Intrahepatic Cholangiocarcinoma - Blumgart 2016 PDF

CHAPTER 50 Intrahepatic cholangiocarcinoma Kheman Rajkomar and Jonathan B. Koea Intrahepatic cholangiocarcinoma is a primary malignancy of the...

CHAPTER 50 Intrahepatic cholangiocarcinoma Kheman Rajkomar and Jonathan B. Koea Intrahepatic cholangiocarcinoma is a primary malignancy of the those of extrahepatic cholangiocarcinoma are decreasing (Endo liver. As with other primary adenocarcinomas of the upper et al, 2008; Khan et al, 2002; Patel 2001). This suggests that gastrointestinal tract, these tumors often present with symp- the tumors may have different etiologic factors despite similar toms caused by advanced local or metastatic disease. They are microscopic morphology. However, these findings must be biologically aggressive, and surgical resection, where possible, interpreted with caution. IHCC presents with solitary or is the only known potentially curative therapy. There are few multiple liver lesions, and in the past, many were probably active systemic therapies. diagnosed as metastatic adenocarcinoma and not further inves- Intrahepatic cholangiocarcinoma is also known as peripheral tigated. In addition, analysis of the Surveillance, Epidemiology, cholangiocarcinoma, cholangiolar cancer, or cholangiocellular carci- and End Results (SEER) database has shown that more than noma, and these terms have previously been used interchange- 90% of hilar cholangiocracinomas were wrongly classified as ably. Cholangiocellular carcinoma was first used in 1959 by IHCCs, and that extrahepatic biliary cancers were often classi- Steiner and Higginson to describe a subtype of cholangiocarci- fied as gallbladder cancers (Shaib & El-Serag, 2004). Even noma in which the glands are small and regular with incon- when these classification issues are addressed, however, the spicuous lumina and resemble proliferating cholangioles. mortality of IHCC is still increasing worldwide (Fig. 50.1) Current nomenclature uses the term intrahepatic cholangiocarci- (Shaib et al, 2005). noma (IHCC) to define tumors arising from biliary epithelium Currently, IHCC has an incidence of 0.85 per 100,000 in intrahepatic bile ducts above the level of the left and right population in the United States (Patel, 2002; Shaib & El-Serag main ducts (Liver Cancer Study Group of Japan, 1990). These 2004; Shaib et al, 2004). The highest incidence worldwide is tumors constitute 10% of primary hepatic malignancies and, recorded in northeast Thailand (96 per 100,000) (Khan et al, although much is known about extrahepatic cholangiocarci- 2002). Typically, patients present in the seventh decade of life, noma, IHCCs are less well understood. and IHCCs are more common in men (Khan et al, 2002; Shaib Hepatic resection for IHCC was infrequently described until et al, 2005). recently. Foster and Berman (1977) described only 13 cases in their summary of early hepatic surgery in the United States ETIOLOGY AND RISK FACTORS whereas they present 112 resections for hepatocellular carci- noma and 47 cases of hepatoblastoma. This low number of The majority of patients presenting with IHCC have no known resections may represent the frequency with which advanced risk factors. However, a number of specific risk factors are disease was diagnosed at presentation. It also likely reflects that recognized, many of which result in chronic inflammation of recognition of IHCCs as a discrete primary liver cancer was the biliary epithelia. Most of these risk factors contribute slow to occur, and many were historically diagnosed as meta- to the development of both intrahepatic and extrahepatic static lesions from unknown primary sites. However, with cholangiocarcinomas. increased recognition of IHCCs in recent years, significant clinical effort has been directed at developing comprehensive Primary Sclerosing Cholangitis (see Chapter 43) treatment strategies incorporating surgery and systemic and Primary sclerosing cholangitis (PSC) is the most common risk regional therapies for patients with this cancer. factor for cholangiocarcinoma in the West. The cumulative annual risk of cholangiocarcinoma in patients with PSC is 1.5% EPIDEMIOLOGY AND DEMOGRAPHICS per year (Farrant et al, 1991), and the prevalence of cholangio- carcinoma in these patients is 8% to 40% (Pitt et al, 1995; The incidence of cholangiocarcinoma is rising worldwide, and Rosen et al, 1991). The risk of developing cholangiocarcinoma it is now the second most common primary cancer of the liver is increased in those with associated inflammatory bowel after hepatocellular carcinoma (Olnes & Erlich, 2004). There disease, (IBD), for whom the 10- and 20-year rates for cholan- are 5000 to 6000 new cases diagnosed annually in the United giocarcinoma are 14% and 31%, versus 2% and 2% in patients States (Jemal et al, 2009; Vauthey & Blumgart 1994) and over without IBD (Claessen et al, 2009). 1000 cases annually in the United Kingdom (Khan et al, 2002). Cholangiocarcinoma often develops 2 to 3 decades earlier Overall, however, cholangiocarcinoma is rare and makes up in patients with PSC than in those with sporadic tumors (30-50 only 3% of all gastrointestinal (GI) tract cancers (Lazaridis & vs. 60-70 years of age) (Berquist & Broome, 2001; Farrant Gores, 2005). This means that cholangiocarcinoma is infre- et al, 1991). In addition, PSC-associated tumors often present quently seen by general surgeons or gastroenterologists, and its later with advanced-stage disease because of difficulties in rarity has frustrated attempts to design therapeutic trials. detecting malignant change in inflammatory strictures. Surgical More detailed analyses of epidemiologic data have shown treatment can be difficult because of the presence of chronic that the incidence and mortality of IHCC are increasing while liver disease, and patients are ineligible for orthotopic liver 805 Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 806 PART 5 BILIARY TRACT DISEASE Section II Neoplastic 10 treatment of hepatolithiasis and the development of cholangio- 9 carcinoma is between 3 and 8 years (Liu et al, 2011). Infection 8 with liver flukes may also be present, but recurrent pyogenic 7 cholangitis appears to be a separate condition and can develop 6 in the absence of parasitic infection (Kim et al, 2003). EAPC 5 Congenital Biliary Cystic Disease (see Chapter 46) 4 3 Untreated choledochal cysts carry an increased risk of develop- ing malignant change. The incidence of cholangiocarcinoma is 2 estimated at 10% to 20% if the cyst is not resected by age 20 1 years (Lipsett et al, 1994; Ohtsuka et al, 2001). Correspond- 0 ingly, patients who have had their cysts resected have a very Canada/ Australia/ Western Central Northern Asia/ US NZ Europe Europe Europe Middle low incidence of cholangiocarcinoma (Hewitt et al, 1995), East although subsequent development of cholangiocarcinoma has FIGURE 50.1. Estimated annual percent change (EAPC) in age- been recorded after cyst excision (Goto et al, 2001). The mech- adjusted mortality rate for intrahepatic cholangiocarcinoma by geo- anism of malignant transformation is not understood, but many graphic region for men (tan bars) and women (blue bars). NZ, New patients with choledochal cystic disease have an abnormally Zealand; US, United States. (Modified from Patel T, 2002: Worldwide long common channel of the pancreatic and bile ducts, sug- trends in mortality from biliary tract malignancies. BMC Cancer 2:1-5.) gesting that biliary stasis and chronic reflux of pancreatic secre- tions may contribute to the development of chronic inflammation transplantation. Consequently, they have a poor prognosis and subsequent malignant degeneration of biliary epithelium (Kaya et al, 2001). Factors predictive of cholangiocarcinoma (Chapman, 1999). in patients with PSC are sudden development of jaundice, weight loss, marked biliary dilation proximal to a dominant Hepatic Cirrhosis and Viral Infections stricture, a sudden rise in CA19-9, the presence of a hypovas- (see Chapters 70 and 76) cular mass with late contrast enhancement on radiologic The risk of developing cholangiocarcinoma is increased in imaging, and cytologic evidence of dysplasia or malignancy patients with cirrhosis (10.7% vs. 0.7% in the general popula- obtained on brushings of the bile ducts (Harewood, 2008). tion) (Shaib & El-Serag, 2004: Sorensen et al, 1998), and 1% of explanted cirrhotic livers at transplantation will harbor a Parasitic Infections (see Chapter 45) previously unsuspected IHCC (Vallin et al, 2013). In addition, Chronic infection with the liver flukes Opisthorchis viverrini and the incidence of cholangiocarcinoma is increased in patients Clinorchis sinensis is closely related to increased risk of develop- with hepatitis C virus (HCV) infection (0.8% vs. 0.2% in ing cholangiocarcinoma in Southeast Asia (Hasweel-Elkins general population) (Donato et al, 2001; Shaib et al, 2005; et al, 2008; Jang et al, 2008; Sripa & Pairojkul, 2008; Sripa Ralphs & Khan, 2013). This may result from a direct viral et al, 2007; Watanapa, 1996; Watanapa & Watanapa, 2002). effect, because biliary dysplasia is more often seen in explanted The mechanism of carcinogenesis is unclear. However, livers of patients transplanted for HCV-related cirrhosis than mechanical irritation, excreted metabolic products, and the in controls (Torbenson et al, 2007). IHCC is also more actions of proinflammatory cytokines, particularly those that common in patients with chronic hepatitis B virus (HBV) infec- stimulate the release of nitric oxide from activated white blood tion (11.5% vs. 5.5% in general population) (Donato et al, cells, may all play a role (Sripa et al, 2007). 2001), and these patients show an increase in tumors with a A further parasitic hepatic infestation is caused by the trema- mass-forming growth pattern,which is associated with a more tode Fasciola hepatica or Fasciola gigantica. These parasites are favorable prognosis after resection (Wu et al, 2013). It has been widespread throughout Asia, Africa, the Americas, and Oceania. suggested the increasing incidence of cholangiocarcinoma in They migrate into the liver from the duodenum and cause the West is related to the increasing prevalence of chronic liver hepatic fibrosis. There is no evidence that fascioliasis increases disease and chronic viral infection (Shaib & El-Serag, 2004; the risk of cholangiocarcinoma, although the radiologic and Shaib et al, 2005). In addition, recent evidence indicates that fibrotic pathologic changes accompanying an infection can nonalcoholic steatohepatitis is present in up to 20% patients be difficult to distinguish from carcinoma (Kim et al, 2005; with IHCC, although this may reflect lifestyle rather than rep- Marcos et al, 2008). resent an etiologic factor (Reddy et al, 2013). Diabetes and obesity are also associated with an increased risk of cholangio- Hepatolithiasis (see Chapters 39 and 44) carcinoma (Malhi & Gores 2006; Oh et al, 2005). Recurrent pyogenic cholangiohepatitis is characterized by Human immunodeficiency virus (HIV) does not cause cir- recurrent episodes of ascending cholangitis, hepatolithiasis, rhosis, but cholangiocarcinomas have been found in up to 0.5% biliary stricturing, and dilation. The syndrome is present in one of HIV patients versus 0.1% in controls, suggesting that HIV fifth of the population of Southeast Asia, and up to 10% of also is associated with an increased risk of biliary carcinogenesis these patients develop IHCC (Chen et al, 1993; Kubo et al, (Shaib et al, 2005). 1995; Lesurtel et al, 2002; Su et al, 1997), possibly because of chronic bile stasis leading to chronic infection and inflamma- Benign Biliary Tumors (see Chapters 48 and 90B) tion with malignant transformation. Patients present with The development of biliary cystadenocarcinomas from biliary recurrent episodes of cholangitis and, on investigation, have cystadenomas is rare and, in general, occurs if a cystadenocar- significant hepatolithiasis and associated inflammatory biliary cinoma is untreated for many years. Biliary cystadenomas strictures (Chu et al, 1997). The mean interval between the without ovarian stromal tissue appear to be at higher risk of Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.  C. Malignant Tumors Chapter 50 Intrahepatic cholangiocarcinoma 807 malignant change. Patients present with cystadenocarcinomas (IL-8), tumor necrosis factor-α (TNF-α), and platelet-derived in the sixth or seventh decade of life, whereas cystadenomas growth factor (PDGF) (Berthiaume & Wands, 2004) (see present at an earlier age (Buetow et al, 1995). IHCCs have also Chapter 11). been reported to develop in patients with biliary papilliomas These cytokines activate nitric oxide synthase in cholangio- (Cox et al, 2005; Galluoglu et al, 2007). cytes, resulting in the generation of nitric oxide, which reacts with other active oxygen species and causes mutagenesis, Chemical Agents impaired DNA repair, cyclooxygenase-2 (COX-2) upregula- Thorotrast (thorium dioxide) was used as a radiologic contrast tion, and cholestasis (Jaiswal et al, 2000). Clonal proliferation agent between 1928 and 1950. It is an alpha emitter with a is led by epidermal growth factor receptor (EGFR), RAS/ biologic half-life of 400 years. It accumulates in the reticuloen- mitogen-activated protein kinase (MAPK), IL-6, and MET. dothelial cells in the liver and spleen and increases the risk of Other changes are induction of limitless reproductive potential developing cholangiocarcinoma by 300 times compared with (telomerase reverse transcriptase activation), evasion of apop- the general population (Lipshutz et al, 2002; Rubel & Ishak, tosis (COX-2, BCL-2), neoangiogenesis (vascular endothelial 1982). Thorotrast is no longer in use, although the latency growth factor, angiopoietin-2), and invasion (matrix metallo- period of 16 to 45 years means that patients who received it proteinase and E-cadherin downregulation) (Andersen et al, during childhood radiologic examinations will occasionally still 2012). Overexpression of KRAS, BRAF, and hepatocyte growth present (Case Records of the Massachusetts General Hospital, factor/c-MET have been demonstrated in cholangiocarcinoma 1981). specimens (Endo et al, 2002; Lai et al, 2005). The proto- A number of other agents have been implicated in the devel- oncogene c-ERB-B2 is activated in cholangiocarcinoma and opment of cholangiocarcinoma. Associations have been shown tumor suppressor genes p16ink4a, p53, APC, and DPC4 are for asbestos (Szendroi et al, 1983), vinyl chloride (Wong et al, underexpressed (Rashid, 2002; Taniai et al, 2002). IL-6 is 1991), nitrosamines (Mitacek et al, 1999), the antituberculosis secreted by cholangiocytes and activates the pro-survival p38 agent isoniazid (Lowenfels & Norman, 1978), and first- MAPK (Ishimura et al, 2004; Park et al, 1999). In addition, generation oral contraceptives (Yen et al, 1987). tissue-based analysis has identified numerous epigenetic changes as well as chromosomal aberrations, along with the General Risk Factors downregulation of messenger RNAs, indicating that carcino- Surgical biliary-eneteric bypass and surgical sphincteroplasty genesis in IHCC is complex and the result of a cascade of increase the risk of developing cholangiocarcinoma (Hakamada genetic and metabolic anomalies (Sia et al, 2013b). et al, 1997). Tobacco smoking is a significant risk factor for cholangiocarcinoma in patients with PSC (Bergquist et al, Pathologic Subtypes and Mode of Spread 1998), although the relationship is less marked in the general (see Chapter 47) population (Shaib et al, 2005). Macroscopically, IHCCs are firm, white sclerotic tumors, often with associated satellite lesions nearby. However, variability in PATHOGENESIS (SEE CHAPTER 9C) gross morphologic appearance has resulted in a number of pathologic subclassifications. Nakanuma and colleagues (1985) Cholangiocarcinoma develops from the malignant transforma- initially classified IHCCs into a mass-forming type and a periduc- tion of cholangiocytes. These cells line the intrahepatic bile tal type. Mass-forming tumors were described as tumors with ducts and canaliculi. Their physiologic functions center on the clear borders between malignant and nonmalignant tissues, modification of bile at the canalicular surface and detoxification whereas the periductal type was more infiltrative and extended of xenobiotics (Alpini et al, 2001). Normal growth and renewal along peri–bile duct tissues without forming a discrete nodular of cholangiocytes are important in the maintenance of func- shape. This classification was widely adopted in Japan (Fujita, tional biliary mass, as well as for hepatic secretory and detoxi- 1990) and further modified by Ohashi and associates (1994), fication functions, and are achieved by careful regulation of who added a specula-forming lesion, present when a nodular proliferation and apoptosis. However, when this process tumor has poorly defined and irregular borders. Yamamoto and becomes uncontrolled, cholangiocarcinogenesis can occur colleagues (1998) emphasized that all three morphologic types (Wise et al, 2008). In a number of patients, IHCC may also appear to have different proliferative activity and different bio- develop from hepatic progenitor cells. This observation is based logic behavior. According to Yamamoto, the distinctive feature on current evidence that up to 25% of hepatic cholangiocarci- of the mass-forming type was its tendency to develop intrahe- nomas (HCCs) may develop from stem cells, and that IHCCs patic metastases because of localized vascular invasion, whereas and HCCs share a number of genetic aberrations as well as the the infiltrative type was distinguished by infiltrative spread via risk factors of viral hepatitis and cirrhosis (Sia et al, 2013a). the Glisson capsule and hilar lymph node metastases. On the Chronic inflammation is the most common and important basis of these observations, the authors recommended hepatec- feature of many of the risk factors associated with malignant tomy as the procedure of choice for the mass-forming subtype transformation of cholangiocytes. Chronic inflammation can and hepatectomy with extrahepatic ductal resection and hilar result in injury to the biliary epithelium, biliary obstruction, and lymphadenectomy as the choice for the infiltrating subtype. increased cholangiocyte turnover (Jaiswal et al, 2000). Chronic These investigators also added a fourth subtype, the intraductal inflammation also causes DNA damage, activates local tissue variant, which is characterized by papillary or granular growth repair, stimulates cellular proliferation, and results in a local within the lumen; they showed that the frequency of lymph environment that promotes growth (Fig. 50.2) (Schottenfeld & node metastases was higher in the mass-forming and periductal Beebe-Dimmer, 2004). Cholangiocytes exert significant para- types than in the intraductal subtype (Yamamoto et al, 1998). crine and autocrine effects and secrete the cytokines interleukin-6 A single report of a Western hepatobiliary unit used this clas- (IL-6), transforming growth factor-β (TGF-β), interleukin-8 sification and was unable to show any difference in overall Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 808 PART 5 BILIARY TRACT DISEASE Section II Neoplastic Intrahepatic bile duct Kupffer cell External stimuli (Liver fluke, Hepatitis) Microenvironment cell interactions Hepatic Endothelial induction of pro-inflammatory signals steflate cell (e.g. IL-6/STA3, TGF- , -SMA) cell Normal cholangiocyte Chronic inflammation DNA genetic/epigenetic alterations (e.g. IL-6/STAT3, TGF- , -SMA) hypermethylation (e.g. p16INK4, RASSF1A, SOCS-3) mutations (e.g. KRAS, TP53, IDH1/2) copy number gains/losses (e.g. 1q.7p, 4q.9p) microRNA deregulation (e.g. mur-214, mir-21) Malignant cholangiocyte Deregulated signaling pathways (e.g. EGFR, ERBB2, IL-6/STAT3, COX-2, HGF/c-Met, VEGFR) Proliferation Survival Invasion/Metastasis Angiogenesis FIGURE 50.2. Summary of mechanisms involved in biliary carcinogenesis. External stimuli lead to the induction of proinflammatory signals mediated by several cell types. The release of growth-promoting factors and cytokines during chronic inflammation (e.g., IL-6, tumor growth factor-β) promote the proliferation of cholangiocytes. This proliferation, along with the accumulation of genetic and epigenetic alterations in oncogenes and tumor sup- pressor genes, leads to the malignant transformation of cholangiocytes and to the deregulation of normal signaling pathways involved in proliferation, survival, invasion, and angiogenesis. (Modified from Sia D, et al, 2013: Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapeutics. Oncogene 32:4861-4870.) survival or the frequency of lymph node metastases (Weber There are other reports of less common, histologic variants et al, 2001), although there is a clinical suspicion that the of IHCC, including mucin-hypersecreting lesions that are intraductal subtype may carry a more favorable prognosis, as it similar in appearance to intraductal papillary mucinous neo- does in the extrahepatic bile duct (Jarnagin et al, 2005). plasms of the pancreas and are characterized by large, mucin- Although the subclassification of IHCC is intriguing and may filled cystic spaces (Chow et al, 1997; Kim et al, 2000; Suh have implications for surgical therapy, one significant weakness et al, 2000), as well as intraductal oncocytic papillary carci- of this approach is that many tumors exhibit features of more noma. These lesions have a distinctive appearance defined by than one of the described subtypes (Shirabe et al, 2002). the presence of oncocytes but appear to behave in a favorable Sia and colleagues (2013a) have used gene expression pro- manner, similar to the papillary type (Sudo et al, 2001; Wolf files and identified two classes of cholangiocarcinomas that et al, 1992). have implications for morphologic growth patterns. The “pro- Metastases to intraabdominal lymph nodes are the most liferative” class (62% of cases) is characterized by activation of common site of metastatic spread for IHCCs and are present in oncogenic signaling pathways (notably KRAS, BRAF, and up to 75% of patients at presentation (Shirabe et al, 2002). In MET) and the “inflammation” class (38% of cases) which was addition, up to two thirds of patients may have evidence of associated with activation of inflammatory signaling pathways remote organ metastases, most frequently lung and bone, (principally inflammatory cytokines and STAT3). Both classes at presentation (Endo et al, 2008; Shirabe et al, 2002). The had site-specific DNA amplifications and deletions. Recently, common sites of lymphatic metastases are hepatic hilar, peripan- reduced expression of β-catenin was highlighted as a marker of creatic, retroperitoneal, paraaortic, and mediastinal (Nakajima poor differentiation and aggressive behavior (Schiffman et al, et al, 1988). Nozaki and colleagues (1998) showed significant 2014). Gu and Choi (2014) measured the expression pattern differences in lymphatic spread between left- and right-sided of E-cadherin, β-catenin, vimentin, and fibronectin and were tumors. Patients with right-sided tumors always had lymph node able to classify IHCC according to the degree of loss of epithe- metastases in the hepaticoduodenal ligament, whereas in patients lial differentiation and the presence of mesenchymal differentia- with left-sided tumors, 50% of the nodal metastases were found tion, with the mesenchymal phenotype exhibiting more distant from the hepaticoduodenal ligament, in the cardia and aggressive behavior. Molecular profiling of IHCC in this way around the lesser curvature of the stomach. Furthermore, in may enhance the predominantly morphologic classifications of patients with left-sided tumors, no lymph node metastases were earlier investigators. present in the hepatoduodenal ligament. Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 810 PART 5 BILIARY TRACT DISEASE Section II Neoplastic A B C FIGURE 50.3. Pathologic appearance of intrahepatic cholangiocarcinoma. Moderately differentiated adenocarcinoma in a desmoplastic stroma. A, Hematoxylin and eosin (×80), with B, positive staining for CK7, and C, negative staining for CK20. a significant role in the evaluation of extrahepatic biliary diagnose and stage the tumors as well as plan resection or other obstruction because they can be easily obtained during endo- possible treatments. Most patients will be imaged with a scopic retrograde cholangiopancreatography (ERCP). These number of modalities. markers have included a variety of specific proteins and micro- RNAs (Li et al, 2014). It is unusual for IHCC to present with Transabdominal Ultrasound (see Chapter 15) biliary obstruction, and use of bile markers in this tumor is Ultrasound is often used as a screening examination by primary limited. However, these may have a future role in the diagnosis health care practitioners investigating patients with right upper of central lesions related to the hilus or intrahepatic lesions quadrant pain, a palpable mass, or unexplained jaundice. developing in patients with PSC (see Table 50.1). IHCC has a nonspecific appearance as a hypoechoic hepatic mass (Bloom et al, 1999; Slattery & Sahani, 2006). Satellite Imaging lesions may be seen as well as capsular retraction. The tumors Patients with IHCC often present with vague and nonspecific are hypovascular and usually have minimal Doppler evidence symptoms. Accurate cross-sectional imaging is required to of internal blood flow. Ultrasound is useful for defining Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.  C. Malignant Tumors Chapter 50 Intrahepatic cholangiocarcinoma 811 TABLE 50.1 Serum and Bile Biomarkers Proposed for the Diagnosis of Cholangiocarcinoma Biomarker Sensitivity (%) Specificity (%) References Serum CA19-9 53-92 50-98 Blechacz & Gores, 2008a, 2008b; Characharoenwitthaya et al, 2008; Patel & Singh, 2007; Schulick, 2008; Yachimski & Pratt, 2008 CEA 33-68 79-100 Blechacz & Gores, 2008a, 2008b; Characharoenwitthaya et al, 2008; Morris-Stiff et al, 2008; Ong et al, 2008; Patel & Singh, 2007, Schulick, 2008, Yachimski & Pratt, 2008 IL-6 73 70-100 Cheon et al, 2007 Trypsinogen 2 AUC = 0.804 Lempinen et al, 2007 MUC5AC 71 90 Bamrungphon et al, 2007; Ruzzenente et al, 2014 CYFRA21-1 75 92 Uenishi et al, 2008 TRR + CA19-9 98 100 Liu et al, 2009 Bile CA19-9 46-61 60-70 Blechacz & Gores, 2008a,2008b; Characharoenwitthaya et al, 2008; Morris-Stiff et al, 2008; Ong et al, 2008; Patel & Singh, 2007; Schulick, 2008; Yachimski & Pratt, 2008 CEA 67-84 33-80 Blechacz & Gores, 2008a, 2008b; Characharoenwitthaya et al, 2008; Morris-Stiff et al, 2008; Patel & Singh, 2007; Schulick, 2008, Yachimski & Pratt, 2008) IGF-1 100 100 Alvaro et al, 2007 Pancreatic elastase/amylase 82 89 Chen et al, 2008 Mcm5 62 92 Ayaru et al, 2008 Mac-2BP 69 67 Bonney et al, 2008 Micro-RNA 67 96 Li et al, 2014 CA19-9, Carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; AUC, area under the ROC curve; IGF-1, insulin-like growth factor 1; IL-6, interleukin-6; MUC5AC, mucin 5AC; CYFRA21-1, soluble fragment of cytokeratin 19; TTR, transthyretin; Mcm5, minichromosome maintenance replication protein; Mac-2BP, tumor antigen 90K-binding protein; RNA, ribonucleic acid. From Alvaro D, 2009: Serum and bile biomarkers for cholangiosarcoma. Curr Opin Gastroenterol 25:279-284. associated biliary dilation, portal venous invasion, hepatic venous invasion, and rarely, portal lymphadenopathy (Bach Positron Emission Tomography (see Chapter 17) et al, 1996, Hann et al, 1997). Positron emission tomography (PET) scanning is now a com- monly used modality for staging gastrointestinal malignancy, Computed Tomography (see Chapter 18) and the integration of PET and CT scans allows anatomic and Triple-phase computed tomography (CT) scan is widely avail- functional information to be obtained in a single scan (Iglehart, able and is the single most effective investigation in diagnosing 2006; Slattery & Sahani, 2006). IHCCs are present as glucose- and staging IHCC. These tumors present as hypodense lesions avid lesions within the liver. PET/CT is also useful in detecting with irregular, infiltrative margins and a variable degree of intraabdominal lymph node metastases (sensitivity 42%, speci- delayed enhancement in the portal venous phase (Fig. 50.4) ficity 80%) and distant metastases (sensitivity 56%, specificity (Bach et al, 1996). CT scan will also demonstrate the presence 88%) (Iglehart, 2006; Srinivasa et al, 2015). However, PET is of proximal intrahepatic biliary dilation, portal or hepatic limited by the finding of false-positive results in patients with venous involvement (Asayama et al. 2006), and lobar atrophy biliary inflammation (Petrowsky et al, 2006), and patients caused by long-standing biliary obstruction or portal venous with mucinous tumors can present with false-negative scans involvement (Kim et al, 2002). CT scan is also useful in (Fritscher-Ravens et al, 2001). detecting metastatic disease affecting regional lymph nodes, peritoneum, or lung fields. Data from newer, multiphase fast- Staging acquisition scanners can also be used to construct three- The American Joint Committee on Cancer (AJCC) classifies dimensional models of hepatic and tumor anatomy (Lamade IHCCs as primary cancers of the liver, and Western hepatobili- et al, 2000) and can provide accurate assessment of hepatic ary centers frequently use the AJCC systems to stage tumors. volumetry, particularly in relation to remnant volume and the The 6th edition of the AJCC staging manual proposed a single risk of postoperative liver failure (Shindoh et al, 2013). staging system for primary cancers of the liver and applied this to both hepatocellular carcinomas and IHCCs (Greene et al, Magnetic Resonance Imaging (see Chapter 19) 2002). The 7th edition of the staging manual (Edge et al, 2009) On magnetic resonance imaging (MRI), IHCCs appear as in 2010 incorporated the staging system of Nathan and col- hypointense lesions on T1-weighted images and hyperintense leagues (2009) (Table 50.2). These investigators used data on T2-weighted images, with pooling of contrast within the from the SEER database to develop a new staging system for lesions on delayed images (6-8 minutes after contrast injection) IHCC. They found that the 6th edition of the AJCC staging (Manfredi et al, 2004). MRI is also useful in defining venous system failed to stratify T2 and T3 cohorts into distinct groups. and arterial involvement by tumor, and cholangiopancreatog- Survival in the T3 group exceeded that of the T2 group (43% raphy is a noninvasive method of obtaining cholangiograms. vs. 31%). In addition, the presence of multiple tumors at Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 812 PART 5 BILIARY TRACT DISEASE Section II Neoplastic A B C D FIGURE 50.4. Arterial (A and C) and portal venous (B and D) axial and coronal CT scans demonstrating the typical appearance of an intrahepatic cholangiocarcinoma with a large, hypovascular mass involving segments VI and VII with associated satellite lesions. (From Valle J, et al, 2010: Cisplatin plus gemcitabine for biliary tract cancer. N Engl J Med 362:1273-1281.) presentation and vascular invasion had an adverse effect on node metastases are key prognostic factors for IHCC but also outcome, and tumor size at presentation was not predictive of suggested that the inclusion of CEA and CA19-9 levels improve outcome. Lymph node metastases and extrahepatic extension prognostic accuracy. were also associated with poorer outcome. Two other staging systems have been proposed from Japan The 7th-edition AJCC staging has been validated in a mul- (Okabayashi et al, 2001;Yamasaki, 2003), with that of Yama- tiinstitutional study (Farges et al, 2011), which demonstrated saki being adopted by the Liver Cancer Study Group of Japan that each staging classification was associated with significantly as their preferred staging system for IHCC (Table 50.3). varying survival, although a single-institution study showed that this system underestimated the influence of tumor histology TREATMENT and overemphasized the importance of periductal invasion (Igami et al, 2011). Two recent publications also emphasized Because of its rarity, treatment protocols for IHCC are in the importance of tumor size and differentiation (Ali et al, development compared with other intrahepatic tumors such as 2015; Spolverato et al, 2014). Wang and colleagues (2013) hepatocellular carcinoma. Nonetheless, there is a clear role for confirmed that tumor multiplicity, vascular invasion, and lymph hepatic resection in well-selected patients. Orthotopic liver Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.  C. Malignant Tumors Chapter 50 Intrahepatic cholangiocarcinoma 813 while leaving a well-vascularized remnant with adequate venous TABLE 50.2 AJCC Staging System for IHCC (7th edition) and biliary drainage. Resection of up to 80% of hepatic volume Classification Description can be contemplated in patients with good liver function and T1 Solitary tumor without vascular invasion up to 60% in patients with compromised liver function (Ebata et al, 2012). Often, however, resections of this magnitude will T2a Solitary tumor with vascular invasion (both major and microvascular) need to be preceded by portal vein embolization (Shindoh et al, T2b Multiple tumors with or without vascular invasion 2013). Patients with untreated IHCC have a median survival of less T3 Tumor perforating visceral peritoneum or involving local extrahepatic structures by direct invasion than 12 months (Chu & Fan, 1999, Kim et al, 1999). Resec- T4 Tumor with periductal invasion tion with positive margins or residual macroscopic disease is associated with median survivals of 1.8 to 3 months, indicating N0 No regional lymph node metastases that a cytoreductive approach is ineffective at prolonging N1 Regional lymph node metastases survival. M0 No distant metastases In contrast, 5-year survival rates after complete resection M1 Distant metastases (includes nodal involvement range between 13% and 43% (Table 50.4). The principal of celiac, periaortic, or caval lymph nodes) reason for the variability in survival appears to be the presence Stage Groupings of lymph node metastases. Lieser and colleagues (1998) Stage I T1N0M0 reported 5-year survival of 42%, but only 13% of patients pre- Stage II T2N0M0 sented with lymph node metastases, whereas in the series of Stage III T3N0M0 Chu and Fan (1999), 50% of patients presented with nodal Stage IVA T4N0M0; any T, N1M0 metastases, and none survived 5 years. All these clinical series Stage IVB Any T, any N, M1 emphasize the prognostic importance of obtaining an R0 resec- tion, which often requires a major hepatic resection. This point IHCC, Intrahepatic cholangiocarcinoma. is further emphasized by Lang and associates (2005), who From Edge SB, et al, 2009: AJCC Cancer Staging Manual, 7th ed. New York, Springer-Verlag, pp 201-209. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, reported a single-center experience with extended hepatectomy Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition for IHCC; 27 patients underwent extended hepatectomy (19 (2010) published by Springer Science and Business Media LLC, www.springer.com. extended right, 8 extended left), with 16 patients having en bloc resection of other structures. The median survival in this series was 46 months, with 3-year survival of 82%. Cherqui and col- TABLE 50.3 Staging System for IHCC Proposed by Liver Cancer leagues (1995) achieved similar results with an aggressive surgi- Study Group of Japan cal policy and liberal use of major extended hepatectomy. Stage T N M Status of Lymphadenectomy I T1 N0 M0 Although the importance of achieving an R0 resection is clear, II T2 N0 M0 the role of routine lymph node dissection is debated. The pres- III T3 N0 M0 ence and extent of nodal metastatic disease are important prog- nostic factors. Chu and Fan (1999) dissected portal lymph IVA T4 or N0 M0 nodes in their series, and all patients with portal lymph node Any T N1 M0 metastases died within 10 months of resection. A further study IVB Any T Any N M1 from Japan (Shirabe et al, 2002) confirmed that there was no T1: meets all requirements (single nodule, tumor 2 cm or less, and no portal vein, hepatic vein, survival benefit for patients undergoing hepatectomy with or serous membrane invasion); T2: meets two of the three requirements; T3: meets one of the portal lymphadenectomy versus hepatectomy alone. However, three requirements; T4: meets none of the three requirements; N0: no lymph node metastases; Nozaki and colleagues ( 1998) recommended routine dissec- N1: metastases to any lymph nodes; M0: no distant metastases; M1: distant metastases. IHCC, Intrahepatic cholangiocarcinoma. tion of cardia and lesser curvature nodes for left-sided tumors From Liver Cancer Study Group of Japan, 2003: General Rules for the Clinical and Pathological and dissection of the hepaticoduodenal ligament for right-sided Study of Primary Liver Cancer, 2nd ed. Tokyo, Kanehara. tumors, although using this approach was not associated with differences in survival. Extended surgery has been associated with higher mortality (Yamamoto et al, 1999). transplantation has also been studied in some detail. The roles Despite these findings, however, recent series show that of neoadjuvant and adjuvant chemotherapy, both systemic and more than half of patients undergo routine lymphadenectomy regional; conformal radiation therapy; and ablative therapies (De Jong et al, 2011; Ribero et al, 2012; Uchiyama et al, are under investigation (Weber et al, 2015). 2011). A systematic review confirms a trend toward routine lymph node dissection, with more than 75% of patients under- Surgical going lymphadenectomy (Aimini et al, 2014). In these series, Hepatic Resection (see Chapter 103B) the rate of lymph node positivity was between 30% (De Jong Surgical therapy for IHCC is based on the surgical principles et al, 2011) and 45% (Aimini et al, 2014). In addition, applied to resection for any malignancy. Criteria for irresect- Nakayama (2014) and Choi (2009) and colleagues suggested ability of IHCC are locally advanced solitary tumors involving an associated prolonged survival for node-positive patients either inflow or outflow bilaterally, multiple intrahepatic undergoing lymphadenectomy. tumors, and metastatic disease (Endo et al, 2008). An R0 Current National Comprehensive Cancer Network (NCCN, resection must be performed to achieve a potential survival 2012) guidelines suggest that regional lymphadenectomy should benefit. Hepatic resection is undertaken to obtain a clear margin be considered in patients to provide staging information, but Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 814 PART 5 BILIARY TRACT DISEASE Section II Neoplastic TABLE 50.4 Summary of Contemporary Results for Surgical Resection of IHCC Patients Median Survival (%) Author Year Country (n) Survival (mo) 1 yr 3 yr 5 yr Cherqui et al 1995 France 14 27 100 Pichlmayr et al 1995 Germany 32 12.8 Casavilla et al 1997 USA 34 60 37 31 Madariaga et al 1998 USA 34 19 67 40 35 Chu et al 1999 Hong Kong 39 12.2 57.3 23.9 15.9 Weber et al 2001 USA 33 37 31 Kawarada et al 2002 Japan 37 31.5 54.1 34 23.9 Ohtsuka et al 2002 Japan 48 62 38 23 Lang et al 2005 Germany 16 46 94 82 Nakagawa et al 2005 Japan 44 22 66 26 De Oliveira et al 2007 USA 34 28 63 Endo et al 2008 USA 82 36 Guglielmi et al 2009 Italy 62 41 26 Lang et al 2009 Germany 83 26 71 21 Nathan et al 2009 USA 598 21 18 Shen et al 2009 China 429 12 51 17 De Jong et al 2011 USA/Europe 449 27 78 31 Farges et al 2011 France 212 28 77 28 Saiura et al 2011 Japan 44 41 87 56 43 Sriputtha et al 2013 Thailand 73 12.4 52.1 21.7 11.2 Luo et al 2014 China 1333 30 79.1 42.6 28.7 Ali et al 2015 USA 150 44 84 43 Tabrizian et al 2015 USA 82 16 60 24 16 IHCC, Intrahepatic cholangiocarcinoma; USA, United States of America. that resection should be carefully considered in patients with After resection, the most common site of recurrence is in bulky nodal disease in the porta hepatis. With respect to staging, the liver, followed by intraabdominal tumor, pulmonary metas- uniform agreement is lacking on the optimal number of nodes tases, and bony metastases (Jan et al, 2005). Salvage surgery harvested per patient. Usually, three or less are harvested (De for intrahepatic recurrence or metastatectomy is usually not Jong et al, 2011), although up to seven nodes are suggested for indicated, because it is destined to be followed by further rapid patients with hilar cholangiocarcinoma (Ito et al, 2010). This recurrences. has lead Guglielmi and associates (2013) to suggest that the lymph node ratio (LNR) is an important prognostic factor, with Transplantation (see Chapter 115B) an LNR of greater than 0.25 associated with worse survival (19 The first significant report regarding liver transplantation for months, compared to 43 months with LNR of zero). IHCC is that of Pichlmayr and associates in 1995. These inves- Currently, there is no clear therapeutic benefit attributable tigators reported a median survival of 5 months in 18 patients to routine nodal dissection accompanying hepatectomy for treated with liver transplantation, with a 1-year survival rate of IHCC. Thorough assessment of all intraabdominal nodal 13.9%. Several studies confirmed these findings (Ismail et al, basins should be undertaken before hepatic resection, and sam- 1990; O’Grady et al, 1988), although Cherqui and colleagues pling of suspicious nodes is indicated to stage disease accu- (1995) reported two long-term survivors and concluded that a rately, which may direct postoperative treatment. patient with an intrahepatic tumor with no extrahepatic spread Most surgical series confirm that the presence of lymph node that cannot be resected for anatomic reasons may be a candi- metastases is the most important prognostic factor. Endo and date for liver transplantation. colleagues (2008) documented a recurrence rate of 93% in More recent experience has resulted in improved survival, node-positive patients undergoing R0 resection versus 47% in with disease-free survival at 5 and 10 years of 27% and 23%, node-negative patients. These investigators also found that respectively, reported in 23 patients with IHCC treated with tumor size greater than 5 cm in diameter and the presence of orthotopic liver transplantation (Robles et al, 2004). Fu and multiple intrahepatic tumors were significant adverse prognos- colleagues (2011) reported 11 patients with IHCC who under- tic factors. Other investigators have also defined lymphatic per- went liver transplantation between 2003 and 2008; median meation, vascular invasion, and intrahepatic satellite lesions as survival was 9 months (range, 2.5-53 months), and recurrence predictors of poor survival. Two Japanese groups (Isaji et al, was 45%. The patients in both reports were deemed irresect- 1999; Shirabe et al, 2002) also showed that survival is better able but had no evidence of extrahepatic spread, and the in patients with the mass-forming type than in those with the authors concluded that transplantation can be considered in periductal infiltrating type of IHCC. this group because the results achieved are better than palliative Downloaded from ClinicalKey.com at Sanjay Gandhi Post Graduate Institute of Medical Sciences JC December 24, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.  C. Malignant Tumors Chapter 50 Intrahepatic cholangiocarcinoma 815 treatment. However, the role of transplantation in IHCC will TACE with irinotecan. The median overall survival was 11.7 continue to be limited by the lack of a truly effective adjuvant months in the DEB TACE group, similar to a group treated systemic treatment regimen. This is in contrast to the emerging with systemic gemcitabine and oxaliplatin. The median survival protocol of neoadjuvant chemoradiation before transplantation in the TACE group was 5.7 months, although heterogeneity in for hilar cholangiocarcinoma (Schwartz et al, 2009). the tumor characteristics in the treatment groups may have contributed to the survival disparities. Despite this, TACE and Tumor Ablation DEB TACE appear to be promising therapies for patients with Tumor ablation refers to the intrahepatic destruction of tumors advanced IHCC, and overall, combination therapy appears to using thermal energy. Historically, cryotherapy (see Chapter be associated with better outcomes than single-agent therapy 98D) had been employed (Cuschieri et al, 1995; Sheen et al, (Gusani et al, 2008), with large tumor size, tumor hypovascu- 2002), but currently, radiofrequency (see Chapter 98B) and larity, and Child-Pugh class B being adverse prognostic factors microwave (see Chapter 98C) are most often used. The role of (Kim et al, 2008). ablative therapies in IHCC is currently limited but subject to significant investigation. Unfortunately, IHCCs are hard, and Transarterial Radioembolization (see Chapter 96B) percutaneous or operative ablation can be difficult to achieve. Three series described the use of selective internal radiation Since many of the lesions are large at presentation, their size therapy (SIRT) in patients with advanced cholangiocarcinoma. often precludes effective ablation. Likewise, the use of ablation Ibrahim and colleagues (2008) described 24 patients with IHCC to treat intrahepatic metastases is unwise because these are treated with selective internal radiation therapy, with median markers of vascular invasion and diffuse disease. However, Rai survival of 15 months and acceptable toxicity. Subsequently, and colleagues (2005) reported a case of recurrent tumor after Mouli and associates (2013) prospectively treated 46 patients, transplantation treated with radiofrequency ablation and con- with a 98% response rate, median survival of 15 months, and trolled for 12 months. Also, a number of small series (Kim et al, five patients downstaged to become eligible for resection or 2011; Xu et al 2012; Yu et al, 2011) have shown that complete transplant. Rafi and colleagues (2013) obtained similar results. tumor ablation can be achieved using percutaneous ablation in A 2013 multiinstitutional analysis investigated the role of patients not suitable for resection. In general, small (