*Department of Pediatrics, USA
†Department of Internal Medicine, Division of Gastroenterology, USA
‡Department of Surgery, Section on Transplantation, USA
§Department of Pathology, University of Utah and Primary Children's Medical Center, Salt Lake City, USA.
Received 30 October, 2009
Accepted 19 April, 2010
Address correspondence and reprint requests to Stephen L. Guthery, MD, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Utah and Primary Children's Medical Center, Salt Lake City UT 84113 (e-mail: Stephen.Guthery@hsc.utah.edu).
The authors report no conflicts of interest.
Cholangiocarcinoma (CCA) is a known complication of primary sclerosing cholangitis (PSC) in adults. We describe a young patient who developed CCA 3 years after diagnosis of inflammatory bowel disease (IBD) and PSC. We describe the use of molecular marker techniques for diagnosis, and neoadjuvant cytoreductive therapy and orthotopic liver transplantation for therapy.
The patient first presented at age 14 with 2 days of jaundice, fever, dyspnea, and chest and abdominal pain. He also complained of several months of nonbloody, watery diarrhea up to 9 times per day and fecal urgency both day and night, often waking him from sleep. This was unrelieved by daily loperamide and a prescribed course of empiric metronidazole. Medical and family histories were unremarkable. He was febrile, tachycardic, tachypneic, and mildly hypoxemic. Physical examination demonstrated jaundice with scleral icterus. He had a soft but tender abdomen with prominent splenomegaly. Breathing was labored with retractions, but the lungs were clear to auscultation.
Initial laboratory studies revealed cholestasis, elevated transaminases, low albumin, leukocytosis, and a normal coagulation profile (Table 1). C-reactive protein and erythrocyte sedimentation rate were elevated and stool was positive for occult blood. Magnetic resonance cholangiopancreatography demonstrated an irregular and narrowed common hepatic duct, without biliary dilatation, cystic lesions, and intrahepatic mass. Liver biopsy revealed bile duct proliferation and periductular fibrosis consistent with PSC and without findings of overlap (Fig. 1). Anti-nuclear antibody and smooth muscle antibody were negative. Anti-nuclear cytoplasmic antibody was present in a 1:512 titer with peripheral staining pattern. Endoscopic retrograde cholangiopancreatography (ERCP) was not obtained at this time because clinical, radiographic, and histological findings were consistent with PSC and there was no biliary ductal dilatation on magnetic resonance imaging.
Stool culture and Clostridium difficile cytotoxins were negative. Colonoscopy revealed regionally distributed inflammation and friable mucosa throughout the colon, with rectal sparing. A biopsy showed transmucosal chronic inflammatory cells, moderate crypt architectural distortion, crypt abscesses, and no granulomas. His colonoscopic, histological, and radiographic findings were most consistent with the chronic IBD described in conjunction with PSC (1).
A chest computed tomography (CT) revealed several 1- to 2.5-cm pulmonary nodules (Fig. 2A). Purified protein derivative was negative. Serum antibodies for coccidioides, histoplasmosis, and blastomyces were negative. Thoracoscopic biopsy demonstrated suppurative necrosis with rare multinucleated giant cells (Fig. 2B). Tissue culture and tissue stains were negative for bacteria, fungi, and acid-fast bacilli. Similar findings have been previously described in conjunction with IBD (2–4).
Subsequently, he underwent successful induction therapy with glucocorticoids and mesalamine, and was discharged. Approximately 3 months after initial diagnosis, he developed an exacerbation of his IBD, and azathioprine was added. For the next 24 months, his intestinal symptoms remained under relative control with only intermittent courses of prednisone. His cholestasis rapidly resolved, weight gain improved, and his pulmonary nodules were improved on repeat CT.
Eighteen months after presentation, cholestasis recurred with a direct bilirubin of 1.8 mg/dL. He underwent an ERCP, which demonstrated a normal mid and distal common bile duct, and normal filling of the cystic duct and gallbladder (Fig. 3). There was diffuse and patchy stricturing of the intrahepatic and proximal extrahepatic bile ducts. There was an area of mild dilatation of the main left intrahepatic duct with a mild to moderate distal stricture that was easily transversed with a 9-mm balloon and with minimal resistance. No dominant strictures were apparent. Cytology was negative for malignancy.
Two years 5 months after initial presentation, he had a worsening of diarrhea and abdominal pain, along with a mild cholestasis. Ultrasound showed a common bile duct measuring 2.2 mm, without dilatation. Repeat colonoscopy demonstrated persistent continuous colitis with rectal sparing. Chest CT demonstrated recurrent pulmonary nodules, and a repeat thoracoscopic biopsy confirmed necrobiotic nodules. Because of active disease, poor linear growth, no evidence for noncompliance, and a maximal dose of azathioprine, infliximab was started. His symptoms improved with an induction course.
Two years 8 months after initial presentation, jaundice recurred in the setting of abdominal pain and a 10-lb unintentional weight loss. CA19–9 was 166 U/mL and remained elevated serially, with a high of 326. Serum α-fetoprotein and human chorionic gonadotropin were negative. An ERCP was repeated, again demonstrating intrahepatic ductal strictures and dilatations consistent with PSC. Proximal to the bifurcation of the left intrahepatic bile duct there was a 1-cm area of focal irregularity (Fig. 4). Biliary cytology was obtained form this area using 2 separate brushes. Biliary cytology showed reactive cellular changes in a background of marked acute inflammation but was negative for malignancy. Digital image analysis could not be performed due to scant sample cellularity. Fluorescence in situ hybridization (FISH) was suspicious for malignancy, with >2 copies of chromosomes 3, 7, and 17 in at least 5 cells. One month later he required a biliary stent, which significantly improved his pain and cholestasis.
Despite his young age, the suspicion for CCA was high. Under an investigative protocol (ClinicalTrials.gov NCT00708877), he was given percutaneous biliary intubation and received external beam radiation in conjunction with a radiosensitizing dose of 5-fluorouracil. This was followed by a transcatheter brachytherapy boost with iridium-192 and administration of oral capecitabine. Subsequently, he underwent staging exploratory laparotomy followed by orthotopic liver transplantation. The patient's hepatic explant demonstrated a CCA measuring 2.3 cm (Fig. 5) and mixed-nodular cirrhosis. His explant demonstrated no choledochal cyst. The patient is well 2 years after transplantation.
CCA is most commonly diagnosed in the late eighth decade of life (5,6). It is exceedingly rare before adulthood. CCA in childhood has been reported in association with HIV infection (7), with biliary atresia (8), following radiation therapy (9), as a sequela of a choledochal cyst (10,11), and with CD40 ligand deficiency (12). An 18-year-old with CCA and long-standing PSC has been reported (13). Risk factors for CCA include PSC, older age, cigarette smoking, and alcohol consumption (14–18). Only PSC as a risk factor was present in this patient.
This patient's case is notable for several reasons. First, molecular diagnostics were used to make the diagnosis of CCA. Second, neoadjuvant therapy plus orthotopic liver transplantation was used for therapy under an investigative protocol. This patient's recurrence of jaundice was abrupt in the context of abdominal pain, weight loss, a newly detected dominant stricture, and CA19–9 that was persistently >100 U/mL. These clinical features alone were concerning for CCA; however, the worsening of PSC may have explained his clinical picture. Furthermore, the positive predictive value of an elevated CA19–9 for CCA is variable (19,20), and levels may fluctuate even among individual patients with PSC over time (21). Thus, the elevated CA19–9 was difficult to interpret. However, cholangiography with biliary brushing and subsequent FISH demonstrated chromosomal abnormalities in chromosomes 3, 7, and 17. In this clinical scenario, the reported sensitivity and specificity for CCA are 85% and 80%, respectively, with a positive predictive value of 79% (19). Given his rapidly progressing PSC, which would likely require transplantation in the near future, the low morbidity associated with the protocol's cytoreductive therapy, and the bleak outcome of CCA without treatment, we elected to enroll this patient in a trial of liver transplantation for CCA.
In patients with PSC in whom CCA develops, prognosis and therapy are dependent on whether the tumor is surgically resectable. In patients with unresectable CCA, the prognosis is dismal, with a median survival of 9 to 12 months (22). For patients with tumors amenable to resection, recent data suggest that neoadjuvant therapy plus liver transplantation is superior to surgical resection alone (23). Studies consider patients eligible for liver transplantation if they have nonmetastatic disease based on imaging studies and exploratory laparotomy, have no preexisting cancers (except cervical or skin cancers), have no comorbidities contraindicating transplantation, and have no tumor extending below the cystic duct. Neoadjuvant therapies include external beam radiation, 5-fluorouracil, brachytherapy with iridium-192, and oral capecitabine until transplantation. This therapy is generally well tolerated, with reported adverse events consisting of mild nausea and/or vomiting, myelosuppression, and infectious complications related to catheter placement (24). Among 65 patients undergoing neoadjuvant therapy plus liver transplantation, the 1- and 5-year survival was 91% and 76%, respectively (25).
This report highlights that age alone does not preclude a diagnosis of CCA in young patients with PSC, and pediatricians caring for patients with PSC must be aware of the evolving strategies for the detection and treatment of CCA. Molecular markers such as FISH may improve substantially the ability to distinguish malignant from nonmalignant biliary strictures in patients with PSC, and neoadjuvant therapy plus liver transplantation may improve survival of patients with CCA.
1. Loftus EV, Harewood GC, Loftus CG, et al
. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54:91–96.
2. Camus P, Colby TV. The lung in inflammatory bowel disease. Eur Respir J 2000; 15:5–10.
3. Camus P, Piard F, Ashcroft T, et al
. The lung in inflammatory bowel disease. Medicine (Baltimore) 1993; 72:151–183.
4. Casey MB, Tazelaar HD, Myers JL, et al
. Noninfectious lung pathology in patients with Crohn's disease. Am J Surg Pathol 2003; 27:213–219.
5. Shaib YH, El-Serag HB, Davila JA, et al
. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 2005; 128:620–626.
6. Welzel TM, Graubard BI, El-Serag HB, et al
. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 2007; 5:1221–1228.
7. Mangeya N, Mafukidze AT, Pascoe M, et al
. Cholangiocarcinoma presenting in an adolescent with vertically acquired HIV infection. Int J STD AIDS 2008; 19:717–718.
8. Kulkarni PB, Beatty E. Cholangiocarcinoma associated with biliary cirrhosis due to congenital biliary atresia. Am J Dis Child 1977; 131:442–444.
9. Cunningham JJ. Cholangiocarcinoma occurring after childhood radiotherapy for Wilm's tumor. Hepatogastroenterology 1990; 37:395–397.
10. Bismuth H, Krissat J. Choledochal cystic malignancies. Ann Oncol 1999; 10(Suppl 4):94–98.
11. Tanaka S, Kubota M, Yagi M, et al
. An 11-year-old male patient demonstrating cholangiocarcinoma associated with congenital biliary dilatation. J Pediatr Surg 2006; 41:e15–e19.
12. Hayward AR, Levy J, Facchetti F, et al
. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol 1997; 158:977–983.
13. Björnsson E, Angulo P. Cholangiocarcinoma in young individuals with and without primary sclerosing cholangitis. Am J Gastroenterol 2007; 102:1677–1682.
14. Broomé U, Olsson R, Lööf L, et al
. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996; 38:610–615.
15. Tischendorf JJ, Hecker H, Kruger M, et al. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol
16. Bergquist A, Glaumann H, Persson B, et al
. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 1998; 27:311–316.
17. de Groen PC. Cholangiocarcinoma in primary sclerosing cholangitis: who is at risk and how do we screen? Hepatology
18. Rosen CB, Nagorney DM, Wiesner RH, et al
. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 1991; 213:21–25.
19. Charatcharoenwitthaya P, Enders FB, Halling KC, et al
. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008; 48:1106–1117.
20. Levy C, Lymp J, Angulo P, et al
. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005; 50:1734–1740.
21. Bjornsson E, Kilander A, Olsson R. CA 19-9 and CEA are unreliable markers for cholangiocarcinoma in patients with primary sclerosing cholangitis. Liver 1999; 19:501–508.
22. Tischendorf JJ, Geier A, Trautwein C. Current diagnosis and management of primary sclerosing cholangitis. Liver Transpl 2008; 14:735–746.
23. Rea DJ, Heimbach JK, Rosen CB, et al
. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005; 242:451–461.
24. De Vreede I, Steers JL, Burch PA, et al
. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000; 6:309–316.
25. Heimbach JK, Gores GJ, Haddock MG, et al
. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006; 82:1703–1707.