Orthotopic liver transplantation with hepatopancreato-duodenectomy for hilar cholangiocarcinoma

Although the surgical treatment for hilar cholangiocarcinoma represents the only potentially curative option, local excision and major hepatectomy1 have failed to produce a favorable survival figure over the last decade. This is partly due to local tumor recurrences within the resection margin, perineural sheaths infiltration, and the regional lymph nodes metastasis after the surgery. Recently, an extended bile duct resection combined with total hepatectomy, pancreatoduodenectomy, and orthotopic liver transplantation (HPLTx) was proposed to eradicate the entire biliary tract without cutting off the hepatoduodenal ligament. The results demonstrated an increased rate of curative (R0) resections from 29% to 93% by HPLTx, and a favourable 5-year survival rate.1-4 We report here on a patient with advanced liver disease associated with hilar cholangiocarcinoma, who was treated successfully by HPLTx. CASE REPORT A 35-year-old woman with advanced liver cirrhosis complaining progressive obstructive jaundice, upper abdominal pain, and weight loss for 2 months was admitted to a local hospital on August 2004. Ultrasonography and endoscopic retrograde cholangiopan-creatography (ERCP) showed a mass at the hila and the dilated intrahepatic bile ducts. At laparotomy, a cholangioma was found not only invading the bifurcation, but also involving the secondary hepatic ducts, gallbladder, and the head of the pancreas along the extrahepatic biliary tree. A palliative operation was performed including cholecystectomy and drainage of the right hepatic duct. After the operation, histological examination revealed an adenocarcinoma with metastasis to the segment 5 of the liver. The patient was then referred to our hospital for liver transplantation on September 15th 2004. On the admission to our hospital, MRI confirmed that the tumor was at stage IVA according to the TNM classification of the American Joint Committee on Cancer5 and Bismuth type IV. (Fig. 1) The preoperative evaluation of the tumor markers demonstrated that AFP <20 μg/L, CEA 2.4 μg/L, CA19-9 136.28 kU/L, CA125 47.61KU/L, and total bilirubin reached up to 110.3 μmol/L. No thrombosis in the portal vein and variation of the hepatic arteries were found by Doppler ultrasonography. The vena cava was non-obstructed. Moreover, positron emission tomography revealed no extrahepatic extension.Fig. 1.: MRI showing an obstruction at the confluence of the left and right hepatic ducts (arrow).On September 25th 2004, an HPLTx was performed according to the methods reported by Neuhaus and colleagues.3 The recipient operation began with a complete exploration of the abdomen to exclude distant spreading and seeding. Modified piggyback orthotopic liver transplantation was carried out without venovenous bypass. The alimentary tract was reconstructed according to the Child’s methods (Fig. 2). The liver graft was harvested from a male donor with Rh positive type B blood under legal permission. A rapid liver procurement was accomplished with 5 minutes warm ischemia time, and the liver was preserved in a cold UW solution for 5 hours. No variation of the blood vessels was found during the back-table trimming procedure.Fig. 2.: Total hepatectomy combined with pancreatoduodenectomy and orthotopic liver transplantation (HPLTX).Under endotracheal combined with intravenous anesthesia, the HPLTx lasted for 12 hours with a 50-minute anhepatic phase. A total of 3600 ml erythrocyte cells and 4000 ml plasma were transfused during the operation. After the operation, FK506 and steroids were prescribed, and lamivudine with HBIG were used to prevent re-infection of hepatitis B virus. Pathological examination revealed a low-differentiated cholangiocarcinoma, immunohistochemistry staining demonstrated positive expression of CEA, CK9, and CK1 7 (Fig. 3). In addition, the expression of hepatocyte protein was negative. Neither the margin of resection nor the periductal lymph nodes were involved, but the peripancreatic invasion and perineural sheath infiltration were found (Fig. 4). The resected liver specimen showed cholestasis, moderate fibrosis, and metastasis nod.Fig. 3.: Positive expression of cytokeratin 9 (A), 17 (B), and CEA (C); and negative expression of the hepatocyte protein (D). (Immunohistochemical staining using monoclonal mouse anti-cytokeratin9, 17, and carcinoembryonic antigens. (A-C: original magnification×400, D: original magnification×100)Fig. 4. A: : A cholangiocarcinoma invading the head of the pancreas. B: A low-differentiated adenocarcinoma with perineural infiltration (hematoxylin and eosin staining, original magnification×100)The patient was discharged from hospital 32 days later and has survived for 28 months without any evidence of recurrence. The serum CEA and CA19-9 were negative during the follow-up. Both the resistance index and the calibers of the vessels were satisfying in the twice post-discharge ultrasonography. Only the left hepatic duct was found dilated a little, and then returned to normal by using chenodeoxycholic acid. DISCUSSION Hilar cholangiocarcinoma is an uncommon tumor that may occur anywhere along the biliary system and continues to present formidable challenges in diagnosis and treatment. Only surgical treatment does offer a chance for a higher radicality and long-term disease-free survival. However, patients with cholangiocarcinoma have extremely poor prognoses after partial hepatectomy because of the tumor recurrence on the margin of excision and unrecognized perineural sheath infiltration or lymphatic invasion at the distal residual bile duct around the head of the pancreas. Extended resections, especially right trisegmentectomies and HPLTx, which result in the highest rate of R0 resection, may be regarded as the surgical procedure of choice.1-4,6 HPLTx involves the removal of the entire biliary tract and the head of the pancreas with lymphatic and perineural tissues, and so theoretically is likely to improve the radicality of resection. In addition, the tumor itself and hepatoduodenal ligament may remain undissected if an ‘en bloc’ resection is performed with no-touch technique, which may reduce tumor cell spillage during the procedure. But the comparable favorable effect with respect to the survival figures is not evident.3 The use of immunosuppressant, intraoperative tumor cell seeding, and microscopic metastases serves as explanations for post-transplantation failure. The latter two are as the same reason as in hepatectomy. It was often the circumstance that many patients, who have a potentially resectable tumor, underwent only palliative stenting or drainage, which is obviously insufficient for treatment. Moreover, the preoperative biliary drainage may cause implantation metastases. Starzl and colleagues7 used upper abdominal organ cluster transplantation to eradicate biliary tumors that extended beyond the bile duct and involved the contiguous organs; however, the “aggressive” attempts resulted in a postoperative mortality of 20% and a 5-year survival rate of only 14%. To our knowledge, the HPLTx is more reasonable than the cluster operation, because it is well tolerated without leading to noticeable nutritional complications. Liver transplantation may be a therapeutic option for the patients with 1) unresectability confirmed at laparotomy; 2) advanced tumor with infiltration of the adjacent tissues that an R0 resection is hardly to be achieved; 3) local intrahepatic recurrence of the tumor; and 4) advanced hepatic cirrhosis and primary sclerosing cholangitis without enough residual functional liver tissues after resection.8,9 Thus, obviously, liver transplantation and partial pancreatoduodenectomy are not general surgical practice. In this case, the unresectability was proved by surgical exploration before the HPLTx, indicating an advantage of liver transplantation for the patient. In this case, pancreatoduodenectomy was deliberately performed to increase radicality. Since the patient did not have lymph node invasion, but had perineural sheath involvement beyond the margin of the regular hepatectomy, which would be curative for her. Moreover, perineural sheath invasion, a characteristic of bile duct cancer, has been shown to be associated with a significant poor prognosis. In summary, we believe that HPLTx is justified for certain cases without extensive spread and aggressive biological behavior. Despite of the necessity of using immunosuppressants and possible recurrence of tumor, the HPLTx is a logical alternative.