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Keywords:

  • Bile ducts;
  • cholangiocarcinoma;
  • liver transplant;
  • primary sclerosing cholangitis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

Orthotopic liver transplantation is the only definitive therapeutic option in patients with primary sclerosing cholangitis (PSC) and end-stage liver disease. However, PSC recurs in up to 20% of patients transplanted for this indication. To date, no patient has been reported to develop cholangiocarcinoma (CCA) post-transplant, without biliary tract cancer having been present pretransplant. Here, we report recurrent PSC complicated by de-novo CCA in a 31-year-old man transplanted for PSC 8 years earlier. Cholangiocarcinoma was confirmed using a combination of computed tomography, cholangiography, positron emission tomography and histological examination of biliary cytology. He has since been successfully re-transplanted following preoperative chemo-radiotherapy. No viable tumor was identified in the explanted liver. This case establishes that long-term complications associated with PSC and biliary-enteric surgery such as CCA may become apparent in new grafts post-transplant.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

Although a number of therapies have been evaluated for primary sclerosing cholangitis (PSC), liver transplantation (LT) is the only effective therapeutic option for patients with end-stage liver disease. Five-year survival rates better than 80% have been reported in many series of patients undergoing LT for PSC (1–4). An early observation in these patients was an apparent increase in the rate of biliary strictures post-transplant (1, 4, 5). Moreover, features characteristic of PSC were seen more frequently in liver biopsy specimens of PSC recipients compared with other recipients (6). Recent studies have estimated the recurrence rate of PSC to be between 8.6% and 20% based on biochemical, radiological, and histologic findings (2, 4, 7, 8). One of the principal difficulties in making the diagnosis of recurrent PSC is differentiating it histologically from chronic rejection (9). Therefore, the diagnosis of PSC recurrence is one of exclusion and requires extensive investigation.

The consequences of recurrent PSC are not well defined. In the largest series reported to date (including 150 patients), patient and graft survival at 5 years in patients with recurrent PSC was significantly less than patients without evidence of disease recurrence (7). Five patients diagnosed with recurrent PSC died, three as a result of end-stage liver disease whereas two other patients required retransplantation at 2 and 8.5 years, respectively, after their first transplant for graft failure related to recurrent disease. The long-term consequences of recurrent PSC following LT remain to be determined.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

In 1990, a 22-year-old male underwent orthotopic liver transplantation for PSC and end-stage liver disease. His explanted liver had no evidence of cholangiocarcinoma. The early postoperative course was complicated by a bile leak that required biliary reconstruction. Despite this, he had progressive biliary injury and stricture formation and was re-transplanted in June 1992 as a consequence of graft failure secondary to chronic biliary sepsis. Following his second transplant, his postoperative course was complicated by one episode of acute cellular rejection treated with methylprednisolone, tacrolimus toxicity. He developed anastomotic stricturing that necessitated revision of his choledochojejunostomy in October 1992. His immunosuppression was changed to cyclosporine-based therapy, and he made a full recovery, returning to work full-time in March 1993.

He remained well between December 1992 and August 1999 with normal graft function on cyclosporine 100 mg twice daily to achieve trough drug levels of 100–150 ng/mL, prednisone 5 mg/day and trimethoprim/sulfamethoxazole three times weekly. He returned to the transplant clinic in September 1999 with an aspartate aminotransferase (AST) level of 159 IU/L [normal range (NR) < 60 IU/L], alanine aminotransferase (ALT) of 260 IU/L (NR < 60 IU/L), alkaline phosphatase level of 829 IU/L (NR 30–120 IU/L), and bilirubin of 1.6 mg/dL (NR < 1.4 mg/dL). Liver biopsy suggested recurrent PSC without evidence of acute or chronic rejection. Percutaneous transhepatic cholangiography (PTC) demonstrated multiple strictures with areas of dilatation and beading within the intrahepatic biliary tree. A percutaneous biliary drain (PBD) was placed across a hilar stricture (Figure 1A). The biliary anastomosis however, was patent. Ursodeoxycholic acid (900 mg/day) was added to his medication regimen with improvement in his AST, ALT and alkaline phosphatase activity to 33 IU/L, 36 IU/L and 349 IU/L, respectively.

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Figure 1. (A) Percutaneous transhepatic cholangiography demonstrating multiple strictures within the liver consistent with recurrent primary sclerosing cholangitis. A dominant stricture ([RIGHTWARDS ARROW]) is seen at the common hepatic duct level. (B) Cholangiography performed 9 months following (A) demonstrating multiple small stenoses involving all the bile ducts and progressive occlusion at the common hepatic duct level ([RIGHTWARDS ARROW]). This dominant lesion now has the appearance of cholangiocarcinoma.

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In October 1999 he complained of diarrhea in conjunction with weight loss of 5 lbs. Colonoscopy was performed, which showed no evidence of colitis or dysplasia on biopsy. However, he continued to have continued weight loss (approximately 10 lbs over a period of 4 months). A computed tomography (CT) scan of the abdomen revealed no significant abnormality. By this time, he also complained of intermittent fevers and night sweats and admitted to periods of intermittent jaundice. He was placed on rotating antibiotic therapy (ciprofloxacin alternating with amoxicillin/clavulanate) and was re-listed for LT with recurrent PSC complicated by infective cholangitis as the indication for transplant.

His symptoms abated but after a further period of 6 months, his AST, ALT and alkaline phosphatase were 97 IU/L, 107 IU/L and 609 IU/L, respectively. A CT scan of the abdomen showed a 2 × 2-cm low-attenuation hepatic parenchymal lesion adjacent to the bifurcation of the left and right intrahepatic ducts (Figure 2). A positron emission tomography (PET) scan showed a small hypermetabolic focus corresponding to the anatomic location of the low attenuation seen on the CT scan (Figure 3). These findings were considered consistent with a hypermetabolic tumor. A PTC was performed and a tight stricture was noted at the biliary confluence consistent with CCA (Figure 1B). A PBD was inserted across the stricture and biliary brushings obtained. These showed markedly atypical ductal epithelium consistent with adenocarcinoma (Figure 4). Carbohydrate antigen 19–9 levels were normal.

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Figure 2. Computed tomography demonstrating intrahepatic biliary ductal dilatation, findings consistent with stricture. There is a 2 × 2-cm low-attenuation hepatic parenchymal lesion adjacent to the bifurcation of the left and right intrahepatic bile ducts ([RIGHTWARDS ARROW]). This finding is consistent with cholangiocarcinoma.

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image

Figure 3. Small focus of intense hypermetabolism ([RIGHTWARDS ARROW]) on a positron emission tomography scan (significantly greater than that of surrounding normal liver) corresponds exactly to the anatomic location of the low-attenuation lesion, seen on computed tomography at the junction of the right and left hepatic ducts. No other abnormal hypermetabolic foci are demonstrated from the abdomen through the mid pelvis. This finding is consistent with cholangiocarcinoma.

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image

Figure 4. Brush cytology from common hepatic duct stricture demonstrating clusters of large pleomorphic cells with irregular nuclear membranes, high nuclear to cytoplasmic ratio, and coarse, irregular chromatin. These findings are diagnostic of malignancy and support the clinical impression of cholangiocarcinoma.

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Following the diagnosis of cholangiocarcinoma, the patient had repeated PBDs placed and completed experimental radio-chemotherapy according to an established protocol (10). Briefly, this included external-beam irradiation and bolus fluorouracil (5-FU), followed by brachytherapy with iridium and a continuous 5-FU infusion until the time of transplant. Exploratory laparotomy revealed no metastatic disease and a repeat CT scan showed improvement in radiological appearance following radio-chemotherapy (Figure 5). He was re-transplanted in October 2001. Careful examination of the explanted liver showed extensive fibrosis around large ducts at the hilum and necrotic tumor, but no evidence of viable CCA was noted.

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Figure 5. Computed tomography of the liver following 4 months of radio-chemotherapy demonstrating interval insertion of a percutaneous biliary drain and less intrahepatic biliary ductal dilatation. The previously seen low-attenuation hepatic parenchymal lesion adjacent to the bifurcation of the left and right intrahepatic bile ducts is less apparent than before ([RIGHTWARDS ARROW]), suggesting tumor regression.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

Liver transplantation alone for unresectable CCA is associated with early disease relapse and poor survival. Because of these discouraging results, most programs have abandoned LT as primary therapy for CCA (11). In natural history studies, the reported frequency of CCA in patients with PSC has ranged between 6% and 11% (12–16). The occurrence of CCA is unpredictable and is often difficult to diagnose. Even in highly selected series, occult or known CCA has been identified in up to 36% of patients undergoing liver transplantation for PSC (4, 11). On the other hand, liver transplantation for PSC without CCA results in excellent patient survival rates (1–9). Although graft failure has been reported in these patients because of recurrent disease, this is the first report of de-novo development of CCA in a patient transplanted for PSC who did not have CCA pretransplant.

Recurrent PSC after transplant is difficult to define and is based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients (7). In one large series, PSC recurrence was found in 20% of patients transplanted for this indication (7). Of these, 22/24 patients showed characteristic features of PSC on cholangiography whereas 11/24 had compatible hepatic histologic abnormalities. Cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. In this case, the diagnosis of recurrent PSC was made on both histologic and radiologic grounds, and all other potential causes of nonanastomotic biliary stricturing were excluded. Until this report, it has been suggested that the consequences of recurrent PSC are benign (4). The development of CCA in this case however, illustrates the importance of long-term follow up in liver allograft recipients in general.

For patients with PSC, no obvious factors are apparent in predisposing towards recurrent disease post-transplant (1–9). Immunosuppression has however, been implicated in the increased incidence of dysplasia and carcinoma in the colon of patients transplanted for PSC with concomitant ulcerative colitis (17). Dysplasia has been noted in the intrahepatic bile ducts both near and remote from CCA foci in the liver and also from the chronically inflamed biliary tree. This histologic lesion shows both telomerase and increased proliferative activities (18). For patients with recurrent PSC in the context of chronic immunosuppression therapy, the consequences of dysplasia would be more severe and although a dysplasia/carcinoma sequence was not tested in this case, it is likely that this was the sequence of events leading to CCA.

A further important consideration in this case is the recent report of bile duct cancer arising de novo, late after surgery in patients who had undergone biliary-enteric surgical procedures for benign disease (19). In a large retrospective study, CCA developed in 5.5% of 1003 patients who had undergone either choledochoduodenostomy, trans-duodenal sphincteroplasty or hepatico-jejunostomy. Onset of CCA occurred between 11 and 19 years following surgery and was most likely to occur in patients who developed cholangitis (19).

This case raises several issues in the management of patients with recurrent PSC post-transplant. First, it illustrates the need not only to confirm the diagnosis histologically, but also to perform cholangiography to evaluate the biliary tree for areas of focal stricturing. Second, where focal or dominant stricturing arises as a consequence of recurrent disease, it is important to obtain brushings to examine for the presence of dysplasia or early CCA. Third, it raises the issue of how to screen patients for CCA in patients with severe recurrent PSC, and also other transplant recipients who have had a hepatico-jejunostomy fashioned to improve their biliary drainage. For patients with PSC in the nontransplant setting, various strategies have been suggested to clarify this issue (20). However, none have 100% sensitivity or specificity. Although, it is difficult to advocate large-scale screening for CCA in all patients transplanted for PSC, it may be appropriate to screen patients with histologic or cholangiographic evidence of disease recurrence or with recurrent infective cholangitis. Lastly, an awareness about the potential for de-novo CCA development is warranted, as re-transplantation for severe PSC recurrence should be considered sooner rather than later.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

MAH is the recipient of an American Association for the Study of Liver Diseases (AASLD) advanced liver fellowship award and an American Digestive Health Foundation (ADHF) TAP Pharmaceuticals Outcomes Research award. DCR is the recipient of a Burroughs Welcome Foundation Clinical Scientist award.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References
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