When it comes to rare diseases, physicians face a twin set of problems that can block swift clinical progress: diagnosing the disease early and accurately (usually amidst a variety of nonpathognomic signs), as well treating the disease in a manner that substantially maintains/increases the quality of life of patients. 

It would do well for us to remember that most rare diseases, such as cholangiocarcinoma (CCA), are diagnosed far too late, past the point of surgical viability. Ney and colleagues from London, England have documented some of the diagnostic conundrums relating to CCA in their paper published in Frontiers In Oncology. We will examine some of their findings in this article. 

Diagnostic Conundrums 

As has been deliberately instilled in physicians since their medical school years, they are wary of making sweeping diagnoses from vague symptoms. This is because of 2 main (and rather solid) reasons: most vague presentations do not eventually lead to the diagnosis of a rare disease, and the cost of pursuing the diagnosis of what could turn out to be common maladies is high. This begs the question: when should physicians go all out in diagnosing certain illnesses?

Continue Reading

In CCA, the varied and vague presentation of early-stage patients makes it difficult for physicians to pin down a diagnosis, at a substantive cost. Forner et al wrote, “The lack of etiological factors linked to patients at risk for CCA . . . makes early detection more challenging.” Unfortunately, more than 70% of CCA cases are unresectable upon diagnosis, which is disheartening news considering that surgical resection or liver transplantation remains the only curative option.

Read more about CCA etiology 

Forner and colleagues, in a study about the clinical presentations, diagnosis, and staging of CCA published in Liver International, gave their expert take on how the diagnosis of CCA should go about. They gave a short but accurate summary about the attitude they believe should be adopted: “The diagnosis of CCA is based on the combination of clinical and imaging findings which will raise the suspicion of CCA diagnosis” and “once the diagnosis of CCA is confirmed, staging investigations will assess the degree of extension of tumor outside the liver and the biliary tree.” The types of imaging findings include ultrasound, CT scans, and MRI. Biopsy/cytology can then be used to confirm CCA diagnosis. 

Early Indicators

Perhaps the first clues for a diagnosis of CCA can be found the moment the patient walks into the consultation room. Forner et al wrote, “The most characteristic and common symptom of extrahepatic CCA is jaundice. In the case of intrahepatic CCA, jaundice is the initial symptom only in around 10%-15% of the cases.” 

Upon the observation of jaundice, physicians can perform a number of physical examinations that can narrow down the cause of jaundice. At this point, Forner and colleagues said, patients should be assessed for signs of chronic hepatic dysfunction such as “the presence of hepatomegaly, splenomegaly, ascites, abdominal collateral circulation, palmar erythema or spider naevi, telangiectasia, gynecomastia, parotid hypertrophy or Dupuytren’s contracture.” 

After physical examination, physicians should order blood tests (including liver function tests) before deciding on the use of imagining modalities. 

Besides conventional imaging and staging, Ney et al wrote about new technologies that can provide unparalleled visualization of the biliary tree and thus help physicians in arriving at more accurate diagnoses. One such example is single operator cholangioscopy.

Ney and colleagues wrote, “Cholangioscopy enables the direct visualization of the biliary epithelium, characterization of filling defects as well as targeted biopsy of suspicious strictures.” In addition, this imaging modality allows for minimally ablative techniques to be applied, including radiofrequency, endoscopic, and photodynamic ablation. 

Another method that can aid in the diagnosis of CCA is the use of biomarkers. Ney and colleagues wrote, “Tissue, cytological and bile-based biomarkers may provide additional diagnostic information over standard methods, with variable sensitivities and specificities – ranging from 58%-87% and up to 98%-100%, respectively.”

Examples of disease markers commonly investigated in CCA are cancer antigens 19.9 (CA 19.9) and 20.5 (CA 20.5), as well as carcinoembryonic antigen (CEA). These are used to differentiate high-risk biliary tract lesions that are associated with CCA, with CA 19.9 being the primary tumor marker for diagnosing CCA. 

Improving Our Diagnostic Abilities 

It seems that a common theme running through both studies regarding the diagnosis of CCA is that scientists agree on one thing: early diagnosis is infinitely important. Forner et al concluded, “CCA includes a heterogeneous group of tumors. Unfortunately, because of the unspecific symptoms at early stages and lack of screening strategies, diagnosis is usually performed at advanced stages.” 

Read more about CCA diagnosis 

Ney et al concur on this point. They wrote, “Most cases (>70%) are unfortunately non-resectable at time of diagnosis, where therapeutic options are limited to systemic therapy and palliation.”

Therefore, it is clear that any new diagnostic modalities that are under investigation must, at the very least, aid in the early diagnosis of CCA in a patient while the disease is still resectable. This is because there remains a world of difference between the management of patients who have resectable disease vs those who do not. In the area of CCA research, time is definitely of the essence.


Ney A, Garcia-Sampedro, A, Goodchild G, Acedo P, Fusai G, Pereira SP. Biliary strictures and cholangiocarcinoma – untangling a diagnostic conundrum. Front Oncol. Published online September 30, 2021. doi:10.3389/fonc.2021.699401

Forner A, Vidili G, Rengo M, Bujanda L, Ponz-Sarvisé M, Lamarca A. Clinical presentation, diagnosis and staging of cholangiocarcinomaLiver Int. Published online March 4, 2019. doi:10.1111/liv.14086