Cholangiocarcinomas can be divided into three subtypes: perihilar (pCCA), intrahepatic (iCCA), and distal (dCCA). This modern classification of cholangiocarcinoma is based on their anatomical site of location. 

Although these distinct subtypes have their own presentations, biomarkers, diagnostic protocols, and management strategies, it is rare to find medical literature that focuses only on one of the three. Many clinical studies seek to compare the subtypes together and contrast their differences. 

Cho and colleagues have written a study about optimizing the diagnosis and biomarker testing of patients with iCCA specifically. To identify gaps in current practices, they convened a meeting between the multidisciplinary hepatobiliary teams from the University of California Davis and the University of California Irvine. The discussion was wide-ranging, covering various aspects, including diagnosis, communication between academicians and healthcare teams, and education. 

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The Importance of Differentiating iCCA

First, let us discuss why it is important for researchers to study and characterize each of the cholangiocarcinoma subtypes individually. We will elaborate on this subject in the context of iCCA.

The incidence of iCCA has risen notably over the last 2 decades, translating to higher global mortality rates. This has driven the demand for mechanistic insights and biomarker-driven approaches for managing this cancer. It is worth noting that the prognosis for iCCA is extremely poor, with only around 30% to 40% of patients qualifying for curative-intent surgery. 

Read more about cholangiocarcinoma epidemiology 

For patients who qualify for and undergo surgery, the recurrence rates are reportedly as high as 40% to 80%. Currently, gemcitabine and cisplatin are the first-line systemic therapy for locally advanced iCCA. However, this treatment is not intended to be curative, and patients have few other therapeutic options.

In a review article published in Hepatology, Sirica and colleagues reported on the growing list of risk factors associated with iCCA: 

  • Hepatitis C virus
  • Hepatitis B virus
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Alcoholic liver disease
  • Autoimmune hepatitis
  • Nonspecific cirrhosis.

Vague Symptoms or None at All 

Let’s now narrow our focus to one specific aspect of iCCA: how it is diagnosed. The problem with iCCA is that it often presents with vague, nonspecific symptoms (if patients present with any symptoms at all). This is worrying, given that the early detection of iCCA increases the likelihood that surgical resection remains a possibility. Studies indicate that the median duration from the onset of symptoms to a diagnosis of cholangiocarcinoma was 19 months (approximately 1.5 years), while initial misdiagnosis was reported in a third of patients.

The presence of a liver mass detected via medical imaging is usually the first sign physicians pick up that raises the suspicion of iCCA. For this potential diagnosis to be explored fully, the following investigations should be carried out: 

  • Liver function tests
  • Serum biomarkers analysis
  • Additional imaging of the liver mass
  • Tissue sample acquisition
  • Histological analysis of the tissue sample. 

The typical histological findings in iCCA are well to moderately differentiated adenocarcinoma, with desmoplasia of varying degrees. However, histological patterns can mimic other tumors, so histological data should include iCCA as a differential diagnosis, but other conditions, such as hepatocellular carcinoma and other rare primary hepatic malignancies, should not be discounted. 

Read more about cholangiocarcinoma diagnosis 

Physicians should take great care in ensuring the highest quality of the biopsy specimens collected. For additional efficacy, a cytologist may be invited to assist with the biopsy procedure to ensure tumor cell content is optimized. Another method to improve tumor cell content is the collection of fine needle aspirations with core biopsies. Pathologists can split each core sample into 2 specimens to conserve tumor tissues; this way, one specimen can be used for histology/diagnosis, while the other can be reserved for biomarker analysis. 

Sirica and colleagues highlighted the challenges of the molecular profiling of iCCA, given its vast intertumor and intratumor heterogeneity. This heterogeneity is due in part to the diverse multifactorial etiologies between various ethnic groups, histological tumor differences, and the evolving progression of malignant disease. All of this represents an additional hurdle for early diagnosis and the definition of drivers responsible for the early stages of cholangiocarcinogenesis. 

Multidisciplinary Approach Recommended

In the journal Cancers, Cho and colleagues wrote, “In clinical practice, pathology may not typically provide a definitive diagnosis of iCCA, instead indicating a tumor of pancreatobiliary origin, underscoring the importance for diagnosis by [a multidisciplinary team], where imaging and histopathology results can be combined.”

The importance of managing iCCA in a multidisciplinary setting is a consistent theme in Cho et al’s study. From the early suspicion of the disease, to the diagnostic procedures, to the long-term management of the patient, Cho and colleagues advocated for physicians to work together and learn from each other.

They described the key features of an excellent multidisciplinary team:

  • Comprising all specialties that are appropriate for the cancer type 
  • Being efficient, organized, and having a good leadership structure 
  • Meeting regularly to discuss cases.

Cho and colleagues go further than some in suggesting that a strong, competent multidisciplinary team be set up even from the point of early clinical suspicion and diagnosis, instead of just down the road during the management of confirmed cases. Given the rarity of iCCA and our notable gaps in knowledge, a well-prepared team of physicians willing to work together may indeed be the key to driving better patient outcomes. 


Sirica AE, Gores GJ, Groopman JD, et al. Intrahepatic cholangiocarcinoma: continuing challenges and translational advancesHepatology. 2019;69(4):1803-1815. doi:10.1002/hep.30289

Cho MT, Gholami S, Gui D, et al. Optimizing the diagnosis and biomarker testing for patients with intrahepatic cholangiocarcinoma: a multidisciplinary approachCancers (Basel). 2022;14(2):392. doi:10.3390/cancers14020392