Abstract
Intra-hepatic cholangiocarcinoma (ICC) arises from the biliary epithelium of secondary bile ducts or beyond. Many patients present with advanced, often unresectable disease due to vague or absent symptoms. Staging is based on tumor number, vascular invasion, extra-hepatic spread, lymph node involvement, and distant metastatic disease. When feasible, complete surgical resection offers the best hope of long-term survival, and may be approached via open or minimally invasive techniques depending on tumor location and surgeon expertise. Extended hepatic resection, vascular resection, and/or biliary-enteric reconstruction may be required for complete tumor resection. Mortality rates in most modern surgical series are 1–5 %. Five-year overall survival following resection ranges from 17 to 44 %. The role of liver transplant is limited to select centers with clinical trials including rigorous neoadjuvant therapy. The role of adjuvant therapy is still being explored as newer, potentially more effective systemic agents are developed.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Primary Sclerosing Cholangitis
- Orthotopic Liver Transplant
- Portal Vein Embolization
- Stereotactic Body Radiation Therapy
- Choledochal Cyst
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
Cholangiocarcinoma is the second most common primary liver cancer after hepatocellular carcinoma (HCC). It arises from the epithelial lining of bile ducts and is anatomically categorized as intra-hepatic or extra-hepatic. Intra-hepatic cholangiocarcinoma (ICC) originates from the secondary or more peripheral bile ducts and does not involve the hepatic duct confluence. Some series in the literature refer to them as peripheral cholangiocarcinomas. These tumors are the least common, representing 5–10 % of cholangiocarcinomas, compared with tumors arising in the peri-hilar extra-hepatic duct (50–60 %) or distal bile duct (20–25 %) [1]. The majority of patients have no identifiable risk factor for ICC, which contributes to the problem of developing an effective screening process. Risk factors that have been associated with ICC relate to chronic inflammation within the bile ducts and include primary sclerosing cholangitis (PSC), choledochal cyst, chronic bile duct stones, exposure to Thorotrast contrast agent, smoking, liver fluke infestation, and chronic typhoid carriers [1–4]. Approximately 6,000 new cases of cholangiocarcinoma are diagnosed in the United States each year; the incidence of ICC in the US and worldwide has been increasing, along with the mortality rate [5–7]. The reasons for these increases are a subject of debate. Some authors argue it is influenced by recent changes in the classification system [6], while others point to hepatitis C as an emerging risk factor for cholangiocarcinoma [8].
Patients with ICC present more often with abdominal pain, constitutional symptoms, or an incidental mass, and less commonly with jaundice, as compared with extra-hepatic cholangiocarcinoma [9, 10]. Historically, staging systems for cholangiocarcinoma were derived from data on HCC patients [11], but in the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) 7th edition staging manual, a unique staging system for ICC was introduced, based on an analysis of SEER data performed by Nathan et al. [12, 13]. Prognostic variables for T classification include vascular invasion, multiple tumors, extra-hepatic extension, and periductal infiltration (Table 1). Noteworthy is that tumor size, which had been a factor in the prior AJCC staging system, was not associated with survival and is not included in the updated edition. The AJCC 7th edition TNM staging correlated well with survival (Fig. 1). This staging system was subsequently found to accurately discriminate outcomes in patients who underwent resection for ICC in a multi-institution European study [14] and was also validated in an international multi-institutional analysis [15].
In addition to TNM staging, macroscopic histologic subtypes of ICC have been associated with prognosis. The main subtypes identified are mass-forming, periductal-infiltrating, and intraductal, although tumors may also have features of more than one subtype, such as mass-forming plus periductal-infiltrating (Fig. 2). These subtypes have different biological behaviors and are associated with different outcomes in Japanese studies [16, 17]. Mass-forming is the most common subtype in Western series, and independent influence on prognosis has not been established in this population [15].
Surgery is the only modality associated with long-term survival; unfortunately, the majority of patients are unresectable at the time of presentation, either due to local invasion or distant metastasis [18, 19]. The remainder of this chapter will address the preoperative preparation, intra-operative technical and decision-making considerations for resection, and postoperative outcomes. The role of adjuvant therapy and liver transplantation will also be discussed.
2 Preoperative Considerations
ICC is commonly identified on ultrasound or cross-sectional imaging, which may be performed for symptoms such as abdominal pain, or for an unrelated indication. Once a liver mass has been identified, an appropriate workup to evaluate for other potential diagnoses such as metastasis should be undertaken. History and physical examination, blood work including hepatitis panel, CA-19-9, CEA, and AFP, and upper and lower endoscopy can help narrow the differential diagnosis. Imaging for preoperative planning is accomplished with contrast-enhanced helical computed tomography (CT) or magnetic resonance imaging (MRI). The goal is to evaluate the local extent of disease to determine resectability and to identify metastatic disease that would preclude resection. A CT of the chest should also be included in the preoperative evaluation to rule out pulmonary metastases.
The definition of a resectable liver tumor in a medically fit candidate is determined by tumor size, number, and location. For ICC, resectability is defined as being able to completely excise a tumor with negative margins, with at least two contiguous segments of liver remaining, and with adequate arterial and portal venous inflow, hepatic venous outflow, and biliary drainage. The amount of sufficient parenchymal future liver remnant required ranges from 20 to 40 %, depending on the health of the background liver [20]. The presence of multiple intra-hepatic tumors and/or grossly involved lymph nodes beyond the porta hepatis influence the likelihood of recurrence and should be considered when determining if a patient will benefit from resection. In addition, there should be no extra-hepatic metastatic disease [1]. ICC is associated with advanced stage at presentation, and thus, a significant number of patients will not be candidates for resection. In one series of 238 patients diagnosed with ICC over a 16-year period, 128 patients (54 %) were initially unresectable, based on the presence of multiple tumors (70), locally advanced intra-hepatic disease (37), or metastatic disease (32); 20 patients had more than one indication for unresectability [19].
Hepatic resections are described in terms of the anatomic segments removed. Couinaud [21] defined the hepatic segments based on internal vascular anatomy (Fig. 3). The main portal vein divides into a left and right branch, supplying each hemi-liver. The right portal vein branches into anterior and posterior sections, which supply segments 5/8 and 6/7, respectively. The left portal vein divides into lateral and medial sections, supplying segments 2/3 and 4a/4b, respectively. In 2000, the International Hepato-Pancreato-Biliary Association (IHPBA) published a standardized terminology for liver resections at the World Congress of the IHPBA in Brisbane, Australia, referred to as the Brisbane terminology of liver anatomy and resections, which follows internal vascular anatomic terms [22].
In surgical series of ICC patients, a hemi-hepatectomy is required in 20–70 % of cases to resect the tumor, while extended resections ( >4 Couinaud segments) are required in up to 60 % of cases. In 5–25 % of cases, tumor clearance can be accomplished by removal of less than a hemi-liver (segmentectomy, bisegmentectomy, or non-anatomic resection) [10, 15, 19, 23–29]. The utility of subjecting patients to extended resections has been studied; one series of 27 patients undergoing at least an extended hepatectomy demonstrated overall 1- and 3-year survivals of 69 and 55 %, which is in the range of published series for ICC. In patients achieving a complete margin-negative resection (R0), the median survival was 46 months, with 1- and 3-year survivals of 94 and 82 %, respectively [30]. Thus, the need for an extended resection should not deter operative planning in experienced hands. The appearance of grossly involved regional lymph nodes on preoperative imaging portends a poor prognosis; however, nodal involvement outside of the regional lymph node basin is considered metastatic disease and a contra-indication to exploration [19].
3 Preoperative Portal Venous Embolization
Postoperative liver failure is a potential complication of hepatic resection for any indication. Risk factors for postoperative liver failure include the ratio of the size of the future liver remnant (FLR) to the total estimated liver volume, and the degree of liver dysfunction, which may be a result of cholestasis, chemotherapy, non-alcoholic steatohepatitis (NASH), or fibrosis/cirrhosis. There are varying criteria for determining a safe FLR; some authors advocate for no less than 40 % FLR in a healthy liver [31], while others use 20–25 % FLR as a cutoff in normal liver [20, 32, 33].
Portal vein embolization (PVE) is a process of inducing compensatory hypertrophy in the FLR preoperatively by interrupting portal venous flow to the portion of the liver that will be resected. First introduced in 1990 for patients with biliary tract cancers, the rationale for PVE prior to surgery is to reduce the risk of complications including postoperative liver failure in patients with marginal FLR by increasing the FLR before resection [34]. The technique is performed by accessing the portal vein on the tumor-bearing side of the liver, usually by a percutaneous trans-hepatic or trans-ileocolic route, and delivering embolic microcoils, and polyvinyl particles, and/or alcohol to the segments of liver that will be resected [35].
In one series of 240 patients undergoing PVE before planned resection for biliary tract cancers, the future liver remnant increased significantly from 33 ± 8 % to 43 ± 8 %. Among patients who ultimately underwent resection, the degree of hypertrophy was not different between those who died in the perioperative period (n = 17) and those who did not (n = 176), but the function of the FLR, as measured by indocyanine green clearance, was significantly worse in non-survivors [36]. This series was recently updated and now includes 353 patients with cholangiocarcinoma and 141 patients with gallbladder cancer [31]. The operative mortality was 6.5 %, and 5-year survival of patients with cholangiocarcinoma (mostly hilar) was 39 %, which is comparable with other published studies. The number of patients with ICC in PVE studies is very low [37, 38], which is likely a reflection of the higher incidence of hilar tumors and the less frequent need for extensive resections in ICC compared with hilar cholangiocarcinoma.
There is evidence to suggest that PVE stimulates tumor growth in an animal model of colorectal cancer liver metastases [39]. The oncologic impact of this is unknown, but an emerging strategy that may address this concern is the addition of intra-arterial therapy (IAT) in a sequential fashion with PVE [40]. This approach has not been shown to cause more hypertrophy than PVE alone, but more tumor necrosis was seen. The role for combined preoperative IAT and PVE remains to be defined.
4 Operative Considerations
4.1 Laparoscopic Staging
Staging laparoscopy with or without laparoscopic ultrasonography at the time of planned surgical resection for hepatobiliary-pancreatic malignancy was originally introduced to spare patients with occult metastatic disease, a non-therapeutic laparotomy [41]. In 62 patients explored for ICC without laparoscopy, metastatic disease was identified in 14 (23 %), suggesting that laparoscopy could benefit up to 1 in 4 ICC patients [42]. Early studies of laparoscopy in mixed hepatobiliary-pancreatic tumors found that laparoscopy identified unresectable disease in up to 46 % of patients [41, 43, 44]. One small study of 11 patients with ICC found that occult metastatic disease was detected at laparoscopy in four patients, for a yield of 36 %. An additional two patients were found to be unresectable at laparotomy, making the sensitivity 67 % (4/6) [45]. A larger review of 53 ICC patients, of whom 22 underwent staging laparoscopy, reported unresectable disease in six of 22 (27 %). Peritoneal metastases (4) and intra-hepatic metastases (2) were the findings precluding resection. At laparotomy, five additional patients had metastatic disease identified in celiac lymph nodes, making the sensitivity of laparoscopy 6/11 or 55 % [28].
As cross-sectional imaging has improved, the efficacy and cost-effectiveness of diagnostic laparoscopy in liver tumors have come into question [46, 47]. This is particularly true for cholangiocarcinoma, which tends to invade locally, such that the determination of resectability may be made only after dissection of biliary or vascular structures, compared with tumors such as gallbladder carcinoma, which demonstrate earlier peritoneal dissemination. Data specific to the utility of laparoscopy in patients with ICC remain sparse.
Studies reporting resectability at laparotomy offer rates of 62–83 %, which varies in part by the era of study, the use of laparoscopy, and the approach to tumors with lymph node or vascular involvement [9, 10, 19, 24, 26, 28].
4.2 Lymphadenectomy
The lymphatic drainage for liver tumors has been described, based on tumor location within the liver (Fig. 4). Left-sided tumors tend to spread toward the gastro-hepatic ligament to the lesser curve and cardia of the stomach, while right-sided tumors drain to the hepatoduodenal ligament [48]. However, left-sided ICC has been shown to follow “right-sided” drainage patterns in half of cases subjected to systematic lymphadenectomy [49]. The incidence of lymph node metastasis in published series of ICC ranges from 16 to 81 %; the higher rates reflect the tendency in many Western centers to perform lymphadenectomy only when suspicious lymph nodes are encountered [9, 10, 15, 19, 23, 24, 26, 29, 50]. In centers where lymphadenectomy is routinely performed, the incidence is 20–50 % [42, 49, 50].
Lymph node metastases are associated with poor prognosis in numerous studies [9, 10, 15, 26, 28]; thus, lymphadenectomy may help select patients for adjuvant therapy. However, routine lymphadenectomy has not been performed in many large Western series [15, 19, 24, 28, 51], with the rationale that routine lymphadenectomy has not been shown to influence survival [52].
4.3 Vascular Resection
Cholangiocarcinoma tends to display locally aggressive growth, which may involve major vascular structures such as the inferior vena cava (IVC) or the main or contra-lateral portal vein. Some form of vascular resection is required in 9–14 % of resections for ICC in large series [19, 23–28]. The impact of major vascular resection on outcomes for ICC patients was studied in a single institution review [23]. In a series of 121 patients, 14 underwent vascular resection. Of the vascular resection group, three of 12 patients with lymph nodes removed had lymph node metastases, and R0 resection was achieved in 86 %. There was no difference in overall survival at 1, 3, or 5 years between patients with (85, 56, 44 %) and without (85, 45, 23 %) vascular resection. Median overall survival was 32 versus 49 months, which was not statistically different. Thus, there is evidence that vascular resection is feasible and should be performed if necessary to achieve complete tumor excision, as outcomes are comparable in experienced hands.
4.4 Minimally Invasive Approach
Minimally invasive liver resections have been performed in over 3,000 patients worldwide for a variety of benign and malignant indications [53]. In the largest review of laparoscopic liver cases, <13 % of malignant cases were for the indication of ICC; overall morbidity and mortality for minimally invasive resection in all patients were 10.5 and 0.3 % [54]. The benefits of a laparoscopic approach, when technically feasible and performed by appropriately trained and experienced surgeons, include shorter length of stay, less pain medication requirements, less blood loss, quicker resumption of oral intake, with equivalent rates of complications [55]. While operating room costs may be higher in a laparoscopic procedure compared with a matched open procedure, the total hospital costs are equivalent or reduced [55, 56].
Peripherally located tumors are most amenable to a laparoscopic approach; the ideal candidate would have no tumor near the planned transection plane. Vascular resections and extra-hepatic bile duct resections are more technically demanding in the minimally invasive setting, and most experienced surgeons would approach those tumors in an open fashion. The use of robotic assistance facilitates the more complex dissection and suturing required in extended hepatectomies, and has been employed in a variety of benign and malignant tumors, including ICC [57, 58]. Preliminary evidence demonstrates feasibility from a technologic and oncologic perspective, and the role of robotic-assisted minimally invasive hepatectomy continues to be explored [59].
4.5 Transplant in ICC
As ICC frequently presents at an advanced stage that precludes complete resection, total hepatectomy with orthotopic liver transplant (OLT) has been explored as a potential solution to this clinical problem. Reports on early experience with OLT for cholangiocarcinoma include a review of 54 patients with ICC who underwent resection (34) or OLT (20) at the University of Pittsburgh Medical Center [60]. OLT was performed for unresectable disease in 12 patients and concurrent advanced cirrhosis in 8. Overall survival at 1, 3, and 5 years for resection was 60, 37, and 31 %, which was similar to survival after OLT (70, 29 and 18 %), and comparable with the authors’ outcomes for OLT in patients with HCC [61].
While these authors concluded that the comparable survival outcomes support the application of transplant to ICC, subsequent reports documented high rates of tumor recurrence in patients undergoing OLT for ICC and questioned the appropriateness of transplant in patients with ICC. Using data from the Cincinnati tumor registry, Meyer et al. [62] reported a 51 % rate of tumor recurrence in 207 patients transplanted for cholangiocarcinoma or mixed HCC-cholangiocarcinoma, including both peri-hilar and intra-hepatic tumors. The median time to recurrence was 9.7 months (range <1–64 months), and the median time between recurrence and death was 2 months (range <1–53 months). These data, and other studies with similar findings [63–66], led to a general consensus that cholangiocarcinoma should not be considered an appropriate indication for liver transplant outside of clinical trials focusing on neoadjuvant and/or adjuvant therapy to improve outcomes.
For ICC, investigators at UCLA have developed a protocol using preoperative radiation—either external beam or short-course stereotactic body radiation therapy (SBRT)—followed by 5-FU-based chemotherapy until the time of transplant [67]. In a review of 40 patients (26 intra-hepatic, 13 hilar), the 5-year recurrence-free survival was 29 %, with a median time to recurrence of 11 months. Multivariate analysis identified seven pathologic and treatment factors independently associated with prognosis: multi-focal disease, perineural invasion, infiltrative subtype, lymphovascular invasion, hilar location, history of PSC, and use of adjuvant and/or neoadjuvant therapy. A scoring system based on these risk factors was created, and the lowest-risk patients’ 5-year recurrence-free survival was 78 %, compared with 19 % for intermediate risk and 0 for high risk.
In another study, the same group compared OLT to radical bile duct resection and partial hepatectomy in 57 patients (37 with intra-hepatic tumors and 20 hilar) [68]. Twenty-five patients with ICC underwent OLT, and 12 underwent resection. The overall 5-year survival for all ICC patients was 34 %. 3- and 5-year recurrence-free survival for all patients was 39 and 6 % for OLT compared with 33 % and 0 (p = 0.05). For intra-hepatic tumors, the improved survival with OLT was not statistically significant. On multivariate analysis, resection versus OLT, hilar versus intra-hepatic location, perineural invasion and multi-focal tumors were factors associated with diminished survival. However, given the global shortage of organ donors, most transplant centers consider ICC a contraindication for OLT, and should only be performed in the setting of a clinical trial or protocol.
4.6 Perioperative Outcomes
Over the past several decades, the rates of postoperative death and complications following hepatic resection have decreased, such that most modern series from high-volume centers report less than 3 % mortality [69–72]. One review of 30-day outcomes of hepatectomies from the National Surgical Quality Improvement Project (NSQIP) database found a 30-day mortality of 2.5 % and morbidity of 19.6 % [73]. Improvements in surgical and anesthetic techniques, better patient selection, and innovations in hemostatic equipment are thought to contribute to these trends. Unfortunately, there is significant disparity in outcomes between high-volume and low-volume institutions performing hepatectomy, with lower mortality at high-volume centers (5.8 vs. 8.9 % in low-volume centers) [74].
In series of ICC patients, surgical mortality ranges from 1 to 14 % [9, 19, 23–25, 27–29, 50], and when reported, the most common causes for mortality are liver failure, sepsis, and cardiac events [19, 24, 27–29]. Several authors anecdotally note an association between extended liver resections, extra-hepatic bile duct resections and/or vascular resections and reconstructions with mortality, but this has not been formally demonstrated.
There is significant variability in how surgical complications are defined and reported; thus, the observed incidences of complications for resection of ICC have a wide range from 6 to 43 % [9, 19, 23–25, 27–29, 50]. The more common complications include intra-abdominal abscess, transient hepatic failure, infections (wound infections, pneumonia or sepsis), other pulmonary complications (pleural effusions or symptomatic atelectasis, ARDS), bile leak, and cholangitis [9, 19, 24, 27–29, 50]. Perioperative outcomes in recent series are summarized in Table 2.
The goal of surgical resection of ICC is the complete removal of all gross and microscopic disease (R0 resection). This was achieved in 45–96 % of attempted curative resections [9, 10, 15, 19, 23, 24, 26–28, 50, 75]. Many studies have found R0 resection to be associated with more favorable outcomes [9, 10, 15, 25–28, 75]. In one recent multi-institutional review of 449 patients with resected ICC, the influence of resection margins on overall survival was significant only in patients with node-negative disease; those with positive lymph nodes had no other factors independently associated with survival [15]. This relationship was also seen in a European multi-institutional study of 212 patients undergoing resection for ICC; patients with N0 disease demonstrated resection margin to be associated with survival, but node-positive patients did not have additional factors influencing survival [75].
While the practice of routine lymphadenectomy is variable, there is consistency across centers that lymph node involvement with ICC is a poor prognostic factor [9, 10, 15, 19, 26, 27]. However, in the absence of more effective treatment, surgical resection with lymphadenectomy is still advocated for patients with ICC and regional nodal disease [18]. Tumor size [10, 19, 27, 28], multiple tumors [10, 15, 19, 25, 26, 75], and vascular invasion [12, 15, 28] have also been associated with survival. Factors associated with survival in modern series are summarized in Table 3. Median overall survival following resection ranges from 12.4 to 52.9 months [9, 10, 15, 23, 25, 27, 28, 50]. Some series report overall survival for a cohort that contains unresected or R2 patients [27]. Overall survival at one year ranges from 51 to 85 %, 3 years 22–66 %, and 5 years 17–44 % [9, 10, 15, 23–28, 50]. Survival outcomes are summarized in Table 4.
5 Adjuvant Therapy
Given the overall poor prognosis of ICC, even following a potentially curative resection, multimodality therapy is an attractive strategy to improve outcomes. The study of adjuvant and/or neoadjuvant therapy in ICC is limited by the relative rarity of ICC compared with other tumors such as HCC. However, studies of systemic therapy in unresectable cholangiocarcinoma may offer some insights.
For many years, 5-FU-based regimens were the only option for biliary tract cancers, with little efficacy [76, 77]. Single-agent gemcitabine was subsequently investigated in small studies of advanced biliary tract cancer, after promising results in pancreatic cancers [78–80]. Most recently, multi-agent gemcitabine-based regimens have been studied in phase II and phase III trials. One of the largest such studies enrolled 410 patients with unresectable biliary tract cancers, including 241 cholangiocarcinomas, which were not stratified by anatomic tumor location. Patients were randomized to receive gemcitabine (1,000 mg/m2) on days 1, 8 and 15 of a 4-week cycle, or cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 3-week cycle. Overall survival in the cisplatin–gemcitabine group was significantly longer at 11.7 months, compared with 8.1 months in the gemcitabine-only group, and progression-free survival was also significantly improved in the cisplatin–gemcitabine group, at 8.0 versus 5.0 months [81].
It is not clear whether these modest but promising results will be applicable in the patients undergoing resection. In a retrospective review, Glazer et al. analyzed 157 patients with biliary tract cancer, 54 of whom had ICC. These patients were treated with a variety of adjuvant and/or neoadjuvant treatments (gemcitabine/platinum based or 5-FU neoadjuvant regimens, 5-FU or capecitabine-based adjuvant regimens). On univariate analysis, chemotherapy was associated with diminished survival, but on multivariate analysis, neither adjuvant nor neo-adjuvant treatment had any impact on survival [82].
6 Conclusions
ICC is increasing in incidence for unclear reasons, but perhaps related to hepatitis C as a risk factor. Over 50 % of patients are unresectable at presentation, most often due to locally advanced disease. Staging laparoscopy may spare some patients a non-therapeutic laparotomy, but will not identify all patients with locally advanced, unresectable disease. Surgical resection is the only possibility for long-term survival, and extended resection and/or vascular resection with reconstruction should be undertaken by an experienced team if needed to achieve complete tumor clearance. Effective neo-adjuvant or adjuvant treatments have not been demonstrated, but this remains the subject of ongoing investigation.
References
Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, Thillainayagam AV, Thomas HC, Thursz MR, Wasan H (2002) Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 51 Suppl 6:VI1–VI9
Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24:115–125
Chapman RW (1999) Risk factors for biliary tract carcinogenesis. Ann Oncol Off J Eur Soc Med Oncol (ESMO) 10 Suppl 4:308–311
Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA (2005) Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 128:620–626
Patel T (2001) Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33:1353–1357
Khan SA, Emadossadaty S, Ladep NG, Thomas HC, Elliott P, Taylor-Robinson SD, Toledano MB (2012) Rising trends in cholangiocarcinoma: is the ICD classification system misleading us? J Hepatol 56:848–854
Patel T (2002) Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10
Sempoux C, Jibara G, Ward SC, Fan C, Qin L, Roayaie S, Fiel MI, Schwartz M, Thung SN (2011) Intrahepatic cholangiocarcinoma: new insights in pathology. Semin Liver Dis 31:49–60
DeOliveira ML, Cunningham SC, Cameron JL, Kamangar F, Winter JM, Lillemoe KD, Choti MA, Yeo CJ, Schulick RD (2007) Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 245:755–762
Paik KY, Jung JC, Heo JS, Choi SH, Choi DW, Kim YI (2008) What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 23:766–770
Vauthey JN, Lauwers GY, Esnaola NF, Do KA, Belghiti J, Mirza N, Curley SA, Ellis LM, Regimbeau JM, Rashid A, Cleary KR, Nagorney DM (2002) Simplified staging for hepatocellular carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol 20:1527–1536
Nathan H, Aloia TA, Vauthey JN, Abdalla EK, Zhu AX, Schulick RD, Choti MA, Pawlik TM (2009) A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 16:14–22
Nathan H, Pawlik TM (2010) Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 26:269–273
Farges O, Fuks D, Le Treut YP, Azoulay D, Laurent A, Bachellier P, Nuzzo G, Belghiti J, Pruvot FR, Regimbeau JM (2011) AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma: by the AFC-IHCC-2009 study group. Cancer 117:2170–2177
de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L, Ferrone CR, Zhu AX, Bauer TW, Walters DM, Gamblin TC, Nguyen KT, Turley R, Popescu I, Hubert C, Meyer S, Schulick RD, Choti MA, Gigot JF, Mentha G, Pawlik TM (2011) Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol Off J Am Soc Clin Oncol 29:3140–3145
Hirohashi K, Uenishi T, Kubo S, Yamamoto T, Tanaka H, Shuto T, Kinoshita H (2002) Macroscopic types of intrahepatic cholangiocarcinoma: clinicopathologic features and surgical outcomes. Hepato-Gastroenterology 49:326–329
Shimada K, Sano T, Sakamoto Y, Esaki M, Kosuge T, Ojima H (2007) Surgical outcomes of the mass-forming plus periductal infiltrating types of intrahepatic cholangiocarcinoma: a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg 31:2016–2022
Nguyen KT, Steel J, Vanounou T, Tsung A, Marsh JW, Geller DA, Gamblin TC (2009) Initial presentation and management of hilar and peripheral cholangiocarcinoma: is a node-positive status or potential margin-positive result a contraindication to resection? Ann Surg Oncol 16:3308–3315
Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D’Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O’Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR (2008) Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 248:84–96
Vauthey JN, Chaoui A, Do KA, Bilimoria MM, Fenstermacher MJ, Charnsangavej C, Hicks M, Alsfasser G, Lauwers G, Hawkins IF, Caridi J (2000) Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 127:512–519
Couinaud C (1954) Lobes de segments hepatiques: notes sur l’architecture anatomique et chirurgical de foie. La Presse medicale 62:709–712
Strasberg S, Gelghiti J, Clavien PA, Gadzijev E, Garden J, Lau W-Y, Makuuchi M, Strong R (2000) The Brisbane 2000 terminology of liver anatomy and resections. HPB 2:333–339
Ali SM, Clark CJ, Zaydfudim VM, Que FG, Nagorney DM (2012) Role of major vascular resection in patients with intrahepatic cholangiocarcinoma. Annals of surgical oncology 20:1–6
Konstadoulakis MM, Roayaie S, Gomatos IP, Labow D, Fiel MI, Miller CM, Schwartz ME (2008) Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery 143:366–374
Madariaga JR, Iwatsuki S, Todo S, Lee RG, Irish W, Starzl TE (1998) Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases. Ann Surg 227:70–79
Nakagawa T, Kamiyama T, Kurauchi N, Matsushita M, Nakanishi K, Kamachi H, Kudo T, Todo S (2005) Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma. World J Surg 29:728–733
Shen WF, Zhong W, Xu F, Kan T, Geng L, Xie F, Sui CJ, Yang JM (2009) Clinicopathological and prognostic analysis of 429 patients with intrahepatic cholangiocarcinoma. World J Gastroenterol (WJG) 15:5976–5982
Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH (2001) Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg 193:384–391
Lang H, Sotiropoulos GC, Sgourakis G, Schmitz KJ, Paul A, Hilgard P, Zopf T, Trarbach T, Malago M, Baba HA, Broelsch CE (2009) Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg 208:218–228
Lang H, Sotiropoulos GC, Fruhauf NR, Domland M, Paul A, Kind EM, Malago M, Broelsch CE (2005) Extended hepatectomy for intrahepatic cholangiocellular carcinoma (ICC): when is it worthwhile? Single center experience with 27 resections in 50 patients over a 5-year period. Ann Surg 241:134–143
Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, Nagino M (2012) Portal vein embolization before extended hepatectomy for biliary cancer: current technique and review of 494 consecutive embolizations. Dig Surg 29:23–29
Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN (2002) Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 137:675–680 (discussion 671–680)
Kishi Y, Abdalla EK, Chun YS, Zorzi D, Madoff DC, Wallace MJ, Curley SA, Vauthey JN (2009) Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg 250:540–548
Makuuchi M, Thai BL, Takayasu K, Takayama T, Kosuge T, Gunven P, Yamazaki S, Hasegawa H, Ozaki H (1990) Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 107:521–527
Madoff DC, Hicks ME, Vauthey JN, Charnsangavej C, Morello FA Jr, Ahrar K, Wallace MJ, Gupta S (2002) Transhepatic portal vein embolization: anatomy, indications, and technical considerations. Radiographics: a review publication of the Radiological Society of North America, Inc 22:1063–1076
Nagino M, Kamiya J, Nishio H, Ebata T, Arai T, Nimura Y (2006) Two hundred forty consecutive portal vein embolizations before extended hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 243:364–372
Hemming AW, Reed AI, Howard RJ, Fujita S, Hochwald SN, Caridi JG, Hawkins IF, Vauthey JN (2003) Preoperative portal vein embolization for extended hepatectomy. Ann Surg 237:686–691
Iida H, Aihara T, Ikuta S, Yoshie H, Yamanaka N (2012) Comparison of percutaneous transhepatic portal vein embolization and unilateral portal vein ligation. World J Gastroenterol (WJG) 18:2371–2376
Simoneau E, Aljiffry M, Salman A, Abualhassan N, Cabrera T, Valenti D, El Baage A, Jamal M, Kavan P, Al-Abbad S, Chaudhury P, Hassanain M, Metrakos P (2012) Portal vein embolization stimulates tumour growth in patients with colorectal cancer liver metastases. Off J Int Heptol Pancreatol Biliary Assoc (HPB) 14:461–468
Peng PD, Hyder O, Bloomston M, Marques H, Corona-Villalobos C, Dixon E, Pulitano C, Hirose K, Schulick RD, Barroso E, Aldrighetti L, Choti M, Shen F, Kamel I, Geschwind JF, Pawlik TM (2012) Sequential intra-arterial therapy and portal vein embolization is feasible and safe in patients with advanced hepatic malignancies. Off J Int Hepatol Pancreatol Biliary Assoc (HPB) 14:523–531
John TG, Greig JD, Crosbie JL, Miles WF, Garden OJ (1994) Superior staging of liver tumors with laparoscopy and laparoscopic ultrasound. Ann Surg 220:711–719
Ohtsuka M, Ito H, Kimura F, Shimizu H, Togawa A, Yoshidome H, Miyazaki M (2002) Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg 89:1525–1531
Callery MP, Strasberg SM, Doherty GM, Soper NJ, Norton JA (1997) Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy. J Am Coll Surg 185:33–39
Tilleman EH, de Castro SM, Busch OR, Bemelman WA, van Gulik TM, Obertop H, Gouma DJ (2002) Diagnostic laparoscopy and laparoscopic ultrasound for staging of patients with malignant proximal bile duct obstruction. J Gastrointest Surg Off J Soc Surg Aliment Tract 6:426–430 (discussion 421–430)
Goere D, Wagholikar GD, Pessaux P, Carrere N, Sibert A, Vilgrain V, Sauvanet A, Belghiti J (2006) Utility of staging laparoscopy in subsets of biliary cancers: laparoscopy is a powerful diagnostic tool in patients with intrahepatic and gallbladder carcinoma. Surg Endosc 20:721–725
Gaujoux S, Allen PJ (2010) Role of staging laparoscopy in peri-pancreatic and hepatobiliary malignancy. World J Gastrointest Surg 2:283–290
Hoekstra LT, Bieze M, Busch OR, Gouma DJ, van Gulik TM (2012) Staging laparoscopy in patients with hepatocellular carcinoma: is it useful? Surg Endosc 27(3):826–831
Shirabe K, Shimada M, Harimoto N, Sugimachi K, Yamashita Y, Tsujita E, Aishima S (2002) Intrahepatic cholangiocarcinoma: its mode of spreading and therapeutic modalities. Surgery 131:S159–S164
Okami J, Dono K, Sakon M, Tsujie M, Hayashi N, Fujiwara Y, Nagano H, Umeshita K, Nakamori S, Monden M (2003) Patterns of regional lymph node involvement in intrahepatic cholangiocarcinoma of the left lobe. J Gastrointest Surg Off J Soc Surg Aliment Tract 7:850–856
Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Valdegamberi A, Nicoli P, Cappellani A, Malfermoni G, Iacono C (2009) Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection. World J Surg 33:1247–1254
Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD (2007) Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg Off J Soc Surg Aliment Tract 11:1488–1496 (discussion 1487–1496)
Morine Y, Shimada M, Utsunomiya T, Imura S, Ikemoto T, Mori H, Hanaoka J, Kanamoto M, Miyake H (2012) Clinical impact of lymph node dissection in surgery for peripheral-type intrahepatic cholangiocarcinoma. Surg Today 42:147–151
Reddy SK, Tsung A, Geller DA (2011) Laparoscopic liver resection. World J Surg 35:1478–1486
Nguyen KT, Gamblin TC, Geller DA (2009) World review of laparoscopic liver resection-2,804 patients. Ann Surg 250:831–841
Nguyen KT, Marsh JW, Tsung A, Steel JJ, Gamblin TC, Geller DA (2011) Comparative benefits of laparoscopic vs open hepatic resection: a critical appraisal. Arch Surg 146:348–356
Vanounou T, Steel JL, Nguyen KT, Tsung A, Marsh JW, Geller DA, Gamblin TC (2010) Comparing the clinical and economic impact of laparoscopic versus open liver resection. Ann Surg Oncol 17:998–1009
Packiam V, Bartlett DL, Tohme S, Reddy S, Marsh JW, Geller DA, Tsung A (2012) Minimally invasive liver resection: robotic versus laparoscopic left lateral sectionectomy. J Gastrointest Surg Off J Soc Surg Aliment Tract 16:2233–2238
Choi GH, Choi SH, Kim SH, Hwang HK, Kang CM, Choi JS, Lee WJ (2012) Robotic liver resection: technique and results of 30 consecutive procedures. Surg Endosc 26:2247–2258
Kitisin K, Packiam V, Bartlett DL, Tsung A (2011) A current update on the evolution of robotic liver surgery. Minerva Chir 66:281–293
Casavilla FA, Marsh JW, Iwatsuki S, Todo S, Lee RG, Madariaga JR, Pinna A, Dvorchik I, Fung JJ, Starzl TE (1997) Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 185:429–436
Iwatsuki S, Starzl TE, Sheahan DG, Yokoyama I, Demetris AJ, Todo S, Tzakis AG, Van Thiel DH, Carr B, Selby R et al (1991) Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 214:221–228 (discussion 228–229)
Meyer CG, Penn I, James L (2000) Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 69:1633–1637
Ghali P, Marotta PJ, Yoshida EM, Bain VG, Marleau D, Peltekian K, Metrakos P, Deschenes M (2005) Liver transplantation for incidental cholangiocarcinoma: analysis of the Canadian experience. Liver Transplant 11:1412–1416 (Official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society)
Goldstein RM, Stone M, Tillery GW, Senzer N, Levy M, Husberg BS, Gonwa T, Klintmalm G (1993) Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 166:768–771 (discussion 762–771)
Becker NS, Rodriguez JA, Barshes NR, O’Mahony CA, Goss JA, Aloia TA (2008) Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 12:117–122 (the official journal of the Society for Surgery of the Alimentary Tract)
Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, Hansen B, Schrumpf E, Oksanen A, Ericzon BG, Hockerstedt K, Makisalo H, Kirkegaard P, Friman S, Bjoro K (2004) Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol 40:815–822
Hong JC, Petrowsky H, Kaldas FM, Farmer DG, Durazo FA, Finn RS, Saab S, Han SH, Lee P, Markovic D, Lassman C, Hiatt JR, Busuttil RW (2011) Predictive index for tumor recurrence after liver transplantation for locally advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll Surg 212:514–520 (discussion 511–520)
Hong JC, Jones CM, Duffy JP, Petrowsky H, Farmer DG, French S, Finn R, Durazo FA, Saab S, Tong MJ, Hiatt JR, Busuttil RW (2011) Comparative analysis of resection and liver transplantation for intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a single center. Arch Surg 146:683–689
Imamura H, Seyama Y, Kokudo N, Maema A, Sugawara Y, Sano K, Takayama T, Makuuchi M (2003) One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 138:1198–1206 (discussion 1206)
Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O (2000) Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 191:38–46
Kamiyama T, Nakanishi K, Yokoo H, Kamachi H, Tahara M, Yamashita K, Taniguchi M, Shimamura T, Matsushita M, Todo S (2010) Perioperative management of hepatic resection toward zero mortality and morbidity: analysis of 793 consecutive cases in a single institution. J Am Coll Surg 211:443–449
Geller DA, Tsung A, Maheshwari V, Rutstein LA, Fung JJ, Marsh JW (2005) Hepatic resection in 170 patients using saline-cooled radiofrequency coagulation. HPB 7:208–213 (official journal of the International Hepato Pancreato Biliary Association)
Aloia TA, Fahy BN, Fischer CP, Jones SL, Duchini A, Galati J, Gaber AO, Ghobrial RM, Bass BL (2009) Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in the NSQIP database. HPB 11:510–515 (the official journal of the International Hepato Pancreato Biliary Association)
Dimick JB, Wainess RM, Cowan JA, Upchurch GR Jr, Knol JA, Colletti LM (2004) National trends in the use and outcomes of hepatic resection. J Am Coll Surg 199:31–38
Farges O, Fuks D, Boleslawski E, Le Treut YP, Castaing D, Laurent A, Ducerf C, Rivoire M, Bachellier P, Chiche L, Nuzzo G, Regimbeau JM (2011) Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group. Ann surg 254:824–829 (discussion 830)
Ducreux M, Van Cutsem E, Van Laethem JL, Gress TM, Jeziorski K, Rougier P, Wagener T, Anak O, Baron B, Nordlinger B (2005) A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer 41:398–403
Choi CW, Choi IK, Seo JH, Kim BS, Kim JS, Kim CD, Um SH, Kim JS, Kim YH (2000) Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol 23:425–428
Raderer M, Hejna MH, Valencak JB, Kornek GV, Weinlander GS, Bareck E, Lenauer J, Brodowicz T, Lang F, Scheithauer W (1999) Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology 56:177–180
Lin MH, Chen JS, Chen HH, Su WC (2003) A phase II trial of gemcitabine in the treatment of advanced bile duct and periampullary carcinomas. Chemotherapy 49:154–158
Tsavaris N, Kosmas C, Gouveris P, Gennatas K, Polyzos A, Mouratidou D, Tsipras H, Margaris H, Papastratis G, Tzima E, Papadoniou N, Karatzas G, Papalambros E (2004) Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs 22:193–198
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. New Engl J Med 362:1273–1281
Glazer ES, Liu P, Abdalla EK, Vauthey JN, Curley SA (2012) Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. Journal of Gastrointest Surg 16:1666–1671 (official journal of the Society for Surgery of the Alimentary Tract)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Brown, K.M., Geller, D.A. (2014). Surgical Management of Intra-Hepatic Cholangiocarcinoma. In: Herman, J., Pawlik, T., Thomas, Jr., C. (eds) Biliary Tract and Gallbladder Cancer. Medical Radiology(). Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40558-7_15
Download citation
DOI: https://doi.org/10.1007/978-3-642-40558-7_15
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-40557-0
Online ISBN: 978-3-642-40558-7
eBook Packages: MedicineMedicine (R0)