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Intrahepatic Cholangiocarcinoma: A Malignancy of Increasing Importance
Intrahepatic Cholangiocarcinoma: A Malignancy of Increasing Importance Chet W Hammill, MD, Linda L Wong, MD, FACS Intrahepatic cholangiocarcinoma is a poorly understood biliary malignancy that is increasing in incidence because of risk factors that are just beginning to be elucidated. The literature on this disease is limited primarily to case series from specialized hepatobiliary centers. But there are no defining studies, and few case series involve more than 100 patients. In addition, there is some confusion as to classification and staging of this little known malignancy, rendering the literature that much more challenging to interpret. It is primarily a disease of surgical importance, but minimal progress has been made in improving diagnosis and treatment. This article reviews current knowledge and recent discoveries on intrahepatic cholangiocarcinoma that surgeons need to be aware of to effectively treat the disease.
in the liver, or “mass-forming,” based on its morphologic growth pattern. The delineation of ICC is a relatively recent phenomenon, with the earliest case reports and series in the 1970s and 1980s.2,3 Because of these inconsistencies in definition and the relatively small numbers of cases reported by each group, there is currently no consensus on classification. Extrahepatic cholangiocarcinoma has been further subdivided into several categories including hilar, perihilar, distal, and diffuse.4,5 “Hilar cholangiocarcinoma,” also called a “Klatskin tumor,” is used to describe tumors that involve the bifurcation of the common hepatic duct. Many sources use “perihilar cholangiocarcinoma,” which includes tumors of the common hepatic duct and its primary and secondary branches proximal to the bifurcation. But there is disagreement about the distal border for perihilar cholangiocarcinomas; some define it as the point at which the bile duct passes under first portion of the duodenum, and others define it as the point at which the cystic duct joins the common hepatic. Many textbooks and articles simply do not define “perihilar,” leaving readers to come to their own conclusions. Further confusion occurs because “hilar,” “perihilar,” and “Klatskin tumors” have all been used to refer to intrahepatic and extrahepatic cholangiocarcinomas. As an example, the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), used by many of the data sources for recent publications on cholangiocarcinoma, includes codes for Klatskin tumors (8162/3) as a subset of both ICC (C22.1) and ECC (C24.0).6,7 Figure 1 illustrates the different anatomic classifications that are currently used. In addition to anatomic classifications, many attempts have been made to categorize ICC based on specific morphology and histologic features. This has generated other descriptive terms such as nodular, massive, diffuse, sclerosing, polypoid, papillary, exophytic, and infiltrating.8 More recently, the Liver Cancer Study Group of Japan proposed a classification consisting of “mass-forming,” “periductalinfiltrating,” and “intraductal-growing,” with morphology as illustrated in Figure 2.9 The mass-forming subtype corresponds to previous classifications of nodular and exophytic; periductal-infiltrating corresponds to the infiltrating and sclerosing subtypes; and intraductal-growing corresponds to the previous subtypes of polypoid and papillary.
Classification
Using the most basic definition, intrahepatic cholangiocarcinoma (ICC) refers to the 10% of bile duct cancers that arise from the epithelial cells of the intrahepatic bile ducts. The other 90% of cholangiocarcinomas arise from the epithelial cells of the extrahepatic bile ducts, and are referred to as extrahepatic cholangiocarcinoma (ECC), with the majority located near the bifurcation of the common hepatic duct.1 Although this definition appears straightforward, development of different definitions and systems of classification by various groups has led to confusion. Historically, these cancers were classified as “biliary tract cancers” if they were located in the extrahepatic bile ducts or “primary liver tumors” if they were located in the liver. Later “primary liver tumors” became known as “cholangiocarcinomas,” and more recently, “cholangiocarcinoma” has been expanded to describe all cancers arising from the epithelial cells of the bile ducts regardless of the location. These cancers have been further classified based on their anatomic location into ICC and ECC. In the literature, ICC also is referred to as “peripheral,” based on its location Disclosure Information: The following disclosure has been reported by the author: Dr Wong is on the Advisory Board and has received an honorarium from Bayer Health Care. Received February 14, 2008; Revised April 14, 2008; Accepted April 22, 2008. From the Departments of Surgery, University of Hawaii John A Burns School of Medicine, and Hawaii Medical Center-East, Honolulu, HI. Correspondence address: Linda L Wong, MD, University of Hawaii, 2226 Liliha Street, Suite 402, Honolulu, HI 96817.
© 2008 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
AJCC CA 19-9 ECC HCC ICC OR SEER
Figure 1. Highlight of the confusing terminology used in conjunction with cholangiocarcinoma. This malignancy has been described with several different and overlapping anatomic classifications based on its location in the biliary system.
Epidemiology
In much of the epidemiologic data, cholangiocarcinoma and other primary liver tumors are grouped together as “liver and biliary tract cancer.” Under this categorization, liver and biliary tract cancer is the sixth most common cancer, and the third most common cause of cancer mortality worldwide, with about 626,000 cases reported in 2002 and nearly as many deaths (598,000). More than 80% of these cases occurred in developing countries located in Asia and Sub-Saharan Africa, with 55% from China alone.10 In the United States, it was estimated that 18,410 people would be diagnosed with primary cancer of the liver and intrahepatic bile ducts in 2008. Using the Surveillance, Epidemiology, and End Results (SEER) data from 2000 to 2004, the overall age-adjusted incidence of these cancers is estimated at 6.2 per 100,000. Although most cancers in the United States are experiencing a decrease in incidence and death rate, liver and bile duct cancers had the highest increase in death rate and second highest increase in incidence of all cancers between 1995 and 2004.11 Although the vast majority of these represent hepatocellular cancer (HCC), an estimated 15% to 20% are intrahepatic cholangiocarcinoma (ICC).12 Worldwide data show an increase in incidence and mortality of ICC with tremendous geographic variation. Patel,13 in reviewing the World Health Organization (WHO) database, demonstrated an increase in ICC mortality in 19 of 22 countries studied. These included both industrialized and developing countries. Regions with the greatest increases were America, Oceania, and Western Europe. The three countries (the former Czechoslovakia, Norway, and Israel) in which increased mortality was not evident had less than 8 years of data available. It also was observed that in 13 of the 19 countries with overall increases in ICC, the rates of increased mortality were higher in males than in females. Interestingly, during this same study period, there was a decrease in mortality from ECC. Another analysis of
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
American Joint Committee on Cancer cancer antigen 19-9 extrahepatic cholangiocarcinoma hepatocellular carcinoma intrahepatic cholangiocarcinoma odds ratio Surveillance, Epidemiology, and End Results
the WHO data by Khan and colleagues14 indicated that mortality from ICC increased in all countries, with the largest increases in Australia, Scotland, England, and the US. A study focusing on Scotland demonstrated an eightfold increase in ICC mortality in both males and females.15 In England, ICC mortality has increased 15-fold, and it is currently the most common cause of mortality in primary liver tumors, surpassing the mortality of HCC.16 Several studies in the US, using the SEER database from 1975 to 1999, demonstrated a 165% increase in incidence
Figure 2. Depiction of the morphology of the three classes of cholangiocarcinoma that have been proposed by the Liver Cancer Study Group of Japan.
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in ICC, with significant racial and gender variations.17-19 In the 2,864 cases identified, the incidence increased from 0.32 to 0.85 per 100,000, with most of the change occurring after 1985. Caucasians and African Americans had similar age-adjusted incidence rates during this time, but Asians had an incidence that was twice as high. The incidence of ICC increased in all age groups, but was particularly evident in the older age groups. Asians older than 65 years had an increase in incidence from 1.35 to 7.88 per 100,000 during this time period.17 The incidence of ICC is higher in males than in females and also increased at a greater rate in males than in females for all races.17,19 During this same time period, the incidence of ECC in the US declined 14%.20 Some have postulated that the increased incidence of ICC may be attributable to more accurate reporting of this cancer, less misclassification, and better microscopic verification and diagnostic imaging. Multiple studies in different countries over long time periods have shown a continued increase in incidence and mortality, so more accurate reporting of ICC is unlikely to be the only reason for this increase in incidence.13-15,17 Risk factors
Cholangiocarcinoma has several frequently described risk factors, but the vast majority of patients present without any of the established risk factors.21 Primary sclerosing cholangitis, associated with ulcerative colitis, is one of the most recognized risk factors. Patients with primary sclerosing cholangitis have a 1.5% cumulative annual risk of developing cholangiocarcinoma per year of disease, and 10% to 20% will eventually develop cholangiocarcinoma.21,22 Fibropolycystic liver disease, including choledochal cysts, Caroli’s syndrome, and congenital hepatic fibrosis, is another commonly recognized risk factor.23-25 In Asia, liver flukes contribute to the high incidence of cholangiocarcinoma. Opisthorchis viverrini, found primarily in Thailand, Laos, and Cambodia, and Clonorchis sinensis, endemic in southern China, Korea, Taiwan, Japan, and Vietnam, are both recognized risk factors.26,27 Other established risk factors include hepatolithiasis, Thorotrast (thorium dioxide, a contrast agent used from 1931 until the 1950s), Lynch syndrome II, and biliary papillomatosis.28 Most of these risk factors appear to have the common theme of repeated episodes or extended inflammation of the biliary tract. Unfortunately, most of these associations were formulated before ICC and ECC were classified as distinct entities, so it is unclear if the established risk factors are more prevalent in one over the other. Three recent studies of large population databases in the US and Denmark have verified old associations and identified multiple new associations with ICC. Risk factors that
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were significant in at least two of the studies include cholangitis, cholelithiasis, choledocholithiasis, alcoholic liver disease, nonspecific cirrhosis, hepatitis C, diabetes mellitus, inflammatory bowel disease, and smoking.29-31 The odds ratios (OR), with 95% confidence intervals, of these risk factors are summarized in Figure 3. The earliest study by Shaib and associates,29 using SEER and Medicare data, matched 625 patients with ICC and 90,834 controls. In addition to the previously mentioned risk factors, this study identified cholestasis (OR 6.7) and HIV (OR 5.9) as risk factors. A second large study by Welzel and coworkers,30 also using SEER and Medicare data, matched 549 ECC and 535 ICC patients to 102,782 cancer-free controls and along with some of the previously mentioned risk factors, found that choledochal cysts (OR 36.9), biliary cirrhosis (OR 19.8), cholecystitis (OR 8.5), cholecystectomy (OR 5.4), nonalcoholic liver disease (OR 3.0), thyrotoxicosis (OR 1.5), duodenal ulcers (OR 3.4), chronic pancreatitis (OR 5.9), and obesity were all associated with ICC. The same study found that when inflammatory bowel disease was divided into ulcerative colitis and Crohn’s disease, ulcerative colitis was significantly associated only with ICC, and not ECC; Crohn’s disease was associated only with ECC. Another study by Welzel and colleagues,31 using population-based data from Denmark, matched 764 ICC patients to 3,056 controls and confirmed many of the same risk factors; in the Denmark cohort, however, obesity, diabetes mellitus, and cholecystectomy were not significantly related to ICC. Three small hospital-based studies, one each from the US, Japan, and Italy found a correlation between hepatitis C and ICC.32-34 In addition, the Italian study demonstrated hepatolithiasis to be a risk factor for ICC.34 These studies point to several new risk factors and associations that could be contributing to the rising incidence of ICC. Although the exact mechanisms for carcinogenesis from these risk factors have not been completely elucidated, translational studies are in progress. There is some evidence that abnormalities in the hepatitis B “X” gene may play a role in development of cholangiocarcinoma.35,36 Specifically, in cholangiocarcinoma cell lines, transactivation of the human telomerase reverse transcriptase (hTERT) gene by the hepatitis B “X” gene is thought to be a mechanism of pathogenesis of both hepatocellular cancer and cholangiocarcinomas related to hepatitis B.36 Experimental models using recombinant plasmids of the hepatitis C virus placed into cholangiocarcinoma cell lines have been developed to better understand the effect of the hepatitis C virus on this cancer.37 Inactivation of the tumor suppressor gene p53 has also been reported to play a role in development of cholangiocarcinoma and in particular, p53 protein overexpression
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Figure 3. Comparison of odds ratios with 95% confidence intervals for risk factors identified in three large population database studies of intrahepatic cholangiocarcinoma.
has been associated with cholangiocarcinoma in patients with primary sclerosing cholangitis.38,39 Finally, microarray analysis has been done in a small group of ICC patients (n ⫽ 25) and has allowed identification of 52 genes that were upregulated and 421 that were downregulated in ICC compared with normal biliary epithelium. This study also identified 30 genes that were commonly associated with lymph node involvement.40 Larger studies on these molecular mechanisms will be needed to further determine the pathogenesis of ICC and how the mechanisms relate to these risk factors. Diagnosis
To the practicing physician, cholangiocarcinoma is typically thought to present with jaundice, which is true of advanced stage ECC. ICC, in contrast, is a subtype of cholangiocarcinoma that is usually asymptomatic, even at advanced stages, and is diagnosed incidentally on imaging studies or on evaluation of abnormal liver enzymes. When ICC presents with symptoms, these usually consist of abdominal pain or nonspecific constitutional symptoms such as weakness, fatigue, or weight loss.41-45 In a large series of 162 patients, the three most common presenting symptoms included abdominal pain (85%), anemia (81.5%),
and weight loss (77.8%).42 Jaundice occurs in only 0% to 28% of patients, and because of this, ICC has been labeled “an intrahepatic tumor in the absence of jaundice.”42-44,46 The literature describes various types of imaging used to diagnose cholangiocarcinoma including ultrasound, CT scan, magnetic MRI, MRI cholangiography, CT cholangiography, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound.28 As mentioned previously, ICC does not usually involve jaundice, and the vast majority of cases are diagnosed with ultrasound, CT scan, or MRI.41,46 Extrahepatic bile ducts typically are not involved in these patients, so unless a centrally located mass is compressing the duct, complex evaluation of the biliary tree with ERCP, MRI cholangiography, or CT cholangiography is generally not required. There is no blood test that is absolutely diagnostic of ICC, although liver function tests and serum tumor markers of cancer antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), and ␣-fetoprotein typically are used. In one study, liver transaminases, alkaline phosphatase, and bilirubin were all lower in patients with ICC than in patients with ECC.43 Of the tumor markers mentioned, CA 19-9 has been described most frequently. CA 19-9 elevation is not pathognomonic of cholangiocarcinoma because it can
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Table 1. American Joint Committee on Cancer Staging System for Liver (Including Intrahepatic Bile Ducts)
Table 2. Okabayashi Proposed Staging System for MassForming Intrahepatic Cholangiocarcinoma, 2000
Classification
Stage
Primary tumor (T) TX T0 T1 T2 T3
T4
Regional lymph nodes (N) NX N0 N1 Distant metastasis (M) MX M0 M1 Stage I II IIIA IIIB IIIC IV
Definition
Primary tumor cannot be assessed No evidence of primary tumor Solitary tumor without vascular invasion Solitary tumor with vascular invasion or multiple tumors, none more than 5 cm Multiple tumors more than 5cm or tumor involving major branch of portal vein or hepatic vein Tumor with direct invasion of adjacent organs other than gall-bladder or with perforation of visceral peritoneum
Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastases cannot be assessed No distant metastasis Distant metastasis T1N0M0 T2N0M0 T3N0M0 T4N0M0 any T N1M0 any T any N M1
increase in cholangitis, alcoholic liver disease, and other malignancies (eg, pancreatic, intestinal, and gastric).47 In all cholangiocarcinomas, CA 19-9 has a sensitivity of 89% and specificity of 86%, but the sensitivity is only 53% in patients with primary sclerosing cholangitis.48,49 An extremely high CA 19-9 also may be helpful in identifying unresectable disease.50 Paik and colleagues44 reviewed 97 patients with ICC and showed that CA 19-9 was elevated in 28.9%, although CEA was elevated in only 3.1%. The differential diagnosis for a liver mass includes primary liver cancers, such as hepatocellular carcinoma and ICC, and metastatic tumors, especially of colorectal origin. If history and tumor markers are not conclusive, other studies such as colonoscopy, esophagogastroduodenoscopy, CT scan of the chest, or positron emission tomography (PET) scan may be indicated to rule out a primary adenocarcinoma originating outside of the liver. A percutaneous liver biopsy can be done to confirm the diagnosis, but it may still be difficult to differentiate ICC from a metastatic adenocarcinoma or a hepatocellular carcinoma with cholangiocellular features. Percutaneous liver biopsy
I II IIIA IIIB IV
Definition
Solitary tumor without vascular invasion Solitary tumor with vascular invasion Multiple tumors with or without vascular invasion Any tumor with regional node metastasis Any tumor with distant metastasis
(From: Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92:2374–2383. This material is reproduced with permission of Wiley-Liss Inc, a subsidiary of John Wiley & Sons, Inc.)
is also invasive and has inherent risks of bleeding, pneumothorax, and needle-tract seeding of the tumor. Although no specific studies have been done on needle-tract seeding of ICC, seeding has been reported in 1% to 5% of patients when percutaneous biopsy is done for hepatocellular carcinoma.51-55 Occasionally laparotomy is required for definitive diagnosis when imaging, laboratory studies, and percutaneous biopsy are inconclusive. Staging
As mentioned previously, classification of cholangiocarcinoma has been an evolving and sometimes confusing problem. Currently the American Joint Committee on Cancer (AJCC) includes ICC in the same category as primary liver cancers for staging, as shown in Table 1, although ECC has completely separate staging criteria.56 Cholangiocarcinoma is the only malignancy that has subtypes with completely different staging systems. In 2000, Okabayashi and associates41 proposed a new staging system for “mass-forming” ICC. The authors believed this classification system was simpler to use, and it was able to predict the differences in survival after resection. Their staging system, shown in Table 2, is similar to the AJCC staging, but stage III has only two subcategories instead of three. The National Cancer Institute, National Cancer Registrars Association, Commission on Cancer, and the AJCC all currently use the AJCC staging system. Efforts by the American Hepato Pancreato Biliary Association, in conjunction with other organizations, are in progress to restructure the staging system and separate ICC from hepatocellular cancer. Treatment and prognosis
The overall worldwide mortality from ICC has been increasing, as has been shown in multiple studies using World Health Organization data.13,28 US-SEER data also indicated an increased mortality from ICC in earlier studies.57 The most recent study from this database showed an improved survival in the most recent decade (1992–2003), when compared with the two previous decades. But despite
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Table 3. Review of Literature on Patient and Disease-Free Survival of Surgically Resected Intrahepatic Cholangiocarcinoma First author
Year
Site
Schlinkert59 Yamamoto60 Pichlmayr67
1992 1992 1995
US-Mayo Japan Germany
Nakeeb46 Jan61 Casavilla64
1996 1996 1997
US-Baltimore China US-Pittsburgh
Madariaga63 Inoue45 Chen42 Valverde62 Okabayashi41 Weber66 DeOliveira43 Paik44 Shimada65
1998 1999 1999 1999 2001 2001 2007 2007 2007
US-Pittsburgh Japan Taiwan France Japan US-New York US-Baltimore Korea Japan
n
6 10 LR-32 OLT-18 9 41 LR-34 OLT-20 34 52 48 30 60 33 44 97 47
1-y survival, %
3-y survival, %
5-y survival, %
59.3
44.4
33 44.4
53.7 64
36.6 34
67 63 35.5 86 68
40 36 20 22 35
74.9
51.8 45
1-y DFS, %
3-y DFS, %
5-y DFS, %
Median survival, mo
LR-12.8 OLT-5 22 12
44 26.8 26
57
34
27
35 36 20.5
77 42 16.5
41 38
41 34
19
28 29 40 31.1 40
37.4 23 21.3
6.4
2.1
DFS, disease-free survival; LR, liver resection; OLT, orthotopic liver transplant.
advances in imaging, diagnosis, and surgical technique, the overall 5-year survival is only 19.7%, and median survival is 22 months.58 Currently, surgical resection of the involved liver segments is the only curative treatment for ICC, but because most patients present at an advanced stage, resectability rates have been quite variable (18% to 70%). Surgery has been successful in the few reported series, with 1-year survival after surgical resection reported as 35% to 86%, 3-year survival as 20% to 51.8%, and 5-year survival as 20.5% to 40%. Disease-free survival at 5 years was widely variable — between 2% and 41%. Median survival after ICC resection was 12 to 37.4 months.41-46,59-67 These data are summarized in Table 3. Several of these studies report perioperative mortality in the range of 2% to 5%.41,42,45 Most series of ICC cases have a limited number of patients, so few studies have specifically addressed surgical resection and outcomes by stage compared with nonoperative treatments. Based on available studies, surgery should be offered to patients with potentially resectable ICC regardless of stage. DeOliveira and coauthors,43 in 44 patients, emphasized the importance of performing a complete resection because 5-year survival was 63% and median survival was 80 months in patients in whom an R0 resection could be achieved. Nakeeb and colleagues46 demonstrated that resection was beneficial; 5-year survival was 44% and median survival was 22 months in those who underwent resection versus 23% and 7 months, respectively, in patients who did not. Okabayashi and associates,41 using his staging system, reported 3-year survival by
stage: I, 74%; II, 48%; IIIA, 18%; and IIIB, 7%; and median survival by stage: II, 26.2 months; IIIA,16.8 months; and IIIB, 11.2 months. Indicators of poor prognosis that were noted in two or more studies included positive lymph nodes, positive margins, multiple nodules, vascular invasion, and large tumor size. Indicators mentioned in only one study included capsular invasion, “histologic type,” “tumor spreading type,” “high T stage,” bilobar disease, mucobilia, left side involvement, and “very high CA 19-9.”42,44,45,61-65 Chen and coworkers42 also reported that patients with hepatolithiasis had higher rates of resection, incidence of papillary type tumors, and postoperative complications, but no difference in survival was noted when compared with patients without hepatolithiasis. These prognostic factors are summarized in Table 4. In a study of 33 patients, recurrence rate was reported as 61% at 12.4 months. Liver was the most common site of recurrence, with recurrence in the lung, lymph nodes, and bone seen less commonly.65,66 Two studies divided ICC into subtypes and compared prognoses between the subtypes. Shimada and colleagues65 divided ICC into mass-forming and mass-forming periductal-infiltrating, which occurs with a definitive mass but also causes infiltration along the portal pedicle and bile ducts. The mass-forming periductal-infiltrating subtype was associated more with jaundice, bile duct invasion, portal invasion, lymph nodes involvement, and positive surgical margins. In their study of 74 patients, those with mass-forming ICC had less local recurrence (76.1% versus 92.9%) and a significantly better median survival
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Table 4. Factors Associated with Poor Outcomes in Intrahepatic Cholangiocarcinoma First author
Year
ICC patients, n
Positive lymph nodes
Vascular invasion
Jan61
1996
41
⫹
⫹
Casavilla64 Madariaga63 Inoue45 Chen42 Valverde62 Weber66 DeOliveira43 Paik44
1997 1998 1999 1999 1999 2001 2007 2007
54 34 52 162 42 53 44 97
⫹ ⫹ ⫹ ⫹ ⫹
⫹
Positive margins
⫹ ⫹ ⫹
Tumor Bilobar size disease
Multiple tumors
⫹ ⫹
⫹ ⫹
Other factors
Histologic type, capsular invasion, tumor spreading type, mucobilia Advanced stage Left side, associated node dissection No hepatic duct stones Satellite nodules
⫹
⫹ ⫹ ⫹
⫹
⫹
High T stage, high CA 19-9
ICC, intrahepatic cholangiocarcinoma.
(32 months versus 22 months) than those with massforming periductal-infiltrating. Aishima and coworkers68 subtyped 87 patients into hilar ICC and peripheral ICC groups and noted that hilar ICC was more likely to be associated with perineural invasion, lymph node metastases, and extrahepatic recurrence; those with peripheral ICC had significantly better survival. One-, 3-, and 5-year survivals of the peripheral ICC patients were 88%, 72%, and 60%, respectively, compared with 66%, 41%, and 36%, respectively, in the hilar ICC patients. Treatment of ICC with liver transplantation has been described in two studies. In 50 patients with ICC, Pichlmayr and associates67 found that median survival was 12.8 months for the 32 patients who underwent resection and 5 months for 18 transplanted patients. In one study, Casavilla and coworkers64 performed 34 liver resections and 20 liver transplants and found the negative predictors to be multiple tumors, bilobar disease, positive margins, and advancedTNM stage. Without these negative predictors, 1-, 3-, and 5-year survivals were 74%, 64%, and 62%, respectively. Currently, liver transplant for cholangiocarcinoma, both intrahepatic and extrahepatic, is done only in the setting of clinical trials and typically involves multimodality therapy. Systemic chemotherapy for cholangiocarcinoma generally has shown poor results. Postsurgical adjuvant therapy has not been supported by the evidence and is not currently recommended outside of clinical trials.28,69 Glimelius70 conducted one of the few prospective randomized trials in 90 patients with pancreatic or biliary tract cancer. This study demonstrated that chemotherapy improved survival and quality of life in advanced disease compared with best supportive care. But median survival was still only 6 months in the group that received chemotherapy consisting of 5-fluorouracil (5-FU) and leucovorin with or without etoposide, depending on performance status. Of the chemotherapeutic agents, 5-FU, alone or in combination with other drugs, is the most extensively studied
treatment, and it has shown response rates of 0% to 40%. 5-FU combined with cisplatin and epirubicin yielded the best response, with an 11-month median survival. Unfortunately, another study using the same combination of drugs attained only a 10% response rate and median survival of 5 months. Gemcitabine also has shown activity in cholangiocarcinoma with response rates of 8% to 60% and median survival of 6.3 to 16 months. Gemcitabine in combination with cisplatin or oxaliplatin did not improve response rates over gemcitabine alone. Chemotherapeutic agents that have shown no or poor response alone or in combination include paclitaxel, docetaxel, irinotecan, and capecitabine. Because of the small number of patients (42 patients in the largest trial) and inclusion of multiple cancers (ICC, ECC, gallbladder, and pancreatic), it is difficult to make any specific conclusions.69 More research on ICC, especially controlled trials, is needed focusing on gemcitabine and on the combination of 5-FU, cisplatin, and epirubicin. Regional chemotherapy in the form of transarterial chemoembolization has been used in several small uncontrolled trials of ICC with median survivals of 12 to 26 months.71-76 These trials are summarized in Table 5. No good evidence is available for the use of radiotherapy in ICC, and in a prospective study of 50 patients with perihilar cholangiocarcinoma, adjuvant radiotherapy did not affect length or quality of survival.77 Further research is necessary before recommendations can be made for the use of chemotherapy or radiotherapy in patients with ICC. Future directions
In summary, ICC is a malignancy of increasing importance to both the practicing physician and surgeon. The incidence of ICC has increased steadily over the past few decades and recently identified risk factors of viral hepatitis, chronic liver disease, and fatty liver disease may be contributing factors. Just as the incidence of HCC increased in the
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Table 5. Review of Literature on Survival of Intrahepatic Cholangiocarcinoma with Chemotherapeutic Agents First author
Year
n
Agents used
Tanaka76 Kirchhoff71 Burger73
2002 2005 2005
11 8 17
Cantore74 Vogl75
2005 2006
Herber72
2007
30 12 12 15
5-Fluorouracil Cisplatin/doxorubicin/starch microsphere Cisplatin/doxorubicin/mitomycin-C/ethiodol with polyvinyl alcohol particles or microspheres Epirubicin/cisplatin Gemcitabine without starch microspheres Gemicitabine with starch microspheres Lipiodol/mitomycin-C
last decade from the epidemic of hepatitis C, a similar phenomenon may be occurring with ICC from viral hepatitis and metabolic syndrome-related liver disease.78 It is important for primary care physicians and gastroenterologists to identify and evaluate these patients promptly for referral to their surgical colleagues. Gastroenterologists and hepatologists frequently screen patients with viral hepatitis for HCC, even though the value of screening is yet to be determined, and whenever a liver mass is identified during screening, ICC and HCC need to be included in the differential diagnosis.79,80 Tumor markers, especially CA 19-9, and percutaneous liver biopsy may be helpful in differentiating ICC from HCC. But in some patients, the diagnosis cannot be made before surgical exploration. Differentiation also needs to be made between ICC and ECC with liver metastases because treatments can differ significantly. Once the diagnosis of ICC has been made, evaluation for extrahepatic metastases needs to be performed and resectability determined. In the absence of metastases, in appropriate surgical candidates, patients with ICC should undergo prompt surgical resection with adequate margins. Lymph node dissection should be considered as well. In the future, a standardized definition, classification, and perhaps a staging system that is unique to ICC is needed to better evaluate the efficacy of our treatments. Acknowledgment: Special thanks to Carla Getz for the illustrations.
REFERENCES 1. Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J Hepatology 2006;45:856– 867. 2. Foucar E, Kaplan LR, Gold JH, et al. Well-differentiated peripheral cholangiocarcinoma with unusual clinical course. Gastroenterology 1979;77:347–353. 3. Nakajima T, Kondo Y, Miyazaki M, Okui K. A histopathologic study of 102 cases of intrahepatic cholangiocarcinoma: histologic classification and modes of spreading. Hum Pathol 1988; 19:1228–1234.
Median survival, mo
26 12 23 13.2 13.5 20.2 21.1
4. Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies of the biliary tree. Curr Probl Surg 1995;32:36–70. 5. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996;224:463–473. 6. Fritz A, ed. International classification of diseases for oncology, 3rd edition. Geneva, Switzerland: World Health Organization; 2000. 7. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Nat Cancer Inst 2006;98:873–875. 8. Lim JH, Park CK. Pathology of cholangiocarcinoma. Abd Imaging 2004;29:540–547. 9. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer, 4th ed. Tokyo: Kanehara; 2000. 10. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin 2002;55:74–108. 11. SEER Cancer Statistics Review 1975–2004. US National Institute of Health. Available at: http://www.SEER.cancer.gov. Accessed May 6, 2008. 12. Centers for Disease Control and Prevention, Department of Health and Human Services, National Program of Cancer Registries, US Cancer Statistics 2004. Available at: http://www.apps.nccd.cdc.gov. Accessed April 2008. 13. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002;2:10–15. 14. Khan SA, Taylor-Robinson SD, Toledano MB, et al. Changing international trends in mortality rates of liver, biliary and pancreatic tumors. J Hepatology 2002;37:806–813. 15. Wood R, Brewster DH, Fraser LA, et al. Do increases in mortality from intrahepatic cholangiocarcinoma reflect a genuine increase in risk? Insights from cancer registry data in Scotland. Eur J Cancer 2003;39:2087–2092. 16. Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 2001;48:816–820. 17. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatology 2004;40:472–477. 18. McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States. Liver Int 2006;26:1047–1053. 19. McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev 2006;15:1198–1203.
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20. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–125. 21. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol 1999;10:308–311. 22. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36:321–327. 23. Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in choledochal cysts: age-related incidence. Arch Surg 1983; 118:986–988. 24. Dayton MT, Longmire WP Jr, Tompkins RK. Caroli’s disease: a premalignant condition? Am J Surg 1983;145:41–48. 25. Yamato T, Sasaki M, Hoso M, et al. Intrahepatic cholangiocarcinoma arising in congenital hepatic fibrosis: report of an autopsy case. J Hepatol 1998;28:717–722. 26. Parkin DM, Srivatankakul P, Khlat M, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer 1991;48:323–328. 27. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;89:962–970. 28. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51:1–9. 29. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005;128:620–626. 30. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 2007;5:1221–1228. 31. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007;120:638–641. 32. Shaib YH, El-Serag HB, Nooka AK, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based casecontrol study. Am J Gastroenterol 2007;102:1016–1021. 33. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001;12:959–964. 34. Yamamoto S, Kubo S, Hai S, et al. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004;95:592–595. 35. Gastelis NK, Tepetes K, Loukopoulos A, et al. Hepatitis B virus and intrahepatic cholangiocarcinoma. Cancer Invest 2007;25: 55–58. 36. Qu ZL, Zou SQ, Cui NQ, et al. Upregulation of human telomerase reverse transcriptase mRNA expression by in vitro transfection of hepatitis B virus X gene into human hepatocarcinoma and cholangiocarcinoma cells. World J Gastroenterol 2005;11: 5627–5632. 37. Liu X, Zou S, Qiu F. Expression of nuclear factor kappa B in hepatitis C virus core gene transfected cholangiocarcinoma cells. Chin Med J 2002;115:998–1001. 38. Khan SA, Thomas HC, Toledano MB, et al. p53 mutations in human cholangiocarcinoma: a review. Liver Int 2005;25:704– 716. 39. Rizzi PM, Ryder SD, Portmann B, et al. p53 Protein overexpression in cholangiocarcinoma arising in primary sclerosing cholangitis. Gut 1996;38:265–268.
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40. Obama K, Ura K, Li M, et al. Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology 2005;41:1339–1348. 41. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92:2374–2383. 42. Chen MF, Jan YY, Jeng LB, et al. Intrahepatic cholangiocarcinoma in Taiwan. J Hepatobiliary Pancreat Surg 1999;6:136– 141. 43. DeOliviera ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one year experience with 564 patients at a single institution. Ann Surg 2007;245:755–762. 44. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008;23:766–770. 45. Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127:498–505. 46. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar and distal tumors. Ann Surg 1996;224:463–473. 47. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 19–9 for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo Clin Proc 1993;68:874– 879. 48. Patel AH, Harnois DM, Kelee GG, et al. The utility of CA 19–9 in the diagnoses of cholangiocarcinoma without primary sclerosing cholangitis. Am J Gastroenterol 2000;95:204–207. 49. Singh P, Patel T. Advances in the diagnosis, evaluation and management of cholangiocarcinoma. Current Opin Gastroenterol 2006;22:294–299. 50. Levy C, Lymp J, Angulo P, et al. The value of serum Ca 19–9 in patients with primary sclerosing cholangitis. Dig Dis Sci 2005;50: 1734–1740. 51. Takamori R, Wong LL, Dang C, et al. Needle-tract implantation from hepatocellular cancer: is needle biopsy of the liver always necessary? Liver Transpl 2000;6:67–72. 52. Huang GT, Sheu JC, Yang PM, et al. Ultrasound guided cutting biopsy for the diagnosis of hepatocellular carcinoma–a study based on 420 patients. J Hepatol 1996;25:334–338. 53. Durand F, Regimbeau JM, Belghiti J, et al. Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 2001;35:254– 258. 54. Kim SH, Lim HK, Lee WJ, et al. Needle-tract implantation in hepatocellular carcinoma: frequency and CT findings after biopsy with a 19.5 gauge automated biopsy gun. Abdom Imaging 2000;25:246–250. 55. Chaupoutot C, Perney P, Fabre D, et al. Needle-tract seeding after ultrasound guided puncture of hepatocellular carcinoma: A study of 150 patients. Gastroenterol Clin Biol 1999;23:552–556. 56. Greene FL, Page DL, Fleming ID, Fritz A. AJCC cancer staging manual, 6th edition. Philadelphia: Lippincott Raven Publishers; 2002. 57. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33:1353–1357. 58. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma: a 30-year populationbased SEER database analysis. J Gastrointest Surg 2007;11: 1488–1496.
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59. Schlinkert RT, Nagorney DM, Van Heerden JA, Adson MA. Intrahepatic cholangiocarcinoma: clinical aspects, pathology and treatment. HPB Surg 1992;78:727–731. 60. Yamamoto J, Kosuge T, Takayama T, et al. Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 1992;111:617–622. 61. Jan YY, Jeng LB, Hwang TL, et al. Factors influencing survival after hepatectomy for peripheral cholangiocarcinoma. Hepatogastroenterology 1996;43:614–619. 62. Valverde A, Bonhomme N, Farges O, et al. Resection of intrahepatic cholangiocarcinoma: a Western experience. J Hepatobiliary Pancreat Surg 1999;6:122–127. 63. Madariaga JR, Iwatsuki S, Todo S, et al. Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases. Ann Surg 1998;227:70–79. 64. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997;185:429–436. 65. Shimada K, Sano T, Sakamoto Y, et al. 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 2007;31:2016–2022. 66. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg 2001;193:384–391. 67. Pichlmayr R, Lamesch P, Weimann A, et al. Surgical treatment of cholangiocellular carcinoma. World J Surg 1995;19:83–88. 68. Aishima S, Kuroda Y, Nishihara Y, et al. Proposal of progression model for intrahepatic cholangiocarcinoma: clinicopathologic differences between hilar type and peripheral type. Am J Surg Pathol 2007;7:1059–1067. 69. Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol 2005;16(suppl 2):ii93–96. 70. Glimelius B. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593–600.
71. Kirchhoff T, Zender L, Merkesdal S, et al. Initial experience from a combination of systemic and regional chemotherapy in the treatment of patients with nonresectable cholangiocellular carcinoma in the liver. World J Gastroenterol 2005;11:1091– 1095. 72. Herber S, Otto G, Schneider J, et al. Transarterial chemoembolization (TACE) for inoperable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol 2007;30:1156–1165. 73. Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol 2005;16: 353–361. 74. Cantore M, Mambrini A, Fiorentini G, et al. Phase II study of hepatic intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable biliary tract tumors. Cancer 2005;103:1402–1407. 75. Vogl TJ, Schwarz W, Eichler K, et al. Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy. J Cancer Res Clin Oncol 2006;132:745–755. 76. Tanaka N, Yamakado K, Nakatsuka A, et al. Arterial chemoinfusion therapy through an implanted port system for patients with unresectable intrahepatic cholangiocarcinoma–initial experience. Eur J Radiol 2002;41:42–48. 77. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995;221:788–797. 78. Davila JA, Morgan RO, Shaib Y, et al. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 2004;127:1372– 1380. 79. Nguyen TT, Gildengorin G, Truong A, McPhee SJ. Factors influencing physicians’ screening behavior for liver cancer among high-risk patients. J Gen Intern Med 2007;22:523–526. 80. Chalasani N, Said A, Ness R, et al. Screening for hepatocellular carcinoma in patients with cirrhosis in the United States: results of a national survey. Am J Gastroenterol 1999;94:2224–2229.
in the liver, or “mass-forming,” based on its morphologic growth pattern. The delineation of ICC is a relatively recent phenomenon, with the earliest case reports and series in the 1970s and 1980s.2,3 Because of these inconsistencies in definition and the relatively small numbers of cases reported by each group, there is currently no consensus on classification. Extrahepatic cholangiocarcinoma has been further subdivided into several categories including hilar, perihilar, distal, and diffuse.4,5 “Hilar cholangiocarcinoma,” also called a “Klatskin tumor,” is used to describe tumors that involve the bifurcation of the common hepatic duct. Many sources use “perihilar cholangiocarcinoma,” which includes tumors of the common hepatic duct and its primary and secondary branches proximal to the bifurcation. But there is disagreement about the distal border for perihilar cholangiocarcinomas; some define it as the point at which the bile duct passes under first portion of the duodenum, and others define it as the point at which the cystic duct joins the common hepatic. Many textbooks and articles simply do not define “perihilar,” leaving readers to come to their own conclusions. Further confusion occurs because “hilar,” “perihilar,” and “Klatskin tumors” have all been used to refer to intrahepatic and extrahepatic cholangiocarcinomas. As an example, the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), used by many of the data sources for recent publications on cholangiocarcinoma, includes codes for Klatskin tumors (8162/3) as a subset of both ICC (C22.1) and ECC (C24.0).6,7 Figure 1 illustrates the different anatomic classifications that are currently used. In addition to anatomic classifications, many attempts have been made to categorize ICC based on specific morphology and histologic features. This has generated other descriptive terms such as nodular, massive, diffuse, sclerosing, polypoid, papillary, exophytic, and infiltrating.8 More recently, the Liver Cancer Study Group of Japan proposed a classification consisting of “mass-forming,” “periductalinfiltrating,” and “intraductal-growing,” with morphology as illustrated in Figure 2.9 The mass-forming subtype corresponds to previous classifications of nodular and exophytic; periductal-infiltrating corresponds to the infiltrating and sclerosing subtypes; and intraductal-growing corresponds to the previous subtypes of polypoid and papillary.
Classification
Using the most basic definition, intrahepatic cholangiocarcinoma (ICC) refers to the 10% of bile duct cancers that arise from the epithelial cells of the intrahepatic bile ducts. The other 90% of cholangiocarcinomas arise from the epithelial cells of the extrahepatic bile ducts, and are referred to as extrahepatic cholangiocarcinoma (ECC), with the majority located near the bifurcation of the common hepatic duct.1 Although this definition appears straightforward, development of different definitions and systems of classification by various groups has led to confusion. Historically, these cancers were classified as “biliary tract cancers” if they were located in the extrahepatic bile ducts or “primary liver tumors” if they were located in the liver. Later “primary liver tumors” became known as “cholangiocarcinomas,” and more recently, “cholangiocarcinoma” has been expanded to describe all cancers arising from the epithelial cells of the bile ducts regardless of the location. These cancers have been further classified based on their anatomic location into ICC and ECC. In the literature, ICC also is referred to as “peripheral,” based on its location Disclosure Information: The following disclosure has been reported by the author: Dr Wong is on the Advisory Board and has received an honorarium from Bayer Health Care. Received February 14, 2008; Revised April 14, 2008; Accepted April 22, 2008. From the Departments of Surgery, University of Hawaii John A Burns School of Medicine, and Hawaii Medical Center-East, Honolulu, HI. Correspondence address: Linda L Wong, MD, University of Hawaii, 2226 Liliha Street, Suite 402, Honolulu, HI 96817.
© 2008 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
AJCC CA 19-9 ECC HCC ICC OR SEER
Figure 1. Highlight of the confusing terminology used in conjunction with cholangiocarcinoma. This malignancy has been described with several different and overlapping anatomic classifications based on its location in the biliary system.
Epidemiology
In much of the epidemiologic data, cholangiocarcinoma and other primary liver tumors are grouped together as “liver and biliary tract cancer.” Under this categorization, liver and biliary tract cancer is the sixth most common cancer, and the third most common cause of cancer mortality worldwide, with about 626,000 cases reported in 2002 and nearly as many deaths (598,000). More than 80% of these cases occurred in developing countries located in Asia and Sub-Saharan Africa, with 55% from China alone.10 In the United States, it was estimated that 18,410 people would be diagnosed with primary cancer of the liver and intrahepatic bile ducts in 2008. Using the Surveillance, Epidemiology, and End Results (SEER) data from 2000 to 2004, the overall age-adjusted incidence of these cancers is estimated at 6.2 per 100,000. Although most cancers in the United States are experiencing a decrease in incidence and death rate, liver and bile duct cancers had the highest increase in death rate and second highest increase in incidence of all cancers between 1995 and 2004.11 Although the vast majority of these represent hepatocellular cancer (HCC), an estimated 15% to 20% are intrahepatic cholangiocarcinoma (ICC).12 Worldwide data show an increase in incidence and mortality of ICC with tremendous geographic variation. Patel,13 in reviewing the World Health Organization (WHO) database, demonstrated an increase in ICC mortality in 19 of 22 countries studied. These included both industrialized and developing countries. Regions with the greatest increases were America, Oceania, and Western Europe. The three countries (the former Czechoslovakia, Norway, and Israel) in which increased mortality was not evident had less than 8 years of data available. It also was observed that in 13 of the 19 countries with overall increases in ICC, the rates of increased mortality were higher in males than in females. Interestingly, during this same study period, there was a decrease in mortality from ECC. Another analysis of
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
American Joint Committee on Cancer cancer antigen 19-9 extrahepatic cholangiocarcinoma hepatocellular carcinoma intrahepatic cholangiocarcinoma odds ratio Surveillance, Epidemiology, and End Results
the WHO data by Khan and colleagues14 indicated that mortality from ICC increased in all countries, with the largest increases in Australia, Scotland, England, and the US. A study focusing on Scotland demonstrated an eightfold increase in ICC mortality in both males and females.15 In England, ICC mortality has increased 15-fold, and it is currently the most common cause of mortality in primary liver tumors, surpassing the mortality of HCC.16 Several studies in the US, using the SEER database from 1975 to 1999, demonstrated a 165% increase in incidence
Figure 2. Depiction of the morphology of the three classes of cholangiocarcinoma that have been proposed by the Liver Cancer Study Group of Japan.
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in ICC, with significant racial and gender variations.17-19 In the 2,864 cases identified, the incidence increased from 0.32 to 0.85 per 100,000, with most of the change occurring after 1985. Caucasians and African Americans had similar age-adjusted incidence rates during this time, but Asians had an incidence that was twice as high. The incidence of ICC increased in all age groups, but was particularly evident in the older age groups. Asians older than 65 years had an increase in incidence from 1.35 to 7.88 per 100,000 during this time period.17 The incidence of ICC is higher in males than in females and also increased at a greater rate in males than in females for all races.17,19 During this same time period, the incidence of ECC in the US declined 14%.20 Some have postulated that the increased incidence of ICC may be attributable to more accurate reporting of this cancer, less misclassification, and better microscopic verification and diagnostic imaging. Multiple studies in different countries over long time periods have shown a continued increase in incidence and mortality, so more accurate reporting of ICC is unlikely to be the only reason for this increase in incidence.13-15,17 Risk factors
Cholangiocarcinoma has several frequently described risk factors, but the vast majority of patients present without any of the established risk factors.21 Primary sclerosing cholangitis, associated with ulcerative colitis, is one of the most recognized risk factors. Patients with primary sclerosing cholangitis have a 1.5% cumulative annual risk of developing cholangiocarcinoma per year of disease, and 10% to 20% will eventually develop cholangiocarcinoma.21,22 Fibropolycystic liver disease, including choledochal cysts, Caroli’s syndrome, and congenital hepatic fibrosis, is another commonly recognized risk factor.23-25 In Asia, liver flukes contribute to the high incidence of cholangiocarcinoma. Opisthorchis viverrini, found primarily in Thailand, Laos, and Cambodia, and Clonorchis sinensis, endemic in southern China, Korea, Taiwan, Japan, and Vietnam, are both recognized risk factors.26,27 Other established risk factors include hepatolithiasis, Thorotrast (thorium dioxide, a contrast agent used from 1931 until the 1950s), Lynch syndrome II, and biliary papillomatosis.28 Most of these risk factors appear to have the common theme of repeated episodes or extended inflammation of the biliary tract. Unfortunately, most of these associations were formulated before ICC and ECC were classified as distinct entities, so it is unclear if the established risk factors are more prevalent in one over the other. Three recent studies of large population databases in the US and Denmark have verified old associations and identified multiple new associations with ICC. Risk factors that
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were significant in at least two of the studies include cholangitis, cholelithiasis, choledocholithiasis, alcoholic liver disease, nonspecific cirrhosis, hepatitis C, diabetes mellitus, inflammatory bowel disease, and smoking.29-31 The odds ratios (OR), with 95% confidence intervals, of these risk factors are summarized in Figure 3. The earliest study by Shaib and associates,29 using SEER and Medicare data, matched 625 patients with ICC and 90,834 controls. In addition to the previously mentioned risk factors, this study identified cholestasis (OR 6.7) and HIV (OR 5.9) as risk factors. A second large study by Welzel and coworkers,30 also using SEER and Medicare data, matched 549 ECC and 535 ICC patients to 102,782 cancer-free controls and along with some of the previously mentioned risk factors, found that choledochal cysts (OR 36.9), biliary cirrhosis (OR 19.8), cholecystitis (OR 8.5), cholecystectomy (OR 5.4), nonalcoholic liver disease (OR 3.0), thyrotoxicosis (OR 1.5), duodenal ulcers (OR 3.4), chronic pancreatitis (OR 5.9), and obesity were all associated with ICC. The same study found that when inflammatory bowel disease was divided into ulcerative colitis and Crohn’s disease, ulcerative colitis was significantly associated only with ICC, and not ECC; Crohn’s disease was associated only with ECC. Another study by Welzel and colleagues,31 using population-based data from Denmark, matched 764 ICC patients to 3,056 controls and confirmed many of the same risk factors; in the Denmark cohort, however, obesity, diabetes mellitus, and cholecystectomy were not significantly related to ICC. Three small hospital-based studies, one each from the US, Japan, and Italy found a correlation between hepatitis C and ICC.32-34 In addition, the Italian study demonstrated hepatolithiasis to be a risk factor for ICC.34 These studies point to several new risk factors and associations that could be contributing to the rising incidence of ICC. Although the exact mechanisms for carcinogenesis from these risk factors have not been completely elucidated, translational studies are in progress. There is some evidence that abnormalities in the hepatitis B “X” gene may play a role in development of cholangiocarcinoma.35,36 Specifically, in cholangiocarcinoma cell lines, transactivation of the human telomerase reverse transcriptase (hTERT) gene by the hepatitis B “X” gene is thought to be a mechanism of pathogenesis of both hepatocellular cancer and cholangiocarcinomas related to hepatitis B.36 Experimental models using recombinant plasmids of the hepatitis C virus placed into cholangiocarcinoma cell lines have been developed to better understand the effect of the hepatitis C virus on this cancer.37 Inactivation of the tumor suppressor gene p53 has also been reported to play a role in development of cholangiocarcinoma and in particular, p53 protein overexpression
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Figure 3. Comparison of odds ratios with 95% confidence intervals for risk factors identified in three large population database studies of intrahepatic cholangiocarcinoma.
has been associated with cholangiocarcinoma in patients with primary sclerosing cholangitis.38,39 Finally, microarray analysis has been done in a small group of ICC patients (n ⫽ 25) and has allowed identification of 52 genes that were upregulated and 421 that were downregulated in ICC compared with normal biliary epithelium. This study also identified 30 genes that were commonly associated with lymph node involvement.40 Larger studies on these molecular mechanisms will be needed to further determine the pathogenesis of ICC and how the mechanisms relate to these risk factors. Diagnosis
To the practicing physician, cholangiocarcinoma is typically thought to present with jaundice, which is true of advanced stage ECC. ICC, in contrast, is a subtype of cholangiocarcinoma that is usually asymptomatic, even at advanced stages, and is diagnosed incidentally on imaging studies or on evaluation of abnormal liver enzymes. When ICC presents with symptoms, these usually consist of abdominal pain or nonspecific constitutional symptoms such as weakness, fatigue, or weight loss.41-45 In a large series of 162 patients, the three most common presenting symptoms included abdominal pain (85%), anemia (81.5%),
and weight loss (77.8%).42 Jaundice occurs in only 0% to 28% of patients, and because of this, ICC has been labeled “an intrahepatic tumor in the absence of jaundice.”42-44,46 The literature describes various types of imaging used to diagnose cholangiocarcinoma including ultrasound, CT scan, magnetic MRI, MRI cholangiography, CT cholangiography, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasound.28 As mentioned previously, ICC does not usually involve jaundice, and the vast majority of cases are diagnosed with ultrasound, CT scan, or MRI.41,46 Extrahepatic bile ducts typically are not involved in these patients, so unless a centrally located mass is compressing the duct, complex evaluation of the biliary tree with ERCP, MRI cholangiography, or CT cholangiography is generally not required. There is no blood test that is absolutely diagnostic of ICC, although liver function tests and serum tumor markers of cancer antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), and ␣-fetoprotein typically are used. In one study, liver transaminases, alkaline phosphatase, and bilirubin were all lower in patients with ICC than in patients with ECC.43 Of the tumor markers mentioned, CA 19-9 has been described most frequently. CA 19-9 elevation is not pathognomonic of cholangiocarcinoma because it can
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Table 1. American Joint Committee on Cancer Staging System for Liver (Including Intrahepatic Bile Ducts)
Table 2. Okabayashi Proposed Staging System for MassForming Intrahepatic Cholangiocarcinoma, 2000
Classification
Stage
Primary tumor (T) TX T0 T1 T2 T3
T4
Regional lymph nodes (N) NX N0 N1 Distant metastasis (M) MX M0 M1 Stage I II IIIA IIIB IIIC IV
Definition
Primary tumor cannot be assessed No evidence of primary tumor Solitary tumor without vascular invasion Solitary tumor with vascular invasion or multiple tumors, none more than 5 cm Multiple tumors more than 5cm or tumor involving major branch of portal vein or hepatic vein Tumor with direct invasion of adjacent organs other than gall-bladder or with perforation of visceral peritoneum
Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastases cannot be assessed No distant metastasis Distant metastasis T1N0M0 T2N0M0 T3N0M0 T4N0M0 any T N1M0 any T any N M1
increase in cholangitis, alcoholic liver disease, and other malignancies (eg, pancreatic, intestinal, and gastric).47 In all cholangiocarcinomas, CA 19-9 has a sensitivity of 89% and specificity of 86%, but the sensitivity is only 53% in patients with primary sclerosing cholangitis.48,49 An extremely high CA 19-9 also may be helpful in identifying unresectable disease.50 Paik and colleagues44 reviewed 97 patients with ICC and showed that CA 19-9 was elevated in 28.9%, although CEA was elevated in only 3.1%. The differential diagnosis for a liver mass includes primary liver cancers, such as hepatocellular carcinoma and ICC, and metastatic tumors, especially of colorectal origin. If history and tumor markers are not conclusive, other studies such as colonoscopy, esophagogastroduodenoscopy, CT scan of the chest, or positron emission tomography (PET) scan may be indicated to rule out a primary adenocarcinoma originating outside of the liver. A percutaneous liver biopsy can be done to confirm the diagnosis, but it may still be difficult to differentiate ICC from a metastatic adenocarcinoma or a hepatocellular carcinoma with cholangiocellular features. Percutaneous liver biopsy
I II IIIA IIIB IV
Definition
Solitary tumor without vascular invasion Solitary tumor with vascular invasion Multiple tumors with or without vascular invasion Any tumor with regional node metastasis Any tumor with distant metastasis
(From: Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92:2374–2383. This material is reproduced with permission of Wiley-Liss Inc, a subsidiary of John Wiley & Sons, Inc.)
is also invasive and has inherent risks of bleeding, pneumothorax, and needle-tract seeding of the tumor. Although no specific studies have been done on needle-tract seeding of ICC, seeding has been reported in 1% to 5% of patients when percutaneous biopsy is done for hepatocellular carcinoma.51-55 Occasionally laparotomy is required for definitive diagnosis when imaging, laboratory studies, and percutaneous biopsy are inconclusive. Staging
As mentioned previously, classification of cholangiocarcinoma has been an evolving and sometimes confusing problem. Currently the American Joint Committee on Cancer (AJCC) includes ICC in the same category as primary liver cancers for staging, as shown in Table 1, although ECC has completely separate staging criteria.56 Cholangiocarcinoma is the only malignancy that has subtypes with completely different staging systems. In 2000, Okabayashi and associates41 proposed a new staging system for “mass-forming” ICC. The authors believed this classification system was simpler to use, and it was able to predict the differences in survival after resection. Their staging system, shown in Table 2, is similar to the AJCC staging, but stage III has only two subcategories instead of three. The National Cancer Institute, National Cancer Registrars Association, Commission on Cancer, and the AJCC all currently use the AJCC staging system. Efforts by the American Hepato Pancreato Biliary Association, in conjunction with other organizations, are in progress to restructure the staging system and separate ICC from hepatocellular cancer. Treatment and prognosis
The overall worldwide mortality from ICC has been increasing, as has been shown in multiple studies using World Health Organization data.13,28 US-SEER data also indicated an increased mortality from ICC in earlier studies.57 The most recent study from this database showed an improved survival in the most recent decade (1992–2003), when compared with the two previous decades. But despite
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Table 3. Review of Literature on Patient and Disease-Free Survival of Surgically Resected Intrahepatic Cholangiocarcinoma First author
Year
Site
Schlinkert59 Yamamoto60 Pichlmayr67
1992 1992 1995
US-Mayo Japan Germany
Nakeeb46 Jan61 Casavilla64
1996 1996 1997
US-Baltimore China US-Pittsburgh
Madariaga63 Inoue45 Chen42 Valverde62 Okabayashi41 Weber66 DeOliveira43 Paik44 Shimada65
1998 1999 1999 1999 2001 2001 2007 2007 2007
US-Pittsburgh Japan Taiwan France Japan US-New York US-Baltimore Korea Japan
n
6 10 LR-32 OLT-18 9 41 LR-34 OLT-20 34 52 48 30 60 33 44 97 47
1-y survival, %
3-y survival, %
5-y survival, %
59.3
44.4
33 44.4
53.7 64
36.6 34
67 63 35.5 86 68
40 36 20 22 35
74.9
51.8 45
1-y DFS, %
3-y DFS, %
5-y DFS, %
Median survival, mo
LR-12.8 OLT-5 22 12
44 26.8 26
57
34
27
35 36 20.5
77 42 16.5
41 38
41 34
19
28 29 40 31.1 40
37.4 23 21.3
6.4
2.1
DFS, disease-free survival; LR, liver resection; OLT, orthotopic liver transplant.
advances in imaging, diagnosis, and surgical technique, the overall 5-year survival is only 19.7%, and median survival is 22 months.58 Currently, surgical resection of the involved liver segments is the only curative treatment for ICC, but because most patients present at an advanced stage, resectability rates have been quite variable (18% to 70%). Surgery has been successful in the few reported series, with 1-year survival after surgical resection reported as 35% to 86%, 3-year survival as 20% to 51.8%, and 5-year survival as 20.5% to 40%. Disease-free survival at 5 years was widely variable — between 2% and 41%. Median survival after ICC resection was 12 to 37.4 months.41-46,59-67 These data are summarized in Table 3. Several of these studies report perioperative mortality in the range of 2% to 5%.41,42,45 Most series of ICC cases have a limited number of patients, so few studies have specifically addressed surgical resection and outcomes by stage compared with nonoperative treatments. Based on available studies, surgery should be offered to patients with potentially resectable ICC regardless of stage. DeOliveira and coauthors,43 in 44 patients, emphasized the importance of performing a complete resection because 5-year survival was 63% and median survival was 80 months in patients in whom an R0 resection could be achieved. Nakeeb and colleagues46 demonstrated that resection was beneficial; 5-year survival was 44% and median survival was 22 months in those who underwent resection versus 23% and 7 months, respectively, in patients who did not. Okabayashi and associates,41 using his staging system, reported 3-year survival by
stage: I, 74%; II, 48%; IIIA, 18%; and IIIB, 7%; and median survival by stage: II, 26.2 months; IIIA,16.8 months; and IIIB, 11.2 months. Indicators of poor prognosis that were noted in two or more studies included positive lymph nodes, positive margins, multiple nodules, vascular invasion, and large tumor size. Indicators mentioned in only one study included capsular invasion, “histologic type,” “tumor spreading type,” “high T stage,” bilobar disease, mucobilia, left side involvement, and “very high CA 19-9.”42,44,45,61-65 Chen and coworkers42 also reported that patients with hepatolithiasis had higher rates of resection, incidence of papillary type tumors, and postoperative complications, but no difference in survival was noted when compared with patients without hepatolithiasis. These prognostic factors are summarized in Table 4. In a study of 33 patients, recurrence rate was reported as 61% at 12.4 months. Liver was the most common site of recurrence, with recurrence in the lung, lymph nodes, and bone seen less commonly.65,66 Two studies divided ICC into subtypes and compared prognoses between the subtypes. Shimada and colleagues65 divided ICC into mass-forming and mass-forming periductal-infiltrating, which occurs with a definitive mass but also causes infiltration along the portal pedicle and bile ducts. The mass-forming periductal-infiltrating subtype was associated more with jaundice, bile duct invasion, portal invasion, lymph nodes involvement, and positive surgical margins. In their study of 74 patients, those with mass-forming ICC had less local recurrence (76.1% versus 92.9%) and a significantly better median survival
600
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Table 4. Factors Associated with Poor Outcomes in Intrahepatic Cholangiocarcinoma First author
Year
ICC patients, n
Positive lymph nodes
Vascular invasion
Jan61
1996
41
⫹
⫹
Casavilla64 Madariaga63 Inoue45 Chen42 Valverde62 Weber66 DeOliveira43 Paik44
1997 1998 1999 1999 1999 2001 2007 2007
54 34 52 162 42 53 44 97
⫹ ⫹ ⫹ ⫹ ⫹
⫹
Positive margins
⫹ ⫹ ⫹
Tumor Bilobar size disease
Multiple tumors
⫹ ⫹
⫹ ⫹
Other factors
Histologic type, capsular invasion, tumor spreading type, mucobilia Advanced stage Left side, associated node dissection No hepatic duct stones Satellite nodules
⫹
⫹ ⫹ ⫹
⫹
⫹
High T stage, high CA 19-9
ICC, intrahepatic cholangiocarcinoma.
(32 months versus 22 months) than those with massforming periductal-infiltrating. Aishima and coworkers68 subtyped 87 patients into hilar ICC and peripheral ICC groups and noted that hilar ICC was more likely to be associated with perineural invasion, lymph node metastases, and extrahepatic recurrence; those with peripheral ICC had significantly better survival. One-, 3-, and 5-year survivals of the peripheral ICC patients were 88%, 72%, and 60%, respectively, compared with 66%, 41%, and 36%, respectively, in the hilar ICC patients. Treatment of ICC with liver transplantation has been described in two studies. In 50 patients with ICC, Pichlmayr and associates67 found that median survival was 12.8 months for the 32 patients who underwent resection and 5 months for 18 transplanted patients. In one study, Casavilla and coworkers64 performed 34 liver resections and 20 liver transplants and found the negative predictors to be multiple tumors, bilobar disease, positive margins, and advancedTNM stage. Without these negative predictors, 1-, 3-, and 5-year survivals were 74%, 64%, and 62%, respectively. Currently, liver transplant for cholangiocarcinoma, both intrahepatic and extrahepatic, is done only in the setting of clinical trials and typically involves multimodality therapy. Systemic chemotherapy for cholangiocarcinoma generally has shown poor results. Postsurgical adjuvant therapy has not been supported by the evidence and is not currently recommended outside of clinical trials.28,69 Glimelius70 conducted one of the few prospective randomized trials in 90 patients with pancreatic or biliary tract cancer. This study demonstrated that chemotherapy improved survival and quality of life in advanced disease compared with best supportive care. But median survival was still only 6 months in the group that received chemotherapy consisting of 5-fluorouracil (5-FU) and leucovorin with or without etoposide, depending on performance status. Of the chemotherapeutic agents, 5-FU, alone or in combination with other drugs, is the most extensively studied
treatment, and it has shown response rates of 0% to 40%. 5-FU combined with cisplatin and epirubicin yielded the best response, with an 11-month median survival. Unfortunately, another study using the same combination of drugs attained only a 10% response rate and median survival of 5 months. Gemcitabine also has shown activity in cholangiocarcinoma with response rates of 8% to 60% and median survival of 6.3 to 16 months. Gemcitabine in combination with cisplatin or oxaliplatin did not improve response rates over gemcitabine alone. Chemotherapeutic agents that have shown no or poor response alone or in combination include paclitaxel, docetaxel, irinotecan, and capecitabine. Because of the small number of patients (42 patients in the largest trial) and inclusion of multiple cancers (ICC, ECC, gallbladder, and pancreatic), it is difficult to make any specific conclusions.69 More research on ICC, especially controlled trials, is needed focusing on gemcitabine and on the combination of 5-FU, cisplatin, and epirubicin. Regional chemotherapy in the form of transarterial chemoembolization has been used in several small uncontrolled trials of ICC with median survivals of 12 to 26 months.71-76 These trials are summarized in Table 5. No good evidence is available for the use of radiotherapy in ICC, and in a prospective study of 50 patients with perihilar cholangiocarcinoma, adjuvant radiotherapy did not affect length or quality of survival.77 Further research is necessary before recommendations can be made for the use of chemotherapy or radiotherapy in patients with ICC. Future directions
In summary, ICC is a malignancy of increasing importance to both the practicing physician and surgeon. The incidence of ICC has increased steadily over the past few decades and recently identified risk factors of viral hepatitis, chronic liver disease, and fatty liver disease may be contributing factors. Just as the incidence of HCC increased in the
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Table 5. Review of Literature on Survival of Intrahepatic Cholangiocarcinoma with Chemotherapeutic Agents First author
Year
n
Agents used
Tanaka76 Kirchhoff71 Burger73
2002 2005 2005
11 8 17
Cantore74 Vogl75
2005 2006
Herber72
2007
30 12 12 15
5-Fluorouracil Cisplatin/doxorubicin/starch microsphere Cisplatin/doxorubicin/mitomycin-C/ethiodol with polyvinyl alcohol particles or microspheres Epirubicin/cisplatin Gemcitabine without starch microspheres Gemicitabine with starch microspheres Lipiodol/mitomycin-C
last decade from the epidemic of hepatitis C, a similar phenomenon may be occurring with ICC from viral hepatitis and metabolic syndrome-related liver disease.78 It is important for primary care physicians and gastroenterologists to identify and evaluate these patients promptly for referral to their surgical colleagues. Gastroenterologists and hepatologists frequently screen patients with viral hepatitis for HCC, even though the value of screening is yet to be determined, and whenever a liver mass is identified during screening, ICC and HCC need to be included in the differential diagnosis.79,80 Tumor markers, especially CA 19-9, and percutaneous liver biopsy may be helpful in differentiating ICC from HCC. But in some patients, the diagnosis cannot be made before surgical exploration. Differentiation also needs to be made between ICC and ECC with liver metastases because treatments can differ significantly. Once the diagnosis of ICC has been made, evaluation for extrahepatic metastases needs to be performed and resectability determined. In the absence of metastases, in appropriate surgical candidates, patients with ICC should undergo prompt surgical resection with adequate margins. Lymph node dissection should be considered as well. In the future, a standardized definition, classification, and perhaps a staging system that is unique to ICC is needed to better evaluate the efficacy of our treatments. Acknowledgment: Special thanks to Carla Getz for the illustrations.
REFERENCES 1. Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J Hepatology 2006;45:856– 867. 2. Foucar E, Kaplan LR, Gold JH, et al. Well-differentiated peripheral cholangiocarcinoma with unusual clinical course. Gastroenterology 1979;77:347–353. 3. Nakajima T, Kondo Y, Miyazaki M, Okui K. A histopathologic study of 102 cases of intrahepatic cholangiocarcinoma: histologic classification and modes of spreading. Hum Pathol 1988; 19:1228–1234.
Median survival, mo
26 12 23 13.2 13.5 20.2 21.1
4. Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies of the biliary tree. Curr Probl Surg 1995;32:36–70. 5. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996;224:463–473. 6. Fritz A, ed. International classification of diseases for oncology, 3rd edition. Geneva, Switzerland: World Health Organization; 2000. 7. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Nat Cancer Inst 2006;98:873–875. 8. Lim JH, Park CK. Pathology of cholangiocarcinoma. Abd Imaging 2004;29:540–547. 9. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer, 4th ed. Tokyo: Kanehara; 2000. 10. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics 2002. CA Cancer J Clin 2002;55:74–108. 11. SEER Cancer Statistics Review 1975–2004. US National Institute of Health. Available at: http://www.SEER.cancer.gov. Accessed May 6, 2008. 12. Centers for Disease Control and Prevention, Department of Health and Human Services, National Program of Cancer Registries, US Cancer Statistics 2004. Available at: http://www.apps.nccd.cdc.gov. Accessed April 2008. 13. Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002;2:10–15. 14. Khan SA, Taylor-Robinson SD, Toledano MB, et al. Changing international trends in mortality rates of liver, biliary and pancreatic tumors. J Hepatology 2002;37:806–813. 15. Wood R, Brewster DH, Fraser LA, et al. Do increases in mortality from intrahepatic cholangiocarcinoma reflect a genuine increase in risk? Insights from cancer registry data in Scotland. Eur J Cancer 2003;39:2087–2092. 16. Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 2001;48:816–820. 17. Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatology 2004;40:472–477. 18. McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic cholangiocarcinoma in the United States. Liver Int 2006;26:1047–1053. 19. McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev 2006;15:1198–1203.
602
Hammill and Wong
Intrahepatic Cholangiocarcinoma
20. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–125. 21. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol 1999;10:308–311. 22. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36:321–327. 23. Voyles CR, Smadja C, Shands WC, Blumgart LH. Carcinoma in choledochal cysts: age-related incidence. Arch Surg 1983; 118:986–988. 24. Dayton MT, Longmire WP Jr, Tompkins RK. Caroli’s disease: a premalignant condition? Am J Surg 1983;145:41–48. 25. Yamato T, Sasaki M, Hoso M, et al. Intrahepatic cholangiocarcinoma arising in congenital hepatic fibrosis: report of an autopsy case. J Hepatol 1998;28:717–722. 26. Parkin DM, Srivatankakul P, Khlat M, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer 1991;48:323–328. 27. Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;89:962–970. 28. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002;51:1–9. 29. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005;128:620–626. 30. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 2007;5:1221–1228. 31. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int J Cancer 2007;120:638–641. 32. Shaib YH, El-Serag HB, Nooka AK, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based casecontrol study. Am J Gastroenterol 2007;102:1016–1021. 33. Donato F, Gelatti U, Tagger A, et al. Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 2001;12:959–964. 34. Yamamoto S, Kubo S, Hai S, et al. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004;95:592–595. 35. Gastelis NK, Tepetes K, Loukopoulos A, et al. Hepatitis B virus and intrahepatic cholangiocarcinoma. Cancer Invest 2007;25: 55–58. 36. Qu ZL, Zou SQ, Cui NQ, et al. Upregulation of human telomerase reverse transcriptase mRNA expression by in vitro transfection of hepatitis B virus X gene into human hepatocarcinoma and cholangiocarcinoma cells. World J Gastroenterol 2005;11: 5627–5632. 37. Liu X, Zou S, Qiu F. Expression of nuclear factor kappa B in hepatitis C virus core gene transfected cholangiocarcinoma cells. Chin Med J 2002;115:998–1001. 38. Khan SA, Thomas HC, Toledano MB, et al. p53 mutations in human cholangiocarcinoma: a review. Liver Int 2005;25:704– 716. 39. Rizzi PM, Ryder SD, Portmann B, et al. p53 Protein overexpression in cholangiocarcinoma arising in primary sclerosing cholangitis. Gut 1996;38:265–268.
J Am Coll Surg
40. Obama K, Ura K, Li M, et al. Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology 2005;41:1339–1348. 41. Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92:2374–2383. 42. Chen MF, Jan YY, Jeng LB, et al. Intrahepatic cholangiocarcinoma in Taiwan. J Hepatobiliary Pancreat Surg 1999;6:136– 141. 43. DeOliviera ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one year experience with 564 patients at a single institution. Ann Surg 2007;245:755–762. 44. Paik KY, Jung JC, Heo JS, et al. What prognostic factors are important for resected intrahepatic cholangiocarcinoma? J Gastroenterol Hepatol 2008;23:766–770. 45. Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127:498–505. 46. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar and distal tumors. Ann Surg 1996;224:463–473. 47. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 19–9 for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo Clin Proc 1993;68:874– 879. 48. Patel AH, Harnois DM, Kelee GG, et al. The utility of CA 19–9 in the diagnoses of cholangiocarcinoma without primary sclerosing cholangitis. Am J Gastroenterol 2000;95:204–207. 49. Singh P, Patel T. Advances in the diagnosis, evaluation and management of cholangiocarcinoma. Current Opin Gastroenterol 2006;22:294–299. 50. Levy C, Lymp J, Angulo P, et al. The value of serum Ca 19–9 in patients with primary sclerosing cholangitis. Dig Dis Sci 2005;50: 1734–1740. 51. Takamori R, Wong LL, Dang C, et al. Needle-tract implantation from hepatocellular cancer: is needle biopsy of the liver always necessary? Liver Transpl 2000;6:67–72. 52. Huang GT, Sheu JC, Yang PM, et al. Ultrasound guided cutting biopsy for the diagnosis of hepatocellular carcinoma–a study based on 420 patients. J Hepatol 1996;25:334–338. 53. Durand F, Regimbeau JM, Belghiti J, et al. Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 2001;35:254– 258. 54. Kim SH, Lim HK, Lee WJ, et al. Needle-tract implantation in hepatocellular carcinoma: frequency and CT findings after biopsy with a 19.5 gauge automated biopsy gun. Abdom Imaging 2000;25:246–250. 55. Chaupoutot C, Perney P, Fabre D, et al. Needle-tract seeding after ultrasound guided puncture of hepatocellular carcinoma: A study of 150 patients. Gastroenterol Clin Biol 1999;23:552–556. 56. Greene FL, Page DL, Fleming ID, Fritz A. AJCC cancer staging manual, 6th edition. Philadelphia: Lippincott Raven Publishers; 2002. 57. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33:1353–1357. 58. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma: a 30-year populationbased SEER database analysis. J Gastrointest Surg 2007;11: 1488–1496.
Vol. 207, No. 4, October 2008
Hammill and Wong
Intrahepatic Cholangiocarcinoma
603
59. Schlinkert RT, Nagorney DM, Van Heerden JA, Adson MA. Intrahepatic cholangiocarcinoma: clinical aspects, pathology and treatment. HPB Surg 1992;78:727–731. 60. Yamamoto J, Kosuge T, Takayama T, et al. Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 1992;111:617–622. 61. Jan YY, Jeng LB, Hwang TL, et al. Factors influencing survival after hepatectomy for peripheral cholangiocarcinoma. Hepatogastroenterology 1996;43:614–619. 62. Valverde A, Bonhomme N, Farges O, et al. Resection of intrahepatic cholangiocarcinoma: a Western experience. J Hepatobiliary Pancreat Surg 1999;6:122–127. 63. Madariaga JR, Iwatsuki S, Todo S, et al. Liver resection for hilar and peripheral cholangiocarcinomas: a study of 62 cases. Ann Surg 1998;227:70–79. 64. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997;185:429–436. 65. Shimada K, Sano T, Sakamoto Y, et al. 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 2007;31:2016–2022. 66. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg 2001;193:384–391. 67. Pichlmayr R, Lamesch P, Weimann A, et al. Surgical treatment of cholangiocellular carcinoma. World J Surg 1995;19:83–88. 68. Aishima S, Kuroda Y, Nishihara Y, et al. Proposal of progression model for intrahepatic cholangiocarcinoma: clinicopathologic differences between hilar type and peripheral type. Am J Surg Pathol 2007;7:1059–1067. 69. Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol 2005;16(suppl 2):ii93–96. 70. Glimelius B. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593–600.
71. Kirchhoff T, Zender L, Merkesdal S, et al. Initial experience from a combination of systemic and regional chemotherapy in the treatment of patients with nonresectable cholangiocellular carcinoma in the liver. World J Gastroenterol 2005;11:1091– 1095. 72. Herber S, Otto G, Schneider J, et al. Transarterial chemoembolization (TACE) for inoperable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol 2007;30:1156–1165. 73. Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol 2005;16: 353–361. 74. Cantore M, Mambrini A, Fiorentini G, et al. Phase II study of hepatic intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable biliary tract tumors. Cancer 2005;103:1402–1407. 75. Vogl TJ, Schwarz W, Eichler K, et al. Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy. J Cancer Res Clin Oncol 2006;132:745–755. 76. Tanaka N, Yamakado K, Nakatsuka A, et al. Arterial chemoinfusion therapy through an implanted port system for patients with unresectable intrahepatic cholangiocarcinoma–initial experience. Eur J Radiol 2002;41:42–48. 77. Pitt HA, Nakeeb A, Abrams RA, et al. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995;221:788–797. 78. Davila JA, Morgan RO, Shaib Y, et al. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 2004;127:1372– 1380. 79. Nguyen TT, Gildengorin G, Truong A, McPhee SJ. Factors influencing physicians’ screening behavior for liver cancer among high-risk patients. J Gen Intern Med 2007;22:523–526. 80. Chalasani N, Said A, Ness R, et al. Screening for hepatocellular carcinoma in patients with cirrhosis in the United States: results of a national survey. Am J Gastroenterol 1999;94:2224–2229.