One of the fundamentals of modern medicine is our ability to decisively diagnose many diseases. This may come about by first recognizing a constellation of signs and symptoms and then performing exploratory tests, including biochemistry, medical imaging, and genetic testing. 

How specific we can be in the diagnosis of certain diseases (for example, dividing them into various subtypes, even if they differ only slightly in phenotype) is a sort of barometer of how much we actually know about said disease. Naturally, the diagnostic pathways of diseases that have been closely studied are relatively more precise; the opposite can also be said to be true. Gone are the days when all the physician can tell a patient is that he or she likely has “liver cancer,” with no additional details. Today, with all the modern investigative tools available, physicians are able to pinpoint the exact type of liver cancer suspected, together with its corresponding treatment options and prognosis. 

However, in reality, physicians do often get the diagnosis of a disease wrong, especially when a patient presents too early, with the signs and symptoms still being so vague that a long list of differentials remains possible. This is the difficult, but inescapable, reality of being a physician (especially those who work in general practice).

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For example, if a patient presents with nonspecific abdominal pain (with a history of possible food poisoning), the physician would be right to suspect that it will resolve with over-the-counter medication in a few days’ time. Escalating every patient’s complaint for further specialist investigation is impractical, expensive, and unsustainable. However, when a physician has a clinical suspicion of something more sinister, it is right that appropriate further action is pursued; the mark of an excellent doctor is to know when to do so.

In this article, we will be discussing diagnosis, specifically the diagnosis of cholangiocarcinomas (CCAs), and summarize what we know about the characteristics of the different CCAs.

Buckholz and Brown Jr wrote about when clinical suspicion of CCA should arise: “There are 3 distinct but interrelated circumstances that should prompt consideration for CCA: a patient with asymptomatic cholestatic elevation of liver enzymes, a patient with symptoms or imaging findings concerning for hepatobiliary malignancy, or a patient with known ulcerative colitis or primary sclerosing cholangitis.”

Read more about CCA etiology

Sarcognato and colleagues describe CCA as ”a heterogeneous group of aggressive malignancies arising from different locations within the biliary tree.”

”Depending on their anatomical site of origin, CCAs are classified into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA), that differ for etiology, risk factors, prognosis, and clinical and therapeutic management,” they explained.

Differentiating CCA Subtypes

In the majority of cases, iCCA presents itself as a single mass, appearing as infiltrating or nodular on cross-sectional imaging. Histology provides the definite diagnosis: a moderately differentiated adenocarcinoma, with a variable amount of fibrous stroma. 

“The WHO classification defines iCCA as a malignant intrahepatic epithelial neoplasm with biliary differentiation,” Sarcognato et al wrote.

The pCCA type develops from the extrahepatic biliary tree, proximal to where the cystic duct originates. The dCCA type differs from pCCA in that it is distal to the insertion of the cystic duct, although like pCCA, it also develops from the extrahepatic biliary tree. 

Since these tumors cause extraobstructive jaundice, they tend to be detected early and hence are mostly small in size upon presentation. Both pCCA and dCCA are mucin-secreting adenocarcinomas that have well-formed, widely-spaced irregular glands and small cell clusters. 

Sarcognato and colleagues wrote about the sometimes difficult task of differentiating them from reactive periductal glands: “The distinction between pCCAs/dCCAs and reactive periductal glands is the main differential issue, since it is not always straightforward on morphology alone. Clinical history and imaging must always be considered.”

Tailoring Treatment Strategy

After diagnosing these CCAs, the next step is to classify them according to their TNM staging. After having done so, surgeons should have a much clearer idea about treatment options (which, of course, is the whole purpose of diagnosis).

“The primary management strategies for CCA include surgical resection, liver transplantation, systemic chemotherapy, and locoregional therapy,“ Buckholz and Brown Jr wrote. “Multidisciplinary expert involvement is critical to quickly identify those patients for whom potentially curative resection or transplant is available.” 

Read more about CCA treatment

Once the location of the CCA and its clinical features have been clearly identified, the surgical resectability of the tumor takes center stage. In other articles on CCA published in Rare Disease Advisor, we have written on various perspectives on how surgeons can arrive at an accurate decision on whether to pursue surgical resection (by far the best outcome) or other nonresection treatment options. As a distinguished team of surgeons and researchers wrote in their 2020 consensus statement, “Better classification and stratification of patients will greatly aid in deciding on the therapeutic regimen and which patients should undergo curative resection and/or liver transplantation.” 

If we are to take a broad view and characterize the identification and treatment of CCA as a journey undertaken together by both patient and physician, then the diagnosis portion can be said to be particularly treacherous; after all, without it, nothing else can proceed further. On one of the areas to improve in CCA care, the 2020 consensus statement mentioned, “Identification of CCA risk factors is of great interest” because “enhancing and implementing screening policies that would enable the early diagnosis of CCA at stages when curative surgery is possible” is absolutely crucial. 


Sarcognato S, Sacchi D, Fassan M, et al. Cholangiocarcinoma. Pathologica. 2021;113(3):158-169. doi:10.32074/1591-951X-252

Buckholz AP, Brown RS Jr. Cholangiocarcinoma: diagnosis and management. Clin Liver Dis. 2020:421-436. doi:10.1016/j.cld.2020.04.005

Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. doi:10.1038/s41575-020-0310-z