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• W4324099596 abstract "Cholangiocarcinoma (CCA), a tumor of the biliary epithelium, is the second most common primary liver malignancy after HCC, accounting for 15% of all primary liver tumors.1 Most cases are sporadic, but risk factors for the development of CCA include primary sclerosing cholangitis (PSC), choledochal cysts, hepatitis B and C infections, infection with specific trematodes, and cirrhosis of any cause.1 The tumors are subdivided by their location as intrahepatic (iCCA; proximal to the second-order bile ducts), perihilar (pCCA; from the right and left hepatic ducts to the joining of the cystic duct), and distal (dCCA; distal to the insertion of the cystic duct) (Figure 1). The most common sites of CCA are intrahepatic (51%), distal (41%), and perihilar (8%), and most CCA are histologically adenocarcinomas.2FIGURE 1: Anatomic relationship of intrahepatic, perihilar, and distal cholangiocarcinoma (Credit: Amy Bloch).Cases are typically identified either as part of the workup of symptoms of biliary obstruction (eg, jaundice, pruritus, and abdominal pain), incidentally on radiographic studies obtained for other reasons or as part of surveillance for conditions such as PSC and cirrhosis. Tumors may present as mass-forming, periductal infiltrations, and intraductal papillary lesions. Diagnosis of an iCCA is often made with cross-sectional imaging, but unlike HCC, imaging is not always definitive and it can be difficult to differentiate iCCA from HCC; hence, an elevated CA 19-9 can be useful for discriminating between these 2 cancers. The diagnosis of pCCA and dCCA employs magnetic resonance cholangiopancreatography (MCRP), which typically demonstrates a stricture with proximal biliary dilatation and is followed by endoscopic retrograde cholangiopancreatography (ERCP) with biliary brushings and fluorescence in situ hybridization that increases the sensitivity for the diagnosis of CCA compared with brushings alone. Cholangioscopy and confocal laser endomicroscopy have been felt to increase diagnostic yield, but this remains unclear. The preferred therapy for CCA is surgical resection, which can be curative, but overall 5-year survival rates are as low as 30%.3 Surgical resection of dCCA involves a pancreaticoduodenectomy or Whipple procedure. iCCA and pCCA are managed with hepatic segmentectomy or lobectomy and may require bile duct resection and biliary reconstruction with a hepaticojejunostomy. Neoadjuvant or adjuvant chemotherapy is not recommended for resectable tumors, but chemoradiation can be offered to those with positive margins or positive lymph nodes after resection. Unfortunately, many tumors are advanced at that time of diagnosis, and resection may not be possible due to metastatic disease, the size of the mass, involvement of vasculature or large biliary ducts, or the quality of the liver parenchyma, with fewer than 50% of CCA being surgically resectable at the time of presentation.4 Resectability may be improved with portal vein embolization and hypertrophy of the contralateral hepatic lobe or with tumor downstaging by systemic chemotherapy or locoregional therapy. For nonresectable tumors, therapy depends on the location and extent of the tumor. For locally advanced or metastatic disease, the preferred therapy is chemotherapy with gemcitabine and cisplatin, with a median survival of 11.7 months.5 Advances in next-gen sequencing may have a role in future therapies as a good proportion of biliary tract cancers have targetable genetic alterations. For unresectable iCCA, locoregional therapy is an option including hepatic arterial infusion, transcatheter arterial chemoembolization (TACE), drug-eluting bead TACE, Yttrium radioembolization (Y-90), and external beam radiation. CCA was long considered a contraindication to liver transplantation due to early studies showing poor outcomes with frequent recurrence, but this has been re-evaluated in specific patient populations. The clearest recommendations are for pCCA, where MELD exception points are granted for unresectable pCCA <3 cm in size and after undergoing neoadjuvant chemoradiotherapy under the Mayo protocol6,7 (Table 1). However, the number of patients meeting these criteria is very small, as few as 2% of CCA cases.7 In addition, in patients initially considered for transplant under these criteria, as many as 32% are ultimately not eligible for transplant due to disease progression beyond transplant criteria during or after the completion of neoadjuvant therapy, findings at operative staging that precluded transplant, or death. Neoadjuvant chemoradiotherapy is based on the Mayo protocol involving external beam radiation with concomitant 5-fluorouracil, followed by brachytherapy and then oral capecitabine until transplant7 (Table 2). Outcomes in the transplant of these patients are good, with a 5-year survival of 63%, which is in line with survival after liver resection.8 A recent benchmark study compared liver transplant with curative resection for low-risk pCCA and demonstrated significantly better 5-year disease-free survival in liver transplantation (50.2% vs. 17.4% in curative resection).9 TABLE 1 - Mayo transplant protocol patient selection6 Inclusion Exclusion Diagnosis of CCA, established by Prior radiation or chemotherapy Intaluminal brush cytology or FISH Uncontrolled infection Intraluminal biopsy, or Prior malignancy other than skin or cervical cancer within 5 y CA 19.9 >100 ng/mL in the setting of radiographic malignant stricture Medical conditions precluding transplantation Unresectable pCCA or resectable pCCA arising in the setting of PSC Evidence of extrahepatic disease Operative biopsy (including percutaneous and EUS-guided FNA) Abbreviations: CCA, cholangiocarcinoma; FISH, fluorescence in situ hybridization; pCCA, perihilar cholangiocarcinoma; PSC, primary sclerosing cholangitis. TABLE 2 - Mayo neoadjuvant chemoradiation protocol7 1. External beam radiotherapy to 4500 cGy in 30 fractions 2. Fluorouracil (5-FU) 500 mg/m2 daily for the first 3 days of radiation 3. Two to 3 weeks after radiotherapy, transluminal radiation delivered by transcatheter Iridium-192 brachytherapy wire for a target dose of 2000–3000 cGy 4. Following brachytherapy, oral capecitabine (2000 mg/m2 per day in 2 divided doses, 2 out of every 3 wk) as tolerated until transplantation Liver transplant in iCCA is more controversial, with no guidelines currently recommending transplants in these patients.10 In studies looking at patients with cirrhosis transplanted for presumed HCC who were found to have iCCA in the explant, 5-year survival is 45% but improved to 65% for single tumors≤2 cm in size. Data are even more limited in patients without cirrhosis with a prospective case series of 21 noncirrhotic patients with unresectable iCCA, 6 of whom were eventually transplanted following neoadjuvant chemoradiation, with a 3-year survival rate of 80% (cancer recurrence in 50% of those transplanted).11 CCA carries a poor overall prognosis due to the often advanced stage of the disease at the time of diagnosis. Currently, the best prospect for curative therapy is surgical resection, but that is not possible in a majority of cases. Transplantation is a treatment option that carries the benefit of wide tumor resection margins and improved hepatic function in those with underlying liver disease, but due to concerns for cancer recurrence and poor outcomes, it has only been considered in a small patient population. Liver transplantation is currently only recommended in combination with neoadjuvant chemotherapy for small (<3 cm) pCCAs. In the future, it may be reasonable to consider a transplant for patients with cirrhosis and iCCA ≤2 cm in size, but studies are currently ongoing on the safety and feasibility of this." @default.
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• W4324099596 title "Liver transplantation for cholangiocarcinoma" @default.
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