Heterogeneity of small duct‐ and large duct‐type intrahepatic cholangiocarcinoma

Aims The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD‐iCCA) and large duct iCCA (LD‐iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD‐ and LD‐iCCA features in different tumour regions. Methods and results All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD‐ and LD‐iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N‐cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD‐ and LD‐iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD‐ or LD‐iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD‐ and LD‐iCCA, seven patients (5.4%) of which had sufficient formalin‐fixed, paraffin‐embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD‐ and LD‐iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD‐iCCA but not in the LD‐iCCA region of the tumour. Conclusions A marked portion of patients with iCCA exhibits both SD‐ and LD‐iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations.