Liver Transplantation For Cholangiocarcinoma Research Articles

From Normal Renal Function to Renal Replacement Therapy after Liver Transplantation: A Case Report

Postoperative renal failure significantly impacts long-term renal function and the overall survival of patients receiving liver transplantation (LT), being a crucial factor in their morbidity and mortality. It is difficult to define whether the causes of renal failure are solely related to surgery or anaesthesia during liver transplantation (LT). Indeed, liver disease requiring liver transplantation is often the cause of preoperative renal failure. We report a case of a 62-year-old patient undergoing LT for cholangiocarcinoma that led to acute kidney injury postoperatively while his preoperative renal function was normal. This report highlights the major influence that the surgical and anaesthetic procedure can have on renal function and identifies the factors that may have led to renal replacement therapy being required for this patient.

Liver Transplantation for Cholangiocarcinoma: Charting a Path With Lessons Learned From Center Experience.

While liver transplantation (LT) with neoadjuvant chemoradiation is increasingly utilized for the management of unresectable cholangiocarcinoma (CCA), data on post-LT survival are limited. We identified 844 patients who underwent LT (2002-2019) for nonincidental (CCA listing) or incidental (CCA on explant, not at listing) CCA in the Scientific Registry of Transplant Recipients. Kaplan-Meier and multivariable proportional hazards regression methods evaluated the effects of patient characteristics, donor type, transplant era (before/after 2010), and center volume (center-level CCALTs/active year) on the risk of graft failure and patient mortality. One center performed >12 CCALTs/y, and the rest performed ≤4. Five-year graft survival was 50.6%. Multivariable models demonstrated laboratory model of end-stage liver disease ≥40 versus <15 and center volumes of 1, >1 to ≤2, and >2 to ≤4 CCALTs/y compared to >12 were associated with increased risk of graft failure and mortality (all P ≤ 0.002). Extra vessel use was associated with center volume. Among all recipients, extra vessel use occurred in 55.4% of CCALTs performed at the highest volume center and in 14.0% of cases at centers having ≤4 CCAs/y (P < 0.05). Center volume-related differences in outcomes and extra vessel use highlight the importance of establishing a unified, effective treatment protocol and the potential utility of regionalization of LT for CCA.

Endoscopic Ultrasound/Fine Needle Aspiration Is Effective for Lymph Node Staging in Patients With Cholangiocarcinoma.

Presence of malignant regional lymph nodes (MRLNs) precludes curative oncological resection or liver transplantation for cholangiocarcinoma (CCA). Limited data support the utility of endoscopic ultrasound (EUS)/fine needle aspiration (FNA) for detection of MRLNs in extrahepatic CCA, but there are no data for its role in intrahepatic CCA (iCCA). The aim of this study is to evaluate the staging impact of EUS for CCA, including analysis by subtype. We identified consecutive patients with CCA who underwent EUS staging at a single tertiary care center from October 2014 to April 2018. Among this cohort, we abstracted clinical demographic, radiographical, procedural, cytopathological, and surgical data. STATA 15 software was used for comparative analysis calculations (StataCorp LP, College Station, TX). The study cohort included 157 patients; 24 (15%), 124 (79%), and 9 (6%) with intrahepatic, perihilar, and distal CCA, respectively. EUS was able to identify regional lymph nodes (RLNs) in a higher percentage of patients compared to cross-sectional imaging (86% vs. 47%; P<0.001). FNA was performed in 133 (98.5%) patients with RLNs, with a median of three passes per node. EUS-FNA identified MRLN in 27 of 31 (87.1%) patients ultimately found to have MRLNs. For iCCA, EUS detected a higher percentage of RLN compared to cross-sectional imaging (83% vs. 50%; P=0.048), with MRLNs identified in 4 (17%) patients. Among the entire cohort, identification of at least one MRLN by EUS was associated with lower median survival (353 vs. 1,050days; P<0.001) and increased risk of death (hazard ratio=4.1; P<0.001). EUS-FNA is effective for identifying MRLN in patients with CCA, and should be routinely incorporated into staging of all CCA subtypes given the impact of MRLN on prognosis and management decisions.

Liver Transplantation for Cholangiocarcinoma and Mixed Hepatocellular Cholangiocarcinoma: Working Group Report From the ILTS Transplant Oncology Consensus Conference.

Liver transplantation for cholangiocarcinoma has been an absolute contraindication worldwide due to poor results. However, in recent years and thanks to improvements of patient management and treatments of this cancer, this indication has been revisited. This consensus paper, approved by the International Liver Transplant Society, aims to provide a collection of expert opinions, consensus, and best practices surrounding liver transplantation for cholangiocarcinoma.

Liver Transplantation for Cholangiocarcinoma: Insights into the Prognosis and the Evolving Indications.

Cholangiocarcinoma (CCA) is a rare malignancy of the biliary ducts that can be classified as intrahepatic, perihilar, or distal based on anatomic location. Although surgical resection can be curative, complete excision with negative margins is often difficult to achieve. In patients with unresectable disease, long-term survival is rarely seen with medical therapy alone. A multimodal treatment approach, including liver transplantation (LT) for select patients with unresectable CCA, should be considered. While currently only an approved indication for early, liver-limited, perihilar cholangiocarcinoma, promising results have been achieved for LT in localized intrahepatic disease. The absolute indication for transplant for intrahepatic tumors is currently the subject of multiple investigations. Continued advances in neoadjuvant/adjuvant therapy and better understanding of tumor biology may further augment the number of candidates for surgical therapies, with liver transplant acting as a promising tool to improve patient outcomes. Thorough consideration for any expansion in the indication for liver transplant in malignancy is necessary in order to balance patient outcomes with utilization of the scarce donor organ resources.

Liver transplantation for cholangiocarcinoma: Past, present, and the future

Management of hilar cholangiocarcinoma (CCA) remains a major challenge incorporating complex diagnostic and therapeutic modalities. The management has evolved over the decades in pursuit of optimal therapeutic outcome for this challenging pathology. The only curative therapeutic option for CCA is complete (R0) surgical resection with negative margins. Curative resection for hilar CCA (HCCA) remains a surgical challenge due to its high propensity for invasion into liver parenchyma, encasement of portal vessels, and metastasis to regional lymph nodes. Liver transplantation (LT) was proposed as an alternative therapeutic option, but the initial results were extremely disappointing due to high rate of recurrence. The management has evolved over decades with introduction of neoadjuvant treatment options followed by LT resulting in optimal outcomes for an otherwise lethal disease. The current review outlines the changing trends in the management of HCCA over the years.

Liver Transplantation for Cholangiocarcinoma Beyond a Clinical Trial

Journal of the American College of Surgeons: February 2014 - Volume 218 - Issue 2 - p 304-305 doi: 10.1016/j.jamcollsurg.2013.10.020

Impact of neoadjuvant chemoradiation on the tumor burden before liver transplantation for unresectable cholangiocarcinoma

The very early experience with liver transplantation (LT) for cholangiocarcinoma (CC) was dismal because of the poor survival outcomes and the high recurrence rates. However, LT for CC in conjunction with neoadjuvant chemoradiation recently has shown encouraging results, although the data are extremely limited. At our institution between 2001 and 2008, 22 CC patients underwent protocol orthotopic LT at a median age of 45 years (range = 24-63 years). At a median follow-up of 601.5 days (range = 111-1388 days), the median survival time of the cohort was 3.3 years. The 1-, 2-, and 3-year Kaplan-Meier survival probabilities were 90%, 70%, and 63%, respectively, whereas the historical 5-year survival rates were 0% to 18% for intrahepatic CC and 23% to 26% for extrahepatic CC when patients underwent transplantation without neoadjuvant therapy. These encouraging survival rates for patients with this type of tumor, which is difficult to diagnose and treat, are no less significant when they are compared to the national 1- and 3-year survival rates (86% and 68%, respectively) of patients undergoing deceased donor LT for malignant neoplasms of the liver (as reported by the United Network for Organ Sharing). In our series, disease recurrence was significantly associated with a larger residual tumor [6.3 versus 2.0 cm (mean values), P = 0.008] and with a shorter waiting time for LT after the chemoradiation protocol [18 versus 56 days (mean values), P = 0.04]. Our LT protocol for CC was found to be promising for patients with truly extrahepatic CC and for patients within stages I to IIB of the American Joint Committee on Cancer Staging system (100% survival at a median follow-up of 2.2 years), but the results were notably poor for patients with stage III extrahepatic CC (median survival = 1.2 years). These observations highlight the need for accurate preoperative staging of CC for ideal LT recipient selection and the importance of a low tumor burden and a longer wait after neoadjuvant therapy. More effective chemoradiation regimens for reducing the tumor burden and the appropriate timing of LT after neoadjuvant chemoradiation require further research.

A review of transplantation for tumors other than hepatocellular carcinoma

Introduction: Debates are ongoing in many centers for the indications of liver transplantation for non-hepatocellular carcinoma tumors due to a number of factors. Standardized protocols are lacking and clinical outcomes vary. Objective: A review was performed of the numerous published articles, with focus on the management and clinical outcome of tumors besides hepatocellular carcinoma (HCC) which were treated by liver transplantation, namely, cholangiocarcinoma, neuroendocrine tumors and hepatic epitheloid hemangioendothelioma in an attempt to promote a more standardized guideline. Discussion: Liver transplantation for cholangiocarcinoma reveals promising results in selected group of patients who underwent neoadjuvant chemoradiation prior to transplantation. For neuroendocrine tumors with liver metastases a number of selection criteria have been proposed in different centers, however the results of which are still variable. Transplantation is a viable option for unresectable hepatic epitheloid hemangioepithelioma with results at par with resection. Conclusion: Over time as patient selection, techniques, peri-operative care and the understanding of the different diseases improves, the results of liver transplantation for these tumors likewise will became favourable. However, standardization of the management and guidelines are still needed.

Retransplantation for donor-derived neuroendocrine tumor

Although tumor transmission through liver transplantation (LT) is a rare occurrence, the consequences can be devastating, even when a very aggressive management approach is adopted. We report the case of a donor-derived small cell neuroendocrine tumor (NET) in a patient who underwent LT for cholangiocarcinoma. Despite locoregional therapy, chemotherapy and ultimately retransplantation, the patient died from metastases. The high grade nature of the NET was the most important determinant of prognosis in this case. Our experience suggests that retransplantation for donor-derived NET should only be considered when tumor biology is favorable.

Liver transplantation for cholangiocarcinoma: Selection is essential for acceptable results

Background and aims. Cholangiocarcinoma (CCA) is considered a contraindication for liver transplantation by most liver transplant centers. The aim of this study has been to report our results as well as to explore factors that influence patient survival after liver transplantation for CCA. Patients. All transplant patients with CCA in Norway, Sweden and Finland during 1984–2005 were included (n = 53). Thirty-three patients (62%) had intrahepatic CCA. Twenty-one patients (40%) had a more advanced tumor (>TNM stage 2). Thirty-four of the 53 recipients (64%) had primary sclerosing cholangitis (PSC). Results. Patients with TNM stage ≤2 transplanted after 1995 had a 5-year survival rate of 48%. The overall 5-year patient survival rate was 25%. There was no difference in survival between patients with extrahepatic and intrahepatic CCA. The 5-year survival rate among patients with TNM stage ≤2 was 36%. Patients with TNM stage >2 had a 10% 5-year survival rate; the difference was significant at p < 0.01. Patients transplanted after 1995 had a significantly better 5-year survival rate than pre-1995 patients (38% vs. 0%, p < 0.01). Patients transplanted after 1995 with TNM ≤2 and CA 19-9 ≤100 had the 5-year survival of 58%. Conclusion. By selecting CCA patients with TNM stage ≤2 and a CA 19-9 ≤100 a reasonable 5-year survival rate is possible. We think that CCA in selected cases can be an acceptable indication for liver transplantation.

The Diagnostic Conundrum and Liver Transplantation Outcome for Combined Hepatocellular‐Cholangiocarcinoma

Combined hepatocellular‐cholangiocarcinoma (cHCC‐CC) is a rare primary liver malignancy with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) histological features. It is almost impossible to obtain an accurate, preoperative noninvasive diagnosis of cHCC‐CC with tumor markers or cross‐sectional abdominal imaging due to the mixed histological features. Despite these difficulties, accurate cHCC‐CC diagnosis remains an important goal with prognostic significance. In our study, we retrospectively reviewed the tumor markers: AFP and CA 19‐9, and cross‐sectional liver imaging, in light of liver explant findings, to identify and characterize cHCC‐CC features followed by liver transplantation (LT) outcome analysis. The results from this 12 patient cohort failed to identify characteristic features for cHCC‐CC. None of the imaging features helped to identify the cHCC‐CC tumor and they mimicked either HCC or CC, depending on the degree of glandular differentiation expressed histologically. In our cHCC‐CC LT recipients, the 1‐, 3‐ and 5‐year cumulative survival probabilities were 79%, 66% and 16%, respectively with a 5‐year survival comparable to or better than LT for intrahepatic CC but poorer than LT for HCC following the Milan criteria. Conceivably explained by its cholangiocarcinoma component the LT outcome for this rare and hard to diagnose tumor appears poor.

Liver Transplantation for Cholangiocarcinoma

Liver transplantation for cholangiocarcinoma (CCA) remains a controversial subject. More than 15 years after, a novel protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation was first used in patients with unresectable hilar CCAs, these methods have yet to reach broad application. Results have confirmed that this approach leads to significantly lower recurrence rates and higher long-term survival rates than other existing treatment modalities. Despite this, protocols to treat patients with CCA are not widespread, and are available at only a handful of transplant programs. At these centers, treatment success may ultimately hinge on regional model for end-stage liver disease scores and waiting time for transplant. While acknowledging these factors as well as a severe organ shortage, it is important that the transplant community not overlook a potentially effective form of therapy for a previously untreatable disease.

Transplantation for cholangiocarcinoma

Cholangiocarcinoma accounts for 2% of all malignancies in the United States and 40-60% are considered hilar arising at the hepatic duct bifurcation.1 The prevalence of cholangiocarcinoma, however in patients with a diagnosis of primary sclerosing cholangitis has been reported to be present in 7 to 13% and develops at a rate of 1% per year.2, 3 The diagnosis of cholangiocarcinoma can be made by interpretation of brush cytology or biopsy of a mass identified by computed tomography or magnetic resonance imaging.4, 5 Non-surgical therapy has been associated with very poor survival long-term, 1 and 5 year survival of 26% and 4%, respectively.6 Surgical excision significantly improves survival. An R0 resection, that is a resection where no known tumor is left behind, increases survival to 60% at 2 years.7 Resection is not possible, however in some patients due to extension of disease to both hepatic lobes or risk from liver resection due to underlying cirrhosis. Liver transplantation has been proposed in these circumstances.8 In the United States 6 to 7% of liver transplants are performed for malignancy. The majority of these are for the presence of hepatocellular carcinoma and only a small minority are for cholangiocarcinoma. For the period of 1988 to June 2006, UNOS reports that 213 patients were transplanted for the diagnosis of cholangiocarcinoma compared to 3,344 patients transplanted for hepatocellular carcinoma.9 Since the introduction of MELD, a provision for an exception for patients with hepatocellular carcinoma has been established to increase the assigned MELD score to increase the ability of patients with a curable malignancy to achieve transplantation prior to spread of the disease. The criteria used to establish these criteria were developed by Mazzafero and colleagues and are referred to as the Milan criteria based on a 1996 publication detailing the outcomes in 48 patients that underwent transplantation that met these criteria.10 Several reports historically have shown poor outcomes after liver transplantation for cholangiocarcinoma, far below the outcome for liver transplantation for other diagnoses.11-13 The reasons for patient death in these earlier reports were due to a high risk for recurrence. The stage of disease in these cases were advanced (the majority with stage III or IV tumors). Two centers have subsequently demonstrated that with selection of patients with only earlier stage disease and the addition of neoadjuvant therapy, the survival after liver transplantation for cholangiocarcinoma approaches the outcomes for other diseases.14, 15 It appears reasonable in the current setting to reconsider application of liver transplantation to patients with cholangiocarcinoma. Currently there are recommendations from the Liver/Intestine committee of UNOS out for public comment that suggest an increase in MELD score for patients that meet criteria similar to the Mayo and Nebraska protocols. In summary, although in the past liver transplantation for cholangiocarcinoma was associated with high rates of malignancy recurrence, most of these patients in earlier reports had in fact advanced disease at the time of transplantation. Better selection of patients for patients with stage I or II and the introduction of neoadjuvant therapy by 2 programs has resulted in acceptable outcomes in the same range as those patients in whom resection is possible.

Primary sclerosing cholangitis: Summary of a workshop

Primary sclerosing cholangitis (PSC) is a rare but important liver disease that leads to cirrhosis and need for liver transplantation in a high proportion of cases. The disease occurs in approximately 1 per 100,000 population per year, usually presents in adulthood, and affects men more often than women. Typical serum biochemical results, autoantibodies and liver biopsy are suggestive but not diagnostic of PSC, the diagnosis requiring cholangiographic demonstration of stricturing and dilatation of the intra- and/or extra-hepatic bile ducts. The natural history of PSC is variable, the average survival being 12 to 17 years. The cause of PSC is still unknown. Although considered an autoimmune disease, PSC has several atypical features and a strong genetic component. The therapy of PSC is unsatisfactory. Standard doses of ursodeoxycholic acid (UDCA) lead to improvements in biochemical abnormalities but not in histology, cholangiographic appearance or survival. Several innovative therapies have been tried in PSC, but with scant evidence of benefit. For patients with high grade strictures, endoscopic dilatation is beneficial. Liver transplantation is successful for end-stage liver disease due to PSC and improves survival. PSC may recur after transplantation but is rarely progressive. The most dreaded complication of PSC is cholangiocarcinoma. Diagnosis of this highly malignant tumor is difficult, and there are no biomarkers for its early detection. Liver transplantation for cholangiocarcinoma has an exceedingly poor outcome, although transplantation with neoadjuvant chemoirradiation holds promise in selected patients. Thus, significant opportunities remain for basic and clinical research into the cause, natural history, and therapy of PSC.

Emerging role of transplantation for primary liver cancers.

Liver transplantation (LT) has been utilized in the treatment of primary hepatic malignancy for decades. Hepatocellular cancer (HCC) remains the most common malignant condition treated with LT, with almost 400 such transplants performed annually in the US. Refinement in the selection criteria for LT in patients with HCC has led to survival rates similar to those for LT in nonmalignant conditions. Excellent results have also been reported following LT for select patients with epithelioid hemangioendothelioma and hepatoblastoma. Patients with cholangiocarcinoma treated with LT have generally faired poorly, with survival rates far below that of LT for nonmalignant conditions. Improved survival has recently been reported following LT for cholangiocarcinoma in highly select patients treated with aggressive neoadjuvant therapy. The future utility of LT in the treatment of malignancy will be influenced by several factors, including a profound organ donor shortage faced worldwide; increasing prevalence of hepatitis C, HCC and cirrhosis; and the evolution of live donor liver transplantation.

Survival after liver transplantation for cholangiocarcinoma has increased during the last decade

INTRAHEPATIC (IH) or peripheral cholangiocarcinoma (CCC), which arises from the IH bile ducts, is the second most common primary liver cancer after hepatocellular carcinoma. Extrahepatic (EH) CCC arises from the biliary tree outside the liver parenchyma; when it is centrally located in the proximal bile duct it is also known as Klatskin tumor. CCC is often unresectable due to its central location or involvment of portal structure. For these patients liver transplantation (LT) provides an opportunity for radical resection. CCC is, however, a rare indication for LT. The limited number of organs available makes LT for CCC controversial; many centers have reported a dismal prognosis; only few cases of long-term survival after liver transplantation have been reported. The purpose of this retrospective analysis was to study the results of LT for CCC and to determine prognostic variables that could improve the selection of recipients for this procedure.

Is liver transplantation indicated for cholangiocarcinoma?

Liver transplantation for unresectable primary liver cancer has met with skepticism due to early aggressive recurrences occurring in early series from many centers. The primary tumors for which transplantation has been performed have been hepatocellular carcinoma and cholangiocarcinoma. In an attempt to improve these poor results, we instituted a protocol with adjuvant chemotherapy and radiotherapy after liver transplantation for cholangiocarcinoma. Between December 1984 and December 1992, 701 patients underwent 795 liver transplants. Seventeen patients had a diagnosis of cholangiocarcinoma and form the basis of this review. Three patients were excluded from the study, two because of early postoperative deaths, and one because of an unknown bony metastasis present at the time of transplant. Eleven patients have experienced a recurrence, and 7 of these died secondary to their recurrence. Three patients are alive with no evidence of disease 44 months, 31 months, and 28 months, respectively, after transplant. The 1-year survival rate in these patients is 53%, and the disease-free survival rate is 40%. Patients were able to tolerate the adjuvant chemotherapy and radiotherapy without apparent morbidity or mortality. Unfortunately, this protocol does not appear to provide significant benefit. Until a better adjuvant therapy protocol is developed, it is questionable whether unresectable cholangiocarcinoma should be considered an indication for liver transplantation.