Today, available therapies for hilar cholangiocarcinomas (CCA) are not satisfactory. Although these tumors are rare, their study is important because of the high death rates in afflicted patients, rivaling that of pancreatic cancer. Surgical resection offers the only current hope for long-term survival, averaging only 20% in major series1. The reality is such that for the majority of patients, CCA is a diagnosis of despair.

Although surgery has offered the only hope of cure, one of the major limiting factors in achieving long-term survival following surgical resection of CCA is the technical ability to achieve negative resection margins. The presence of malignant cells at the surgical margins following resection is a major prognostic factor predicting recurrence and death1. Theoretically, the likelihood of achieving negative margins can be increased with total hepatectomy and orthotopic liver transplantation (OLT). Previous experience with OLT performed in isolation for hilar CCA's has been discouraging with dismal survival rates27-30 . However, a recent report has demonstrated that long-term survival can occur in carefully selected patients by combining the benefits of radiotherapy, chemosensitization, and OLT31. With this strategy, patients survival rates of 92%, 82%, and 82% at 1, 3, and 5 years after transplantation have been achieved31. It is not clear that these preliminary results can be confirmed at other centers, nor is it clear what selection criteria should optimally be used for this treatment strategy.

Natural History Protocol:

We will investigate the additional hypothesis that a sequence of events occurs in the biliary epithelium as it progresses from normal histology to PSC to CCA, akin to the polyp-cancer sequence described in certain types of colorectal cancer32. Accordingly, we will examine resection specimens from patients undergoing liver resection for non-biliary tract malignancy; PSC patients undergoing diagnostic brushings, biliary aspirates, or biopsy; and liver biopsies obtained at operation in patients with inflammatory bowel disease. These will be compared to patients enrolled in the liver transplant protocol (see below) with a known, biopsy-proven diagnosis of cholangiocarcinoma. Finally, to study the effects of chronic bile exposure on the biliary epithelium, gene expression in the proximal biliary tree will be compared to more distal segments in those resection specimens obtained from patients with non-biliary tract malignancies.

Liver Transplant Protocol:

Our hypothesis is that select patients undergoing liver transplantation for CCA in the context of multi-modality neoadjuvant therapy exhibit survival equivalent to other established indications for liver transplantation as previously demonstrated31. We will also attempt to extend previously published criteria for liver transplantation in the setting of CCA by offering this protocol to patients with evidence of intrahepatic disease and regional nodal disease. Patients undergoing transplantation for CCA will be followed longitudinally for their entire post-transplant course and compared with a matched cohort of liver transplant recipients in regard to post-transplant survival, survival on the waiting list, as well as complications pre-and post-transplantation. Explanted livers will be examined for the presence of residual tumor.

Data will be collected on the rate of regional lymph node metastasis, invasion of adjacent organs and tissues, and the rate of peritoneal metastases. The rate of tumor recurrence, site, and time to recurrence will also be assessed.

Objectives

Natural History Study:

Specific Aim #1: By examining unique patterns of gene expression and immunohistochemistry, elucidate and describe the continuum of malignant transformation which may occur in normal biliary epithelium when it exhibits changes characteristic of PSC and ultimately CCA.

Specific Aim #2: Explore the hypothesis that the biliary epithelium of the hepatic ductal confluence is at higher risk for malignant transformation due to location and increased exposure to the irritant effects of chronic bile exposure.

Liver Transplant Study:

Specific Aim #3: Determine whether results obtained in select patients with American Joint Commission on Cancer (AJCC) Staging System Stage I or II CCA are transferable to select patients with T3 or N1 disease.

Specific Aim #4: To determine whether success achieved with the only published protocol currently in use is directly transferable to the University of Utah's liver transplant program.

Liver Transplant Protocol:

The surgical protocol will initially be offered to liver transplant candidates with de novo hilar CCA or CCA arising in the setting of PSC. Diagnosis of CCA will be established by intraluminal brush cytology, intraluminal biopsy, or a carcinoma antigen (CA) 19.9 level greater than 100 ng / mL in the setting of a radiographic malignant stricture. Biliary aneuploidy demonstrated with DIA and FISH will be considered equivalent to cytology.

All patients with CCA will be evaluated by the liver transplant team which includes experienced hepatobiliary and liver transplant surgeons. Patients will be presented at the weekly liver transplant selection conference to assess their candidacy as well as the weekly GI Multidisciplinary Tumor Conference at the Huntsman Cancer Institute. Clinical staging prior to neoadjuvant therapy will include chest and abdominal computed tomography, liver ultrasound, and bone scan. Patients will also undergo endoscopic ultrasound with fine needle aspiration of suspicious lymph nodes. Exclusion criteria will include previous chemotherapy or radiotherapy, uncontrolled infection, a previous malignance other than non-melanoma skin cancer or in situ cervical cancer within the last five years, medical conditions precluding transplantation, metastatic disease (including N2 disease), and patients with hilar tumors extending below the cystic duct.

All patients will undergo staging laparoscopy to rule out the presence of peritoneal disease followed by staging laparotomy. Patients with extrahepatic metastases, local spread of disease to adjacent organs, and N2 nodal disease (metastasis to peripancreatic, periduodenal, periportal, celiac, superior mesenteric, and / or posterior pancreaticoduodenal nodes) will be excluded as will patients with extension of tumor into the main portal vein. Patients with N1 disease (metastasis to lymph nodes within hepatoduodenal ligament) will remain eligible for the protocol. Tumor size will not be included in the exclusion criteria. Patients with evidence of disease progression beyond study criteria will not be eligible to continue on to liver transplantation.

Natural History Protocol:

Inclusion Criteria:

Subjects without cholangiocarcinoma that are not undergoing the liver transplant protocol will complete a different consent form from those in the liver transplant protocol.

• The protocol and consent for obtaining tissue in these subjects will be under the umbrella of IRB_00019568. We summarize both parts of the study in this protocol such that the reviewer can understand how each piece fits into the whole study schema.
• Patients harboring a diagnosis of PSC without evidence of malignancy will be enrolled as control patients for the comparison of immunohistochemistry and microarray data from their biliary aspirates or from biopsies performed for diagnostic purposes.
• A third group of patients will be enrolled who are undergoing liver resection for non-biliary tract malignancies (i.e. colorectal metastases) Additional patients will be enrolled who have been diagnosed with inflammatory bowel disease (Crohn's disease and ulcerative colitis) who will undergo surgical intervention for resection of diseased bowel or who will undergo creation of ileal-anal pouch procedures.
• Patients are eligible for the protocol once they have attained their sixteenth birthday. Patients will be excluded for medical co-morbidities that would preclude the use of general anesthesia. Pregnant patients and those patients hoping to become pregnant will not be eligible for the study.

Liver Transplant Protocol:

• The surgical protocol will initially be offered to liver transplant candidates with de novo hilar CCA or CCA arising in the setting of PSC. Diagnosis of CCA will be established by intraluminal brush cytology, intraluminal biopsy, or a carcinoma antigen (CA) 19.9 level greater than 100 ng / mL in the setting of a radiographic malignant stricture.
• Biliary aneuploidy demonstrated with DIA and FISH will be considered equivalent to cytology.
• All patients with CCA will be evaluated by the liver transplant team which includes experienced hepatobiliary and liver transplant surgeons. Patients will be presented at the weekly liver transplant selection conference to assess their candidacy as well as the weekly GI Multidisciplinary Tumor Conference at the Huntsman Cancer Institute. Clinical staging prior to neoadjuvant therapy will include chest and abdominal computed tomography, liver ultrasound, and bone scan. Patients will also undergo endoscopic ultrasound with fine needle aspiration of suspicious lymph nodes.

All patients will undergo staging laparoscopy to rule out the presence of peritoneal disease followed by staging laparotomy.

• Patients with N1 disease (metastasis to lymph nodes within hepatoduodenal ligament) will remain eligible for the protocol.

Tumor size will not be included in the exclusion criteria. Patients with evidence of disease progression beyond study criteria will not be eligible to continue on to liver transplantation.

** Patients with metastatic disease are not eligible for this trial **

Exclusion criteria will include:

• previous chemotherapy or radiotherapy,
• uncontrolled infection,
• a previous malignance other than non-melanoma skin cancer or in situ cervical cancer within the last five years,
• medical conditions precluding transplantation,
• metastatic disease (including N2 disease), and
• patients with hilar tumors extending below the cystic duct.

Patients with extrahepatic metastases, local spread of disease to adjacent organs, and N2 nodal disease (metastasis to peripancreatic, periduodenal, periportal, celiac, superior mesenteric, and / or posterior pancreaticoduodenal nodes) will be excluded as will patients with extension of tumor into the main portal vein.