There is a famous Korean saying: “After 10 years, even the mountains and rivers change.” This proverb poignantly captures the truth that reality shifts and what is here today may be gone tomorrow. 

However, apply this to medicine and this saying takes on a more hopeful tone. Every few years, significant breakthroughs in medicine do happen. In addition, we have teams of researchers who spend years researching a drug or testing a single theory; in time, a conclusion will be reached, impacting medicine one way or another. 

What does this mean when it comes to surgery? This is a broad overgeneralization, but there seems to be 2 types of surgeons: one likes to stick to the book as much as possible and the other believes their skills go beyond established procedure and is not afraid to occasionally test their own surgical theories on their patients. 

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Masato Nagino, MD, has written 2 papers on a surgeon’s perspective on perihilar cholangiocarcinoma a decade apart: one in 2012, and another in 2022. We will be examining whether any of his views on perihilar cholangiocarcinoma have changed, and which views have stood the test of time. 

Staging and Imaging Tools Evolve

First, the definition of perihilar cholangiocarcinoma. In his 2012 paper, Nagino defined perihilar cholangiocarcinomas as “tumors that are located in the extrahepatic biliary tree proximal to the origin of the cystic duct.”

There was an old debate whether perihilar and distal cholangiocarcinoma should be classified under the umbrella term of “extrahepatic bile duct cancers.” Nagino and others like him believed that a category of “perihilar cholangiocarcinoma” is beneficial from a diagnostic and treatment standpoint. In his 2022 study, Nagino repeated the definition of perihilar cholangiocarcinoma that he wrote in 2012. 

However, in terms of the staging of the disease, things have changed since a decade ago. In 2012, Nagino wrote, “The TNM staging system, widely used in the world, has become a universal rule; therefore, further refinement is essential.” In 2017, the most recent attempt to refine the definition of intrahepatic cholangiocarcinoma was undertaken by the American Joint Commission on Cancer (AJCC). In his later paper, Nagino wrote: “The most significant revision was that Bismuth type IV tumors were removed from the T4 determinants, so that the T4 stage is no longer linked to Bismuth type IV [perihilar cholangiocarcinoma].” 

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In 2012, radiological evaluation for liver cancer was not as sophisticated as it is today. Multi-detector-row computed tomography (MDCT) was seen to be the most important tool in diagnosing perihilar cholangiocarcinomas. 

Today, the MDCT retains its position as one of the most important tools for diagnosing perihilar cholangiocarcinomas. However, more refined imaging tools have become available, such as magnetic resonance imaging (MRI) coupled with magnetic resonance cholangiopancreatography (MRCP). Even positron emission tomography (PET) plays a role in the staging of perihilar cholangiocarcinomas.

“With evolution of cross-sectional imaging, the role of endoscopic retrograde cholangiopancreatography (ERCP) during preoperative workup has gradually evolved from a radiological diagnostic tool into an interventional procedure aimed at providing cytological specimens when pathological confirmation is required,” Nagino wrote in the 2022 report.

New Treatment Recommendations and Protocols

Another area that has undergone tremendous change is our knowledge of adjuvant chemotherapy for cholangiocarcinoma. In 2012, Nagino wrote, “Studies on adjuvant chemotherapy for cholangiocarcinomas are scarce.” Drugs such as gemcitabine and oxaliplatin were considered fairly new then. 

In his 2022 study, Nagino delved into some of the clinical trials on adjuvant chemotherapy and what had been discovered. One study found that fluorouracil and gemcitabine did not improve overall survival. Another trial indicated that adjuvant capecitabine improved overall survival and reference-free survival. Hence, many countries now recommend adjuvant capecitabine for 6 months following potentially curative resection for resected cholangiocarcinoma.

A different study demonstrated that fluoropyrimidine is more effective than gemcitabine or gemcitabine-combined therapy and that it may improve the survival of node-positive patients with perihilar cholangiocarcinoma. Another research team studying adjuvant S-1 chemotherapy found it to be a promising drug for node-positive biliary tract cancer. 

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The conflicting results from these clinical trials “have led to confusion in the biliary tract cancer medical community,” Nagino wrote. However, regardless of their outcomes, the very fact that these clinical trials have been conducted is important. It appears we still have not settled on the best adjuvant chemotherapy medication for patients with perihilar cholangiocarcinoma, if any of them indeed yield any benefit at all. 

Liver transplantation protocol has also become much more established since Nagino’s 2012 paper was published. At that time, successful transplantations were rarer, and the inclusion criteria were still being refined. Now we have the Mayo criteria, which state that good liver transplantation candidates have solitary tumors that are less than 3 cm in diameter; in addition, the patient must have no lymph node metastasis and have an unresectable tumor.

We conclude with Nagino’s take on what has changed in the last decade: “Surgical and oncological outcomes of [perihilar cholangiocarcinoma] have steadily improved, but there are still several issues to be resolved in the surgical treatment of [perihilar cholangiocarcinoma]. Further synergy of endoscopists, radiologists, oncologists, and surgeons is essential to conquer this intractable disease.” 


Nagino M. Perihilar cholangiocarcinoma: a surgeon’s viewpoint on current topicsJ Gastroenterol. 2012;47(11):1165-1176. doi:10.1007/s00535-012-0628-6

Nagino M. Perihilar cholangiocarcinoma: a surgeon’s perspective. iLiver. Published online April 5, 2022. doi:10.1016/j.iliver.2022.03.004