Transplantation for Cholangiocarcinoma

Background

Cholangiocarcinoma (CCA), first described by Durand-Fardel in 1840, is a malignant neoplasm arising from epithelial cells of the extrahepatic and intrahepatic bile ducts, excluding the papilla of Vater and the gallbladder. CCA is the second most common primary hepatobiliary malignancy in the United States. The incidence of CCA is increasing, and its prognosis remains grim without surgical treatment. Early diagnosis has been a constant challenge because there is no effective screening test, and most patients with unresectable disease die within 6 to 12 months of diagnosis.

Anatomically, CCA is classified into the proximal type, also known as hilar (HCCA) , perihilar , or Klatskin tumors , which accounts for 60% to 70% of cases; distal type for 20% to 30%; and intrahepatic (ICCA) or peripheral for the remaining 5% to 10% ( Fig. 17-1 ). The three different types of CCA have distinct pathophysiological characteristics, differ in epidemiological features and clinical presentations, and vary in surgical treatments. The primary modality of treatment for HCCA is radical bile duct resection with partial hepatectomy; for ICCA, partial hepatectomy; and for the distal type of CCA, pancreaticoduodenectomy. Survival outcomes after resection for distal CCA are superior than for perihilar tumors. For patients with unresectable HCCA or ICCA, orthotopic liver transplantation (OLT) presents a viable option and has been reported to provide survival benefits. This chapter focuses on the role of OLT in combination with neoadjuvant therapies and reviews patient selection criteria predictive of survival outcomes and post-OLT outcomes for patients with unresectable HCCA and ICCA.

Risk Factors

The cause of CCA is associated with chronic biliary inflammation. Malignant transformation of the cholangiocyte occurs in the background of chronic inflammation and cholestasis. This environment induces the production of cytokines and reactive oxygen species that cause permanent DNA damage. Established risk factors for ICCA include primary sclerosing cholangitis (PSC), liver fluke infestations, hepatolithiasis, Thorotrast exposure, choledochal cysts, biliary-enteric anastomosis, Caroli’s disease, and hepatitis. Patients with PSC have a definite risk for developing CCA, approximately 1.5% per year after diagnosis of cholestatic liver disease. Because only a minority of patients with CCA present with known risk factors, early diagnosis remains a challenging task.

Clinical Presentation

The typical age of presentation for CCA is the seventh decade of life, although with predisposing risk factors CCA can develop up to 2 decades earlier. The clinical presentation depends on the anatomical location of the tumor and is often nonspecific. HCCA and distal CCA often present with jaundice, pruritus, and cholangitis, whereas ICCA frequently presents as incidentally discovered large tumors in the absence of jaundice or other constitutional symptoms. In advanced ICCA, symptoms may include abdominal pain, weight loss, malaise, and cachexia.

Preoperative Workup and Diagnosis

There is no effective screening for CCA. The laboratory test results often indicate obstructive cholestasis with elevated levels of bilirubin and alkaline phosphatase. Levels of all three serum tumor markers—CA 19-9, CEA, and CA-125—may be elevated; however, only CA 19-9 is sensitive and specific, 79% and 98% respectively, at a cutoff value of 129 units/mL. CA 19-9 has less sensitivity in patients with PSC, 53% at a cutoff of greater than 100 units/L and would be undetectable in patients lacking the blood type Lewis antigen (10%), who do not produce CA 19-9. An elevated α-fetoprotein level in conjunction with CA 19-9 suggests a mixed hepatocellular-cholangiocarcinoma. Another diagnostic limitation of using CA 19-9 is that elevation of the marker is often seen in advanced stages of CCA where radical excisions are not possible. Although CA 19-9 does not serve as a sole diagnostic test for CCA, this tumor marker can support a diagnosis or be used to assess response to treatment and progression of disease in patients who demonstrated elevated CA 19-9 level before treatment.

The preoperative workup for HCCA and ICCA aims to exclude extrahepatic tumor spread from CCA, another primary malignancy with metastatic disease to the liver, and to evaluate feasibility of complete extirpation of the tumor, including all microscopically detectable tumor (R0 resection). With regard to diagnostic imaging studies, HCCA and ICCA may present as an irregular soft tissue mass along the ductal system or may not be visible. Although tumor may not be apparent in some cases, radiological findings of ipsilateral hepatic atrophy strongly suggest the presence of portal venous inflow compromise from tumor encasement and/or long-standing bile duct obstruction. As such, preoperative high–resolution contrast-enhanced imaging modalities are imperative to adequately assess the tumor extent and vascular involvement for operative planning. The diagnostic accuracy of computed tomography (CT) has been reported to be significantly higher for ICCA than for extrahepatic CCA (79% to 97% versus 56% to 84%). Although CT and magnetic resonance imaging (MRI) are comparable in diagnostic accuracy for ICCA, MRI in conjunction with magnetic resonance cholangiopancreatography (MRCP) provides a superior anatomical visualization of the bile ducts and the relationship of the tumor to the vascular structures. Integrated positron emission tomography (PET) and CT imaging has an emerging role in preoperative staging of CCA. Although PET/CT scanning has a similar diagnostic accuracy for primary tumors compared to conventional CT, it has a significantly better sensitivity (58% to 100%) for detecting distal metastases.

Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography allow therapeutic interventions, as well as collection of tissue samples for pathological and cytological analysis. Preoperative diagnostic accuracy from tissue or brushing remains a challenge because of the desmoplastic characteristic of CCA that frequently results in acellular samples. Advanced cytological technique for detection of aneuploidy using digital image analysis and fluorescence in situ hybridization (FISH) analysis of the brushing has improved the diagnostic accuracy. The sensitivity of digital image analysis for CCA is 39% compared to 18% for conventional cytological techniques. FISH analysis in PSC patients has a sensitivity and specificity of 47% and 100%, respectively, for the detection of CCA.