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Screen Patients With CUP for Intrahepatic Cholangiocarcinoma, Study Suggests


In patients with liver involvement, intrahepatic cholangiocarcinoma was a common diagnosis among some patients with cancer of unknown primary (CUP).

About one-third of patients with liver-involved cancer of unknown primary (CUP) meet the criteria for a diagnosis of intrahepatic cholangiocarcinoma (iCCA), according to a new study.

The report, published in British Journal of Cancer, offers new insights into the prevalence of iCCA and the importance of considering the diagnosis in patients with otherwise ambigious cancers.

Investigators wrote that even thought rates of CUP—in which clinicians are unable to positively identify the point of origin of a cancer—are declining, it remains the sixth most common cause of cancer death in the United Kingdom. The diagnosis typically begins with a provisional CUP diagnosis followed by a status of “confirmed” CUP if the primary site remains unknown following radiological and pathological review.

While some patients with CUP have clinical characteristics that resemble a known tumor type and can be treated accordingly, most patients (80%) do not, the authors noted. Those with “unfavorable” CUP face an uncertain prognosis; their treatment generally involves first-line doublet chemotherapy, but there is no defined second-line standard of care.

“This ‘one-size-fits-all’ approach does not reflect the clinical, pathological, and molecular heterogeneity of these tumors and emphasizes the need for better patient stratification in the unfavorable subset,” they wrote.

One solution is to do a better job of identifying patients with treatable cancers, the authors argued. Among potentially treatable patients are those with characteristics of iCCA. The rare but treatable cancer type is located in the biliary epithelium. Given its relative rarity and the obscurity of its location, the investigators wanted to know whether iCCA might be overrepresented among CUP cases.

They tracked patients at their cancer center who were referred with provisional CUP diagnoses between January 2017 and April 2020. The 228 sequential patients who were enrolled in the study were examined independently by a radiologist and oncologist using baseline diagnostic imaging. The clinicians sought to identify patients with liver involvement and then pare down the list to identify those who met the clinical criteria for iCCA.

Following the analysis, 32% of the patients (n = 72) were found to have cancer with liver involvement. Of those 72 patients, 24 had radiological features indicative of iCCA. Thirty-five patients went on to have a confirmed CUP diagnosis; the remaining 13 had a non-iCCA primary diagnosis following further review.

Seventy-five percent of the 24 patients with iCCA were female, with an average age of 63 years. Most (63%) had an Eastern Cooperative Oncology Group performance status of 2 or lower.

The authors noted that only one of the patients with iCCA received their diagnosis during the normal CUP diagnostic pathway; in the remaining 23 cases, iCCA was discovered retrospectively via radiological review.

“This emphasizes the need for further subtyping of patients with CUP with liver involvement by radiological features and consideration of iCCA as a potential diagnosis in these patients,” the authors noted.

Those with iCCA had a median overall survival of 4.1 months compared with 4.4 months among the other patients with liver involvement, and those who received a primary diagnosis had a median overall survival of 10.2 months.

The investigators said careful analysis of radiological and pathological features, along with access to molecular profiling, can be used to diagnose iCCA in patients with liver-involved CUP, but they also proposed the creation of a “liver-dominant” subset of CUP. Guidelines for such patients should be developed, they argued, and then applied to all patients for whom a CT scan suggests liver-only or liver-dominant lesions. Those guidelines should include molecular profiling to identify actionable targets, followed by treatment based on iCCA clinical guidelines, they concluded.


Conway A-M, Morris GC, Smith S, et al. Intrahepatic cholangiocarcinoma hidden within cancer of unknown primary. Br J Cancer. Published online April 28, 2022. doi:10.1038/s41416-022-01824-4

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