J Hepatobiliary Pancreat Sci (2015) 22:138–143\ DOI: 10.1002/jhbp.159
TOPIC
Liver transplantation for intrahepatic cholangiocarcinoma Koji Hashimoto · Charles M. Miller
Published online: 12 September 2014 © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract The indication of liver transplantation for intrahepatic cholangiocarcinoma (ICC) is highly controversial. Initially, liver transplantation was embraced as a promising treatment for ICC, providing both a wider surgical margin and a potential cure for the underlying liver disease. However, the majority of transplant centers have abandoned liver transplantation for ICC due to poor long-term survival and high recurrence rates. Interestingly, these decisions were based on studies with highly inconsistent outcomes due to a limited number of patients, various patient selection criteria, and the use of nonstandardized adjunctive therapy protocols. Indeed, recent studies have revealed that ICC patients with small solitary tumors have excellent long-term survival after liver transplantation. Moreover, as seen in early-stage hilar cholangiocarcinoma, neoadjuvant and adjuvant therapy hold promise for improved long-term survival in patients with locally advanced ICC. As we work to expand treatment options for ICC, further evidence of success in this area is needed in order to justify the use of limited organ resources to treat ICC. Continued efforts to improve diagnosis of ICC, hone patient selection criteria, and implement standardized treatment protocols could provide certain patients with ICC access to potentially lifesaving liver transplantation. Keywords Intrahepatic cholangiocarcinoma · Liver transplantation · Neoadjuvant therapy · Prognosis · Tumor recurrence Introduction Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy that carries a poor prognosis. Due to the lack of both early clinical symptoms and efficient diagnostic modalities, ICC
frequently presents as an advanced disease. Non-surgical treatments almost never achieve complete eradication of this malignancy, with radical resection offering the only possibility of long-term survival [1, 2]. Even worse, most ICC tumors are deemed unresectable at the time of diagnosis and only a limited number of patients with confined disease are eligible for surgical resection. Reported survival rates for these patients at 5 years range from 22% to 40% [3–5]. For these reasons, liver transplantation held out hope as a promising treatment for unresectable tumors. Experience from the late 1980s to the mid 1990s, however, showed poor survival and high rates of recurrence [6–9]. Assuming that the high recurrence rate was attributable to residual tumor cells due to local invasion, a transplant group in Pittsburgh introduced cluster abdominal transplantation to achieve a wider surgical margin [10]. Despite assumptive advantages with this technique, the outcomes unfortunately were not convincing enough to justify ICC as a reasonable indication for transplantation. Subsequently, data from larger cohorts confirmed poor post-transplant outcomes in patients with ICC [11–13]. Based on these experiences, most transplant centers currently consider ICC to be a contraindication for liver transplantation [1, 2, 14]. However, recent data show excellent outcomes in a select patient population, thereby justifying transplantation for certain ICC patients [15–17]. Moreover, as seen in the treatment of early hilar cholangiocarcinoma [18, 19], the role of neoadjuvant therapy in combination with liver transplantation could be promising for ICC treatment [20, 21]. This article provides an up-to-date review of liver transplantation for ICC, discusses various challenges, and examines ways to improve long-term survival rates for ICC patients receiving liver transplantation.
An overview of the historical evidence K. Hashimoto · C. M. Miller (*) Liver Transplant Program, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]
Liver transplantation for hepatocellular carcinoma (HCC) is a well-established treatment with excellent long-term survival and a low recurrence rate under the known tumor
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J Hepatobiliary Pancreat Sci (2015) 22:138–143 Fig. 1 Computed tomography (CT) images of a 60-year-old man who underwent a liver transplantation from a deceased donor for the Allen-Lisa classification type A combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the cirrhotic liver. Arrows indicate a lesion of hepatocellular carcinoma in the left lateral segment with early global arterial enhancement followed by wash-out during the venous phase. Arrowheads indicate a lesion of cholangiocarcinoma in the right lobe with arterial peripheral rim enhancement followed by a progressive contrast uptake during the venous phase
Arterial phase
Venous phase
HCC
ICC
criteria [22, 23]. However, the use of liver transplantation for cholangiocarcinoma is controversial due to a low survival rate and a high recurrence rate and is currently restricted to patients with early stage hilar tumors. In cases where these types of tumors are present, liver transplantation has achieved excellent long-term survival with neoadjuvant chemoradiation therapy [18, 19]. In contrast, the majority of previous studies on ICC and liver transplantation consistently have shown a high rate of recurrence and poor long-term survival, with the 5-year patient survival varying from 0% to 42%. Weimann et al. reviewed 162 ICC patients who underwent surgical treatment including 95 surgical resections, 24 liver transplantations, and 43 exploratory laparotomies. Unfortunately, the 1-year patient survival for liver transplantation (21%) was similar to that of exploratory laparotomy (23%) and significantly worse than that for liver resection (64%) [24]. Shimoda et al. reported that the 3-year recurrence-free survival was only 35% in 13 patients with ICC after liver transplantation [25]. In this series, the recurrence rate was 54% and the median time to recurrence was 11 months. Another study revealed that 23 patients with ICC achieved only 27% of recurrence-free survival 5 years after liver transplantation [26]. A study from China reviewed 11 patients with ICC who underwent liver transplantation [27]. The 1-year recurrence-free survival was 52% and all tumor recurrences were observed within 10 months after liver transplantation. While these studies caused many transplant centers to abandon liver transplantation as a treatment for ICC, recent reports in the literature have identified studies
and potential practices that could help expand access to transplantation for patients with ICC.
The challenge of tumor assessment Management of ICC can be different from other intrahepatic lesions, such as HCC, and effective treatment selection requires accurate diagnosis and assessment of tumor burden [1, 2]. Because ICC and HCC have similar risk factors and image findings, it can be difficult to differentiate between the two, especially in cirrhotic patients. In fact, ICC is frequently misdiagnosed as HCC or even unrecognized before transplant [28]. Accurate diagnosis requires a high index of suspicion and a multidisciplinary effort with laboratory and radiographic analyses. Preoperative contrast-enhanced imaging studies are essential to assess the extent of tumor and vascular involvement [1, 2, 29, 30]. HCC in imaging studies is characterized by early enhancement during the arterial phase followed by a delayed wash-out during the venous phase. Conversely, ICC shows heterogeneous contrast uptake during the arterial phase, so-called rim enhancement, and a progressive contrast uptake during the venous phase (Fig. 1). To identify extrahepatic metastasis, an integrated positron emission tomography scan provides better sensitivity and specificity compared to conventional imaging modalities [31, 32]. When imaging studies show an intrahepatic lesion with features atypical of HCC, tumor biopsy would be the next diagnostic step. However, biopsy is not always safe due to
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coagulopathy and refractory ascites and does not always provide reliable diagnosis [33]. Therefore, the decision to perform a tumor biopsy should be determined on a case-bycase basis. Endoscopic ultrasound is increasingly used to help enhance staging accuracy in patients with hepatobiliary malignancy. Since the involvement of regional lymph nodes negatively affects post-transplant outcomes, enlarged lymph nodes should be further examined with endoscopic fineneedle aspiration to rule out metastasis [34]. Measurement of the serum carbohydrate antigen 19-9 (CA19-9) level can provide additional insight, but is not without limitation. While serum CA19-9 can be helpful in diagnosing cholangiocarcinoma, the sensitivity and specificity of CA19-9 for ICC detection is just 62% and 63%, respectively [35]. Another issue with this marker is that benign diseases such as bacterial cholangitis and choledocholithiasis cause an elevated CA19-9 level. When serum CA19-9 levels are greater than 1000 U/mL, however, the presence of extrahepatic disease is highly suspicious [36, 37]. It should be noted that 10% of patients do not produce CA19-9 due to lack of the Lewis antigen [38]. While other tumor markers such as cytokeratin-19 fragment (CYFRA 21-1) and CA242 have been reported to have better specificities for detecting ICC, these are not routinely used in the current daily practice [39].
Opportunities for improvement Identifying risk factors to improve outcomes In order to achieve better outcomes, rigorous identification of patient risk factors is essential. Previous studies have identified various factors predictive of risk for patients with ICC who have undergone liver transplantation. In a review of 54 patients including 34 surgical resections and 20 liver transplants, the Pittsburgh transplant group identified three unfavorable prognostic factors, including positive surgical margin, multifocality, and lymph node metastasis [40]. When patients had none of these three factors, the 5-year survival was 64%. In contrast, when at least one of these risk factors was present, the 5-year survival dropped significantly to 9%. Shimoda et al. reported that smaller tumor size, a single nodule, and no involvement of other organs were associated with improved survival [25]. Robles et al. reviewed 23 transplant patients with ICC and identified perineural invasion and advanced pTNM stages as poor prognostic factors [26]. Hong et al. identified four unfavorable tumor histologic features: multifocality, perineural invasion, infiltrative tumor growth pattern, and lymphovascular invasion [21]. These predictors were used for risk stratification and to help estimate the likelihood of
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tumor recurrence. This study also revealed that the absence of neoadjuvant therapy before liver transplantation was strongly associated with tumor recurrence. Another study demonstrated that patients without recurrence had smaller tumor size, no lymph node metastasis or vascular invasion, and TNM stages I and II [27]. A more recent study showed larger tumor size and volume, vascular invasion, and poor differentiation as risk factors for tumor recurrence [16]. The majority of risk factors are tumor-related and similar to the risk factors for liver resection [3–5]. Liver transplantation for small intrahepatic cholangiocarcinoma In an early report from the University of California, Los Angeles (UCLA), among 127 transplant patients with primary sclerosing cholangitis, 10 patients had small incidental ICC less than 1 cm in diameter. These 10 patients did not experience tumor recurrence and had a 5-year survival rate of 83%, comparable to that of patients without ICC. In contrast, all four patients with known tumors before liver transplantation had tumor recurrence within 6 months and none survived [15]. A Spanish multicenter study reported the outcomes of “very early” solitary ICC of ≤ 2 cm in cirrhotic patients [16]. Eight patients with “very early” ICC, including four incidental tumors, experienced excellent 5-year survival at 73% without tumor recurrence. Collectively, these studies demonstrate that a select patient population with small solitary tumors appears to achieve favorable long-term survival after liver transplantation. Further studies of this patient population could help reverse the current exclusion of patients with small ICC from transplantation. Mixed hepatocellular carcinoma and cholangiocarcinoma Mixed HCC and ICC (HCC-CC) is a rare tumor with histological features of both HCC and ICC. In the modern era of liver transplantation, HCC-CC is often unrecognized preoperatively or it is treated as HCC. Just as with ICC, low survival rates have been reported in patients with HCC-CC, but data on outcomes after liver transplantation are limited [41–43]. The prognosis of patients with HCC-CC is mostly determined by the ICC component. In a study of 12 patients with incidental HCC-CC, the 5-year survival after liver transplantation was only 16% [28]. According to Sapisochin et al., when comparing the tumor size and tumor number among HCC-CC patients to a matched cohort of HCC patients, the HCC-CC cohort had significantly poorer 5-year recurrence-free survival (32% vs. 62%). Tumor recurrence was observed in 60% of patients with ICC-contained tumors, but in only 16.7% of the patients with HCC [43].
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100 Neoadjuvant + adjuvant therapy
Survival (%)
80 60
P = 0.03 Adjuvant therapy
40
None
20 0
0
12
24 36 Survival time (months)
48
60
Fig. 2 Effects of adjunctive therapy on recurrence-free survival after liver transplantation for cholangiocarcinoma. Patients who received both neoadjuvant and adjuvant therapy show excellent recurrence-free survival. In contrast, patients who received only adjuvant therapy and no treatment show poorer survival. Reprinted with permission from Hong et al. [20]
Groeschl et al. reported the outcomes of larger cohorts from the Surveillance, Epidemiology, and End Results database (n = 19) and the United Network for Organ Sharing database (n = 65). Despite similar short-term survival, the 3-year patient survival was 45–48% in patients with HCC-CC, significantly lower than the survival rate of those with HCC (75–78%) [44]. In contrast to these studies exhibiting poor outcomes, a Spanish study showed comparable post transplantation recurrence rates and survival rates between an HCC-CC group and a matched HCC control group [17]. It should be noted, however, that in this study, tumor burden was relatively favorable with a 2.9 cm median tumor size, an incidence of microvascular invasion of 16.7%, a poorly differentiated histology of 8.8%, and bilobar disease of 19%. Role of adjunctive therapy for locally advanced intrahepatic cholangiocarcinoma in combination with liver transplantation Despite the disappointing results of previous studies, certain transplant centers have reported acceptable outcomes after liver transplantation in combination with adjunctive therapy for locally advanced ICC. In a retrospective analysis by the UCLA group, 24 patients with ICC had locally advanced tumors characterized by either tumor size ≥ 5 cm, poorly differentiated histology, multifocality, lymphovascular invasion, perineural invasion, parenchymal invasion, positive margin, or lymph node metastasis [20]. Interestingly, patients who received both neoadjuvant and adjuvant therapy had better recurrence-free survival rates compared to patients with only adjuvant therapy or no adjunctive therapy (Fig. 2). Overall, the recurrence rate was 28% in patients receiving both neoadjuvant and adjuvant therapy, significantly lower than patients who received adjuvant therapy only or no therapy (50% and 40%, respectively). In
contrast to the UCLA experience, a small study of patients at Mayo Clinic in Florida showed disappointing outcomes with a median survival of 1 year after neoadjuvant chemoradiation therapy followed by liver transplantation [45]. However, taking into account the benefits of neoadjuvant therapy for early hilar cholangiocarcinoma, future clinical trials should evaluate the potential use of combining neoadjuvant therapy with liver transplantation for ICC. Locoregional therapies can be used for the treatment of ICC as a bridge to liver transplantation [46]. Transarterial chemoembolization (TACE) achieves local disease control (partial regression and stabilization) of up to 76% [47]. Currently, external beam radiation therapy has been more widely used for cholangiocarcinoma. Recent reports have demonstrated that stereotactic body radiation therapy (SBRT) effectively reduces tumor burden [48, 49]. While liver transplantation may still be considered for patients who exhibit disease down staging, definitive therapy is not recommended in the absence of a favorable tumor response to neoadjuvant treatments. With the demonstrated benefits of locoregional therapies for unresectable ICC, Hong et al. proposed a treatment protocol using locoregional therapy followed by systemic chemotherapy. Tumors ≤ 6 cm were treated with SBRT for a total dose of 40 Gy [20, 21]. For tumors > 6 cm, TACE was chosen instead of SBRT [21, 50]. Neoadjuvant chemotherapy includes a 5-fluorouracil or capecitabine-based regimen until the time of transplantation. Other agents used include oxaliplatin, leucovorin, and gemcitabine [51, 52]. Inclusion criteria for the UCLA treatment protocol include tumor size ≤ 8 cm, tumors confined within the operative field for total hepatectomy and regional lymphadenectomy, and the absence of distant metastasis. Tumor biology prior to neoadjuvant therapy helps obtain an accurate pretreatment assessment that facilitates pre-transplant risk stratification of liver transplant candidates. This assessment also identifies patients who might benefit from additional chemotherapy after transplantation [21]. If a tumor is found to have progressed beyond the confines of the operative field, patients are disqualified for transplantation. The survival benefit of post-transplant adjuvant chemotherapy in reducing the risk of tumor recurrence with impaired immune surveillance from immunosuppressive therapy has yet to be determined. The Baylor group reported their early experience with adjuvant radiotherapy and chemotherapy in patients with ICC after liver transplantation [8]. This review of 17 patients showed that the 1- and 3-year recurrence-free survival rate was only 40% and 13%, respectively. Moreover, as shown above in the study from the UCLA group, adjuvant chemotherapy alone did not improve either survival or tumor recurrence [20]. Taken together, the data currently do not support the benefit of
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adjuvant chemotherapy alone as a means to improve outcomes after liver transplantation for ICC. However, further studies are needed to better understand the role of adjuvant therapy in ICC. The major challenge in liver transplantation for locally advanced ICC is the long waiting period from neoadjuvant therapy to liver transplantation due to the severe shortage of donor organs. Since candidates for neoadjuvant therapy usually have a low Model for End-Stage Liver Disease (MELD) score, they typically are not eligible for a deceased donor organ under the current organ allocation system. Moreover, unlike small hilar cholangiocarcinoma, there is no consensus for a MELD exception point for ICC [53]. Therefore, with the current organ allocation system, patients with locally advanced ICC have no priority on the liver transplant waiting list, even when they demonstrate a good response to neoadjuvant therapy. Summary Currently, the use of liver transplantation in patients with ICC remains highly controversial and based on the published data, generally not recommended. However, recent studies have revealed that a select patient group with very early ICC clearly benefits from liver transplantation with excellent long-term survival. The use of adjunctive therapy in combination with liver transplantation might be a promising treatment modality for locally advanced ICC. Nonetheless, liver transplantation for ICC remains contraindicated at many centers. The development of standardized patient selection criteria and well-designed clinical research protocols is needed to further study the role of liver transplantation for ICC. Acknowledgments The authors would like to acknowledge Ms Sally Garrett Karyo for her assistance. Conflict of interest
None declared.
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TOPIC
Liver transplantation for intrahepatic cholangiocarcinoma Koji Hashimoto · Charles M. Miller
Published online: 12 September 2014 © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract The indication of liver transplantation for intrahepatic cholangiocarcinoma (ICC) is highly controversial. Initially, liver transplantation was embraced as a promising treatment for ICC, providing both a wider surgical margin and a potential cure for the underlying liver disease. However, the majority of transplant centers have abandoned liver transplantation for ICC due to poor long-term survival and high recurrence rates. Interestingly, these decisions were based on studies with highly inconsistent outcomes due to a limited number of patients, various patient selection criteria, and the use of nonstandardized adjunctive therapy protocols. Indeed, recent studies have revealed that ICC patients with small solitary tumors have excellent long-term survival after liver transplantation. Moreover, as seen in early-stage hilar cholangiocarcinoma, neoadjuvant and adjuvant therapy hold promise for improved long-term survival in patients with locally advanced ICC. As we work to expand treatment options for ICC, further evidence of success in this area is needed in order to justify the use of limited organ resources to treat ICC. Continued efforts to improve diagnosis of ICC, hone patient selection criteria, and implement standardized treatment protocols could provide certain patients with ICC access to potentially lifesaving liver transplantation. Keywords Intrahepatic cholangiocarcinoma · Liver transplantation · Neoadjuvant therapy · Prognosis · Tumor recurrence Introduction Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy that carries a poor prognosis. Due to the lack of both early clinical symptoms and efficient diagnostic modalities, ICC
frequently presents as an advanced disease. Non-surgical treatments almost never achieve complete eradication of this malignancy, with radical resection offering the only possibility of long-term survival [1, 2]. Even worse, most ICC tumors are deemed unresectable at the time of diagnosis and only a limited number of patients with confined disease are eligible for surgical resection. Reported survival rates for these patients at 5 years range from 22% to 40% [3–5]. For these reasons, liver transplantation held out hope as a promising treatment for unresectable tumors. Experience from the late 1980s to the mid 1990s, however, showed poor survival and high rates of recurrence [6–9]. Assuming that the high recurrence rate was attributable to residual tumor cells due to local invasion, a transplant group in Pittsburgh introduced cluster abdominal transplantation to achieve a wider surgical margin [10]. Despite assumptive advantages with this technique, the outcomes unfortunately were not convincing enough to justify ICC as a reasonable indication for transplantation. Subsequently, data from larger cohorts confirmed poor post-transplant outcomes in patients with ICC [11–13]. Based on these experiences, most transplant centers currently consider ICC to be a contraindication for liver transplantation [1, 2, 14]. However, recent data show excellent outcomes in a select patient population, thereby justifying transplantation for certain ICC patients [15–17]. Moreover, as seen in the treatment of early hilar cholangiocarcinoma [18, 19], the role of neoadjuvant therapy in combination with liver transplantation could be promising for ICC treatment [20, 21]. This article provides an up-to-date review of liver transplantation for ICC, discusses various challenges, and examines ways to improve long-term survival rates for ICC patients receiving liver transplantation.
An overview of the historical evidence K. Hashimoto · C. M. Miller (*) Liver Transplant Program, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]
Liver transplantation for hepatocellular carcinoma (HCC) is a well-established treatment with excellent long-term survival and a low recurrence rate under the known tumor
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J Hepatobiliary Pancreat Sci (2015) 22:138–143 Fig. 1 Computed tomography (CT) images of a 60-year-old man who underwent a liver transplantation from a deceased donor for the Allen-Lisa classification type A combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the cirrhotic liver. Arrows indicate a lesion of hepatocellular carcinoma in the left lateral segment with early global arterial enhancement followed by wash-out during the venous phase. Arrowheads indicate a lesion of cholangiocarcinoma in the right lobe with arterial peripheral rim enhancement followed by a progressive contrast uptake during the venous phase
Arterial phase
Venous phase
HCC
ICC
criteria [22, 23]. However, the use of liver transplantation for cholangiocarcinoma is controversial due to a low survival rate and a high recurrence rate and is currently restricted to patients with early stage hilar tumors. In cases where these types of tumors are present, liver transplantation has achieved excellent long-term survival with neoadjuvant chemoradiation therapy [18, 19]. In contrast, the majority of previous studies on ICC and liver transplantation consistently have shown a high rate of recurrence and poor long-term survival, with the 5-year patient survival varying from 0% to 42%. Weimann et al. reviewed 162 ICC patients who underwent surgical treatment including 95 surgical resections, 24 liver transplantations, and 43 exploratory laparotomies. Unfortunately, the 1-year patient survival for liver transplantation (21%) was similar to that of exploratory laparotomy (23%) and significantly worse than that for liver resection (64%) [24]. Shimoda et al. reported that the 3-year recurrence-free survival was only 35% in 13 patients with ICC after liver transplantation [25]. In this series, the recurrence rate was 54% and the median time to recurrence was 11 months. Another study revealed that 23 patients with ICC achieved only 27% of recurrence-free survival 5 years after liver transplantation [26]. A study from China reviewed 11 patients with ICC who underwent liver transplantation [27]. The 1-year recurrence-free survival was 52% and all tumor recurrences were observed within 10 months after liver transplantation. While these studies caused many transplant centers to abandon liver transplantation as a treatment for ICC, recent reports in the literature have identified studies
and potential practices that could help expand access to transplantation for patients with ICC.
The challenge of tumor assessment Management of ICC can be different from other intrahepatic lesions, such as HCC, and effective treatment selection requires accurate diagnosis and assessment of tumor burden [1, 2]. Because ICC and HCC have similar risk factors and image findings, it can be difficult to differentiate between the two, especially in cirrhotic patients. In fact, ICC is frequently misdiagnosed as HCC or even unrecognized before transplant [28]. Accurate diagnosis requires a high index of suspicion and a multidisciplinary effort with laboratory and radiographic analyses. Preoperative contrast-enhanced imaging studies are essential to assess the extent of tumor and vascular involvement [1, 2, 29, 30]. HCC in imaging studies is characterized by early enhancement during the arterial phase followed by a delayed wash-out during the venous phase. Conversely, ICC shows heterogeneous contrast uptake during the arterial phase, so-called rim enhancement, and a progressive contrast uptake during the venous phase (Fig. 1). To identify extrahepatic metastasis, an integrated positron emission tomography scan provides better sensitivity and specificity compared to conventional imaging modalities [31, 32]. When imaging studies show an intrahepatic lesion with features atypical of HCC, tumor biopsy would be the next diagnostic step. However, biopsy is not always safe due to
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coagulopathy and refractory ascites and does not always provide reliable diagnosis [33]. Therefore, the decision to perform a tumor biopsy should be determined on a case-bycase basis. Endoscopic ultrasound is increasingly used to help enhance staging accuracy in patients with hepatobiliary malignancy. Since the involvement of regional lymph nodes negatively affects post-transplant outcomes, enlarged lymph nodes should be further examined with endoscopic fineneedle aspiration to rule out metastasis [34]. Measurement of the serum carbohydrate antigen 19-9 (CA19-9) level can provide additional insight, but is not without limitation. While serum CA19-9 can be helpful in diagnosing cholangiocarcinoma, the sensitivity and specificity of CA19-9 for ICC detection is just 62% and 63%, respectively [35]. Another issue with this marker is that benign diseases such as bacterial cholangitis and choledocholithiasis cause an elevated CA19-9 level. When serum CA19-9 levels are greater than 1000 U/mL, however, the presence of extrahepatic disease is highly suspicious [36, 37]. It should be noted that 10% of patients do not produce CA19-9 due to lack of the Lewis antigen [38]. While other tumor markers such as cytokeratin-19 fragment (CYFRA 21-1) and CA242 have been reported to have better specificities for detecting ICC, these are not routinely used in the current daily practice [39].
Opportunities for improvement Identifying risk factors to improve outcomes In order to achieve better outcomes, rigorous identification of patient risk factors is essential. Previous studies have identified various factors predictive of risk for patients with ICC who have undergone liver transplantation. In a review of 54 patients including 34 surgical resections and 20 liver transplants, the Pittsburgh transplant group identified three unfavorable prognostic factors, including positive surgical margin, multifocality, and lymph node metastasis [40]. When patients had none of these three factors, the 5-year survival was 64%. In contrast, when at least one of these risk factors was present, the 5-year survival dropped significantly to 9%. Shimoda et al. reported that smaller tumor size, a single nodule, and no involvement of other organs were associated with improved survival [25]. Robles et al. reviewed 23 transplant patients with ICC and identified perineural invasion and advanced pTNM stages as poor prognostic factors [26]. Hong et al. identified four unfavorable tumor histologic features: multifocality, perineural invasion, infiltrative tumor growth pattern, and lymphovascular invasion [21]. These predictors were used for risk stratification and to help estimate the likelihood of
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tumor recurrence. This study also revealed that the absence of neoadjuvant therapy before liver transplantation was strongly associated with tumor recurrence. Another study demonstrated that patients without recurrence had smaller tumor size, no lymph node metastasis or vascular invasion, and TNM stages I and II [27]. A more recent study showed larger tumor size and volume, vascular invasion, and poor differentiation as risk factors for tumor recurrence [16]. The majority of risk factors are tumor-related and similar to the risk factors for liver resection [3–5]. Liver transplantation for small intrahepatic cholangiocarcinoma In an early report from the University of California, Los Angeles (UCLA), among 127 transplant patients with primary sclerosing cholangitis, 10 patients had small incidental ICC less than 1 cm in diameter. These 10 patients did not experience tumor recurrence and had a 5-year survival rate of 83%, comparable to that of patients without ICC. In contrast, all four patients with known tumors before liver transplantation had tumor recurrence within 6 months and none survived [15]. A Spanish multicenter study reported the outcomes of “very early” solitary ICC of ≤ 2 cm in cirrhotic patients [16]. Eight patients with “very early” ICC, including four incidental tumors, experienced excellent 5-year survival at 73% without tumor recurrence. Collectively, these studies demonstrate that a select patient population with small solitary tumors appears to achieve favorable long-term survival after liver transplantation. Further studies of this patient population could help reverse the current exclusion of patients with small ICC from transplantation. Mixed hepatocellular carcinoma and cholangiocarcinoma Mixed HCC and ICC (HCC-CC) is a rare tumor with histological features of both HCC and ICC. In the modern era of liver transplantation, HCC-CC is often unrecognized preoperatively or it is treated as HCC. Just as with ICC, low survival rates have been reported in patients with HCC-CC, but data on outcomes after liver transplantation are limited [41–43]. The prognosis of patients with HCC-CC is mostly determined by the ICC component. In a study of 12 patients with incidental HCC-CC, the 5-year survival after liver transplantation was only 16% [28]. According to Sapisochin et al., when comparing the tumor size and tumor number among HCC-CC patients to a matched cohort of HCC patients, the HCC-CC cohort had significantly poorer 5-year recurrence-free survival (32% vs. 62%). Tumor recurrence was observed in 60% of patients with ICC-contained tumors, but in only 16.7% of the patients with HCC [43].
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100 Neoadjuvant + adjuvant therapy
Survival (%)
80 60
P = 0.03 Adjuvant therapy
40
None
20 0
0
12
24 36 Survival time (months)
48
60
Fig. 2 Effects of adjunctive therapy on recurrence-free survival after liver transplantation for cholangiocarcinoma. Patients who received both neoadjuvant and adjuvant therapy show excellent recurrence-free survival. In contrast, patients who received only adjuvant therapy and no treatment show poorer survival. Reprinted with permission from Hong et al. [20]
Groeschl et al. reported the outcomes of larger cohorts from the Surveillance, Epidemiology, and End Results database (n = 19) and the United Network for Organ Sharing database (n = 65). Despite similar short-term survival, the 3-year patient survival was 45–48% in patients with HCC-CC, significantly lower than the survival rate of those with HCC (75–78%) [44]. In contrast to these studies exhibiting poor outcomes, a Spanish study showed comparable post transplantation recurrence rates and survival rates between an HCC-CC group and a matched HCC control group [17]. It should be noted, however, that in this study, tumor burden was relatively favorable with a 2.9 cm median tumor size, an incidence of microvascular invasion of 16.7%, a poorly differentiated histology of 8.8%, and bilobar disease of 19%. Role of adjunctive therapy for locally advanced intrahepatic cholangiocarcinoma in combination with liver transplantation Despite the disappointing results of previous studies, certain transplant centers have reported acceptable outcomes after liver transplantation in combination with adjunctive therapy for locally advanced ICC. In a retrospective analysis by the UCLA group, 24 patients with ICC had locally advanced tumors characterized by either tumor size ≥ 5 cm, poorly differentiated histology, multifocality, lymphovascular invasion, perineural invasion, parenchymal invasion, positive margin, or lymph node metastasis [20]. Interestingly, patients who received both neoadjuvant and adjuvant therapy had better recurrence-free survival rates compared to patients with only adjuvant therapy or no adjunctive therapy (Fig. 2). Overall, the recurrence rate was 28% in patients receiving both neoadjuvant and adjuvant therapy, significantly lower than patients who received adjuvant therapy only or no therapy (50% and 40%, respectively). In
contrast to the UCLA experience, a small study of patients at Mayo Clinic in Florida showed disappointing outcomes with a median survival of 1 year after neoadjuvant chemoradiation therapy followed by liver transplantation [45]. However, taking into account the benefits of neoadjuvant therapy for early hilar cholangiocarcinoma, future clinical trials should evaluate the potential use of combining neoadjuvant therapy with liver transplantation for ICC. Locoregional therapies can be used for the treatment of ICC as a bridge to liver transplantation [46]. Transarterial chemoembolization (TACE) achieves local disease control (partial regression and stabilization) of up to 76% [47]. Currently, external beam radiation therapy has been more widely used for cholangiocarcinoma. Recent reports have demonstrated that stereotactic body radiation therapy (SBRT) effectively reduces tumor burden [48, 49]. While liver transplantation may still be considered for patients who exhibit disease down staging, definitive therapy is not recommended in the absence of a favorable tumor response to neoadjuvant treatments. With the demonstrated benefits of locoregional therapies for unresectable ICC, Hong et al. proposed a treatment protocol using locoregional therapy followed by systemic chemotherapy. Tumors ≤ 6 cm were treated with SBRT for a total dose of 40 Gy [20, 21]. For tumors > 6 cm, TACE was chosen instead of SBRT [21, 50]. Neoadjuvant chemotherapy includes a 5-fluorouracil or capecitabine-based regimen until the time of transplantation. Other agents used include oxaliplatin, leucovorin, and gemcitabine [51, 52]. Inclusion criteria for the UCLA treatment protocol include tumor size ≤ 8 cm, tumors confined within the operative field for total hepatectomy and regional lymphadenectomy, and the absence of distant metastasis. Tumor biology prior to neoadjuvant therapy helps obtain an accurate pretreatment assessment that facilitates pre-transplant risk stratification of liver transplant candidates. This assessment also identifies patients who might benefit from additional chemotherapy after transplantation [21]. If a tumor is found to have progressed beyond the confines of the operative field, patients are disqualified for transplantation. The survival benefit of post-transplant adjuvant chemotherapy in reducing the risk of tumor recurrence with impaired immune surveillance from immunosuppressive therapy has yet to be determined. The Baylor group reported their early experience with adjuvant radiotherapy and chemotherapy in patients with ICC after liver transplantation [8]. This review of 17 patients showed that the 1- and 3-year recurrence-free survival rate was only 40% and 13%, respectively. Moreover, as shown above in the study from the UCLA group, adjuvant chemotherapy alone did not improve either survival or tumor recurrence [20]. Taken together, the data currently do not support the benefit of
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adjuvant chemotherapy alone as a means to improve outcomes after liver transplantation for ICC. However, further studies are needed to better understand the role of adjuvant therapy in ICC. The major challenge in liver transplantation for locally advanced ICC is the long waiting period from neoadjuvant therapy to liver transplantation due to the severe shortage of donor organs. Since candidates for neoadjuvant therapy usually have a low Model for End-Stage Liver Disease (MELD) score, they typically are not eligible for a deceased donor organ under the current organ allocation system. Moreover, unlike small hilar cholangiocarcinoma, there is no consensus for a MELD exception point for ICC [53]. Therefore, with the current organ allocation system, patients with locally advanced ICC have no priority on the liver transplant waiting list, even when they demonstrate a good response to neoadjuvant therapy. Summary Currently, the use of liver transplantation in patients with ICC remains highly controversial and based on the published data, generally not recommended. However, recent studies have revealed that a select patient group with very early ICC clearly benefits from liver transplantation with excellent long-term survival. The use of adjunctive therapy in combination with liver transplantation might be a promising treatment modality for locally advanced ICC. Nonetheless, liver transplantation for ICC remains contraindicated at many centers. The development of standardized patient selection criteria and well-designed clinical research protocols is needed to further study the role of liver transplantation for ICC. Acknowledgments The authors would like to acknowledge Ms Sally Garrett Karyo for her assistance. Conflict of interest
None declared.
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