronger hypertrophy of the residual liver and a higher completion rate of the second step of liver resection, but also with significantly increased morbidity and mortality. Overall, the evidence regarding the best technique for hypertrophy induction in staged liver resections is very sparse. Mortality rates of 12% and more after ALPPS show that the indication for ALPPS must be very strictly set [26]. There is almost no data on the oncological long-term results of the various procedures as an important target criterion.
Resection Strategies
In general, all technical possibilities of liver surgery are used in resections of primary liver tumors, taking into account the functional residual capacity of the liver [27 – 30]. In perihilar tumors, the spectrum ranges from local resection of the bile ducts with intrahepatic bile duct resection to mesohepatectomy as local hilar resection of the liver parenchyma to left (segments II–V, VIII+I) or right (segments IV–VIII+I) hemihepatectomies. For reasons of radicality, the resection generally includes the caudate lobe (segment I), as its short bile ducts drain into the tumor-infiltrated hepatic bifurcation and tumor growth towards segment I is likely [32]. For reasons of radicality, an extended right hemihepatectomy is generally favored [33]. Biliary reconstruction is performed using Roux-en-Y hepatojejunostomy.
Mesohepatectomy
The sole resection of the "middle liver" for the treatment of central liver tumors was already described in 1972 [37]. In this resection procedure, known as mesohepatectomy, only the central liver segments IVa+b, V, VIII + I are removed, resulting in 15 – 35% less parenchymal loss compared to an extended liver resection, thus reducing the risk of postoperative liver failure [37]. Despite this advantage, mesohepatectomy has not found widespread application, which is probably due in part to the considerable technical effort involved [38 – 43]. Another disadvantage is the significantly larger resection surfaces in mesohepatectomy with corresponding risks for the development of bile fistulas, bleeding, and parenchymal necrosis [42]. Mesohepatectomy is therefore an alternative to extended liver resection that should be discussed on a case-by-case basis.
Lymphadenectomy
For the resection of hepatobiliary tumors, lymphadenectomy is predominantly required, although the underlying data is weak. Since the lymphatic drainage of the liver is very complex and variable, there is still no standardization of lymphadenectomy for liver tumors. Various studies have shown that the detection of lymph node metastases has a negative impact on the prognosis of liver tumors (including liver metastases), pancreas, and bile ducts [34, 35]. In addition to the total number of affected lymph nodes, the ratio of affected to examined lymph nodes (LN ratio) also seems to have prognostic significance, at least in intrahepatic (ICC) and perihilar bile duct carcinoma (PHCC).
Nevertheless, it is consensus that the liver hilum should always be included in a lymphadenectomy. However, there is uncertainty about how "aggressively" the dissection of lymph and connective tissue in the liver hilum should be performed.
In liver cirrhosis, hilar lymphadenectomy is associated with increased morbidity: venous bleeding due to portal congestion, frequent respiratory or cardiovascular complications, wound and intra-abdominal infections [36]. Occasionally, pronounced lymph leaks or massive ascites development occur postoperatively. Due to the various postoperative risks, a very precise weighing of the benefits and risks of lymphadenectomy is necessary in liver cirrhosis.
Prognostic Factors and Long-term Survival after Surgery
Although the treatment of Klatskin tumors has improved over the years, the prognosis remains poor. The only available and effective therapy with a prospect of cure is tumor resection [44, 45, 46]. Only R0 resection offers the chance for long-term survival and cure [47]. However, local tumor infiltration and/or metastasis are already present in over 50% of cases at the time of diagnosis. The 5-year survival rate is between 22 – 40% with tumor resection and approximately 52% with R0 resection [48].
Tumor-infiltrated resection margins and lymph node metastases are the most important negative prognostic factors and are associated with reduced survival in perihilar cholangiocarcinoma. Furthermore, perineural invasion, moderate or poor tumor differentiation, and higher-grade T-stages are associated with a poor prognosis [49]. Other negative influencing factors include the need for blood transfusions [17, 50] and an increase in bilirubin > 3 mg/dl [51]. Special techniques have been published that can offer a survival advantage, such as hilar en-bloc or vascular resections [17, 33].
To achieve complete tumor resection, perihilar lymph node dissection, extrahepatic bile duct resection in combination with partial liver resection, and possibly extensive vascular resection are indicated. This approach leads to a mortality rate of up to 19% and a complication rate of 14 – 76% [11]. In combination with the resection of the caudate lobe (segment I), this resection strategy leads to a significant survival advantage [52, 53, 54]. The background is that histological processing of the caudate lobe reveals tumor infiltration in a large number of cases [55]. It is therefore recommended to perform caudate lobe resection as part of the main procedure from Bismuth-Corlette stage II onwards [56].
After strict patient selection, liver transplantation is also available for curative surgical therapy of perihilar tumors, achieving 5-year survival rates of 38 – 50% [57, 58]. Neoadjuvant strategies (chemo-, radiotherapy) achieve rates of up to 65% [59].