In patients with intrahepatic cholangiocarcinoma (ICC), tumour multiplicity – particularly the presence of ≥4 tumours – is associated with inferior overall survival (OS), a study conducted in Hong Kong, Seoul and Shanghai has shown.
The retrospective study included 849 patients (mean age, 61.12 years; male, 60.5 percent) with resectable or unresectable ICC diagnosed between May 2008 and December 2019, who were enrolled from the Prince of Wales Hospital in Hong Kong, Asan Medical Center in Seoul, and Zhongshan Hospital in Shanghai. The objective was to analyze the prognostic impact of tumour multiplicity and determine the threshold number of tumours associated with a significantly worse prognosis. [JHEP Rep 2026;8:101756]
At baseline, 563 patients had no distant metastasis. Among these patients, 434 (77.1 percent) had a solitary liver tumour, while 129 (22.9 percent) had multiple liver tumours.
A total of 439 patients had no distant or nodal metastasis at baseline. Of these, 362 (82.5 percent) had a solitary liver tumour, 37 (8.4 percent) had 2–3 tumours, and 40 (9.1 percent) had ≥4 liver tumours.
Prognostic impact
Over a median follow-up of 91.9 months, median OS was 39.5 months for M0 patients with a solitary liver tumour, 14.8 months for M0 patients with multiple intrahepatic tumours, and 7.1 months for M1 patients with distant metastasis (log-rank p<0.001). One-year OS rates were 82.9, 57.4 and 29.6 percent, respectively, while 3-year OS rates were 53.0, 26.7 and 4.5 percent, respectively.
Subgroup analysis showed that tumour multiplicity was an independent adverse prognostic factor for patients who received any type of palliative systemic therapy (ie, chemotherapy, targeted therapy or immunotherapy) (adjusted hazard ratio [aHR], 1.70; 95 percent confidence interval [CI], 1.10–2.63; p=0.016).
In the subgroup of patients treated with surgery, however, tumour multiplicity was not independently associated with poor survival. Patients with multiple tumours who underwent surgery had longer median OS (20.9 vs 7.1 months; p<0.001) and higher 1-year OS rate (70.3 vs 26.3 percent; p<0.001) than those who did not undergo surgery.
N0M0 with ≥4 tumours: Comparable OS vs N1
“Our study demonstrated a stepwise effect between the number of tumours and OS, identifying ≥4 intrahepatic tumours as a threshold with survival outcomes comparable to nodal metastases, currently classified as stage III disease,” the researchers reported.
Among N0M0 patients, median OS was 51.6 months for those with a solitary tumour, 36.9 months for those with 2–3 tumours, and 15.5 months for those with ≥4 tumours.
Multivariable analysis showed that N0M0 patients who presented with ≥4 tumours had similar survival as those with N1 disease (aHR, 1.01; 95 percent confidence interval [CI], 0.58–1.75; p=0.98), and nearly double the mortality risk compared with N0M0 patients with a solitary tumour (aHR, 0.47; 95 percent CI, 0.26–0.83; p=0.009).
Upstaging needed for ICC with multiple tumours
According to the researchers, accumulating evidence from this study and prior cohorts provide compelling evidence for revising the American Joint Committee on Cancer (AJCC) staging system, which currently classifies ICC with multiple tumours as T2 disease. [J Gastrointest Surg 2020;24:786-795; World J Surg 2011;35:2501-2509; J Hepato-Biliary-Pancreatic Sci 2014;21:499-508; HPB (Oxford) 2021;23:1456-1466]
“Collectively, these data [highlight the need] for upstaging of patients with multiple liver tumours to a more advanced disease category,” they suggested. “Considerations beyond a simple binary classification of multifocality [solitary vs multiple], including the number and distribution of lesions, may better reflect tumour burden and subsequent prognoses of tumour multiplicity.”