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Department of Pathology Case of the Month May 2002 38-year old man with jaundice, intense pruritus and dark urine Allison Miller, W. W. L. Chang M.D., Ph.D
Final Diagnosis
Discussion Primary sclerosing cholangitis (PSC) is a biliary destructive disease of unknown etiology, characterized by inflammation and fibrosis of the intra- and extra-hepatic bile ducts. It often occurs in association with inflammatory bowel disease (IBD). In one series, IBD was present in 71% (47/66) of patients with PSC: 59% with ulcerative colitis and 12% with Crohn’s disease. In a multicenter study (n=117), IBD was found in 54% of symptomatic PSC patients, and ulcerative colitis was 36% of total. In a series of patients with Crohn’s disease (n=102), the prevalence of PSC was 9%, and all PSC patients had large-bowel involvement. PSC has two types: large duct classic type and small duct type. The large duct classic PSC manifests more advanced clinical stage than the small duct PSC. It was noted that patients with PSC and Crohn’s disease had a milder liver disease than patients with PSC and ulcerative colitis, perhaps because large-duct PSC was less common in patients with Crohn’s disease. In the current case, PSC was of large duct classic type and led to a rapid clinical deterioration. Although ultrasound, CT scan, and MR cholangiography disclose bile duct changes, ERCP reveals characteristic features of irregular beadings and strictures diagnostic of PSC. On the other hand, the histologic features of the liver biopsy are variable and often non-specific, seemingly due to a sampling problem. A long-standing, large duct classic PSC leads to secondary biliary cirrhosis. Bile lakes and bile infarcts are anticipated complications. However, the most serious complication of PSC is the development of cholangiocarcinoma (CCA), as the median survival time following the diagnosis of CCA was 5-7 months. The prevalence of CCA in PSC ranges from 4 to 20%. PSC patients who developed CCA had a higher incidence of IBD, particularly ulcerative colitis. CCA might develop concurrently with PSC or within months of the diagnosis of PSC. In one series, the diagnosis of PSC was made coincident with the diagnosis of CCA in 12 out of 25 patients (48%), and was preceded it by a mean of 62 months in the remaining 13 patients. The early diagnosis of CCA in patients with PSC is needed, because for patients with a single tumor within the liver and negative nodes, complete resection is curative, or liver transplantation may give a promising outcome. The diagnosis of CCA in PSC requires a high index of suspicion because endoscopic brush cytology and/or biopsies and imaging studies are often negative for malignancy. Positron emission tomography (PET) is a promising imaging modality for the diagnosis of CCA, even in patients with PSC. Early studies suggest that this technique is sensitive in identifying small bile duct cancers. On the other hand, serum carcinoembryonic antigen (CEA) and CA19-9, although not specific, are of diagnostic value. Serological screening with a calculated index based on CEA and CA19-9 (CEA x 40 + CA19-9) equal to or greater 400 units was shown to be 86% accurate in detecting CCA. Furthermore, p53 protein overexpression, K-ras oncogene mutation, and p16 gene mutation have been reported in CCA specimens of PSC patients but not in liver tissue from PSC patients without CCA. Approximately 60-80% of CCA occurs in the perihilar region of the liver and others are intrahepatic or distal. As in 1965 Klatskin reported 13 cases of cancers involving the perihilar region, perihilar CCA has been designated as Klatskin’s tumor. The latter often involves major portal vascular structures, and thus surgical resection of the tumor is difficult. Total hepatectomy and liver transplantation have been advocated, but the results of liver transplantation for patients with clinically apparent CCA were extremely poor. However, in patients in whom a microscopic tumor was detected in the explanted liver, survival was similar to those transplanted with PSC without CCA (5-year survival rate being better than 85%). The general recommendation is that liver transplantation should be restricted to patients with single tumors confined to the liver and without lymph node metastasis.
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