Nov. 20, 2021
Perihilar cholangiocarcinoma is a small tumor that can cause big problems for patients. According to Julie K. Heimbach, M.D., transplant surgeon at Mayo Clinic in Rochester, Minnesota, these tumors exist in the bile ducts leading out of the liver, which are very high-stakes real estate. An artery, portal vein and the bile duct run through this area. Even though these tumors can be relatively small, they may obstruct key structures, making complete resection difficult while still preserving adequate blood supply into the liver and bile outflow from the liver.
Cholangiocarcinoma is classified according to location (intrahepatic, perihilar, and distal), and perihilar is the most common form. In many cases, these tumors are found to be unresectable at the time of presentation. Initially, physicians tried isolated liver transplant in order to improve the chance to attain a complete resection, but had negative results primarily due to high disease recurrence. It was recognized that some patients who had radiation therapy seemed to have prolonged disease-free survival, although many ultimately had progressive liver damage from the radiation.
In 1993, the liver transplant team at Mayo Clinic in Minnesota partnered with their colleagues in radiation and medical oncology to combine radiation and liver transplant for highly selected patients with early stage unresectable perihilar cholangiocarcinoma using neoadjuvant chemoradiation followed by liver transplantation. Physicians at Mayo Clinic have completed more than 200 liver transplants following this protocol and it is available at all three Mayo Clinic locations.
"We have developed quite an experience with this," said Dr. Heimbach. "It's definitely a challenging tumor to manage on many levels. We keep pushing to move the field forward."
Stringent selection drives protocol forward
According to a 2020 article published in the Journal of Gastrointestinal Surgery, the diagnostic criteria for this protocol at Mayo Clinic requires the presence of a malignant-appearing stricture on the cholangiography with at least one of the following:
- Endoscopic intraluminal brushings or tissue biopsy that is positive or strongly suspicious of cholangiocarcinoma
- A CA 19-9 level greater than 100 U/ml in the absence of acute bacterial cholangitis
- Polysomy by fluorescence in situ hybridization or a well-defined mass on a cross-sectional imaging at the site of the malignant-appearing structure
Patients with metastatic disease, irradiation of the abdomen precluding additional radiation or a previous attempt at surgical resection are excluded.
Once a patient is selected as a candidate, they begin neoadjuvant chemoradiation therapy including external beam therapy, high-dose brachytherapy and oral capecitabine. All patients then undergo operative staging as close to the time of transplant as possible to ensure the tumor has remained localized to the bile duct.
There is a sweet spot in the timing of transplantation following neoadjuvant therapy, although researchers are still learning exactly what that window is. If a patient receives a transplant too early, biologically aggressive tumors might be missed, putting the patient at greater risk for recurrence following surgery. Additionally, there may be ongoing inflammation from the treatment. If a patient waits too long for a transplant, however, the malignancy or underlying liver disease may progress and the patient can suffer complications from the therapy. Physicians are learning more about this ideal timeframe as more patients are treated with this protocol.
Volume empowers positive outcomes
This protocol is being adopted more widely around the world, but it is a technically challenging procedure that takes a large team working collaboratively toward success. It is designed specifically for perihilar cholangiocarcinoma and experience in that area truly does make a difference in outcomes. In fact, a 2020 study published in the Annals of Surgical Oncology from a group at Henry Ford Medical Center found that post-transplant outcomes were significantly better at centers that had performed more than six liver transplants for perihilar cholangiocarcinoma than at centers that had performed fewer of the same procedure.
Early detection and being aware of transplantation as a treatment option are key to success in this protocol. It can be very difficult to get a good sample of this type of tumor because of its size and location. Physicians at Mayo Clinic can support patients throughout the process and follow the patient until the diagnosis is clear either by attaining a tissue diagnosis by repeat endoscopic retrograde cholangiopancreatography, or by a combination of imaging characteristics combined with biomarkers, fluorescent in-situ hybridization (FISH) on cytology and clinical findings. It is not required to attain a definitive tissue diagnosis before referring a patient to physicians at Mayo Clinic. Throughout this process, it's important to avoid a transperitoneal biopsy, which can disseminate the tumor making the patient ineligible for transplant.
For more information
Tan EK, et al. Liver transplantation for peri-hilar cholangiocarcinoma. Journal of Gastrointestinal Surgery. 2020; 24:2679.
Kitajima T, et al. Center experience affects liver transplant outcomes in patients with hilar cholangiocarcinoma. Annals of Surgical Oncology. 2020;27:5209.