A 44-year-old native woman was admitted to our hospital for right upper quadrant discomfort and jaundice in July 2006. The patient had been healthy until 4 months prior to admission when upper abdominal pain of unknown origin first began; at that time, icteric eyes and skin with darkened urine were noted. She felt somewhat nauseous but did not vomit. There was no fever, cough, headache, diarrhea or other mental or physical complaints. Despite taking ursodeoxycholic acid capsules prescribed by her primary care provider for 20 days, she still felt malaise with no improvement in her symptoms. Three days prior to this hospitalization, she experienced a sudden onset of colicky pain in the stomach and back. The patient's past medical history and family history were unremarkable, and she had not been exposed to any drugs, toxins, or blood products. She had been a rural resident until marriage as an adult and resided in town. She had been in a monogamous relationship with her husband for more than 20 years and had no risk factors for HIV infection.
On physical examination, she was a well-developed woman with a body weight of 54 kg (body mass index: 20.6 kg/m2), although she had lost 10 kg over the last 4 months. Her vital signs were stable and within normal limits, and no positive physical exam findings except scleral icterus were present. Her complete blood count, coagulation factors, erythrocyte sedimentation rate, serum immunoglobulin, CEA, AFP and CA125 were normal, whereas anti-hepatitis viruses (A-E), anti-HIV and abnormal autoimmune antibodies were negative. Urine and stool tests were consistent with obstructive jaundice. The liver function tests and CA19-9 results are summarized in Table 1. Moreover, the flow cytometry lymphocyte subpopulations were normal at 49% CD3+, 21% CD4+, 23.4% CD8+, and 19.5% natural killer cells (TBNKTM, Latonia, KY). Her chest CT, gastroscopy and colonoscopy demonstrated no abnormalities, although abdominal ultrasonography revealed extra- and intrahepatic biliary dilatation. The outer CBD diameter was dilated to 16.1 mm as its maximum, but the lumen was narrowed to almost zero due to an irregular thickened wall (7.4 mm at its maximum). No findings that were consistent with bile duct calculus, liver neoplasm or cirrhosis were identified. Furthermore, an abdominal contrast-enhanced CT scan and an MRCP produced similar findings, i.e., a hilar biliary stricture with no evidence of abdominal masses or lymphadenopathy (Fig. 1). Accordingly, an ERCP was performed, which revealed an isolated irregular proximal CBD stricture with dilated intrahepatic biliary trees and no duodenal or ampullary tumors as well as negative brush cytology (Fig. 2A). After a multidisciplinary consultation with the gastroenterologists, radiologists and oncologists, a consensus diagnosis of primary sclerosing cholangitis rather than cholangiocarcinoma was made, partly due to the lack of malignant features consistent with cholangiocarcinoma in all of the medical images. Thus, the patient was transferred to the Gastroenterology Dept. and received a conventional diagnostic plan of glucocorticoid-free treatment. Unfortunately, within the first week posterior to the ERCP, her hyperbilirubinemia worsened, with TBil and DBil increasing to 203.5 mumol/L and 123.1 mumol/L, respectively. At that time, a repeat MRCP revealed a more indistinct biliary bifurcation and CHD, which was pathognomonic for malignancy (Fig. 1F). Therefore, a hepatic hilar cholangiocarcinoma (Klatskin tumor) emerged as the new presumptive diagnosis, and thus, an exploratory laparotomy was scheduled after comprehensive consent was obtained.
Intraoperatively, the liver was noted to be tough, green-brown in color, of generally normal size and without any masses or perihepatic enlarged lymph nodes. Thickened walls of the cystic duct, CHD, proximal CBD and initial part of the bilateral hepatic ducts were detected and ranged from 0.5-1.0 cm, which consequently narrowed the bile channels. Upon choledochotomy, packed gelatin-like exudates were found inside the lumen, and thus, a flexible choledochoscopy was performed, the results of which supported the above findings. The gallbladder and a strip of the morbid CBD were removed and submitted for frozen section pathological examination. Both samples demonstrated inflammatory granulomas with round refractive corpuscles based on hematoxylin-eosin staining. Therefore, the diagnosis of biliary cryptococcosis was made, and only T-tube drainage was performed.
Next, following the operation, the blood, bile, sputum, CSF, urine and stool samples were cultured simultaneously with ink staining at least in triplicate. All samples were negative for Cryptococcus, but the final paraffin pathology of the intraoperative biliary samples confirmed the definite diagnosis. Microscopic examination demonstrated numerous encapsulated yeast-like organisms measuring 7-10 mum in diameter scattered in multinucleated giant cells and fibrous tissues throughout the CBD and gallbladder wall. The periodic acid methenamine silver stain, periodic acid Schiff stain and India ink stain were all positive (Fig. 4), whereas the pathogen identified by polymerase chain reaction from the paraffin-embedded gallbladder was Cryptococcus neoformans (VNI type1). As soon as she completed an uneventful recovery, she was transferred to the Gastroenterology Dept. again for anti-fungal therapy (beginning on POD11), an itraconazole regimen consisting of 2 weeks of inpatient intravenous injections (Sporanox  IV, Xian-Janssen Pharmaceutical Ltd., Beijing, China) followed by 10 weeks of per os outpatient therapy (Sporanox  Capsule). At two weeks after discharge (i.e., 4 weeks after starting the therapy), her transaminases had returned to normal levels, whereas TBil/DBil levels normalized after an additional 4 weeks. Moreover, her T-tube was removed after a cholangiography (Fig. 2B).
During her follow-ups, she appeared to have some occasional abdominal discomfort, mainly in the right upper quadrant, but no jaundice. Regular repeat abdominal ultrasonographies revealed no extra- or intrahepatic biliary dilatation, and the thickness of CBD wall dropped to 2.2 mm (April 2009).
Unexpectedly, more than 4 years after her original presentation (September 2010), she was re-hospitalized for hyperbilirubinemia. Similar to the first admission, her examination was otherwise normal, and all body fluids were negative for Cryptococcus. The liver function test results from this presentation are listed in Table 1. Radiologic exams at this time revealed a thickened CBD wall, narrow CBD lumen and moderately dilated intrahepatic bile ducts, which were also similar to but slightly less severe than her initial presentation (Fig. 3). Instead of an ERCP, an EUS was performed; it demonstrated a benign change of her CBD entirely from the hilar bifurcation to the duodenal ampulla. A cholangioenterostomy was under deliberation; however, her icterus gradually and spontaneously vanished. By the 14th inpatient day, the patient had recovered and was again discharged. As of the time of this writing, another 16 months of follow-up have passed with no abnormalities detected.