New insights into the adverse prognostic role of squamous differentiation in intrahepatic cholangiocarcinoma: A comprehensive analysis

• Published in: Human pathology Vol. 160; p. 105824
• Main Authors: Nguyen Thi, Quynh, Nguyen Canh, Hiep, Li, Zihan, Nguyen Thi, Khuyen, Yoshimura, Kaori, Takahashi, Kenta, Yang, Rui, Le Thanh, Dong, Nguyen Thi, Tram, Yagi, Shintaro, Harada, Kenichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2025
• Subjects: Adenosquamous carcinoma; Intrahepatic cholangiocarcinoma; Squamous cell carcinoma; Squamous differentiation; Squamous differentiation; Adenosquamous carcinoma; Squamous cell carcinoma; Intrahepatic cholangiocarcinoma
• ISSN: 0046-8177; 1532-8392; 1532-8392
• DOI: 10.1016/j.humpath.2025.105824

Squamous differentiation is uncommon in intrahepatic cholangiocarcinoma (iCCA) with limited systematic studies in the literature, mostly case reports. The study aimed to determine the rate of squamous differentiation in iCCA utilizing markers p63, Keratin 5/6, and p40, and to examine its correlation with clinicopathological characteristics and survival outcomes. A retrospective analysis was performed on 147 patients with histologically confirmed iCCA based on surgical specimens. A sample was classified as having squamous differentiation if it exhibited a solid growth pattern of polygonal tumor cells with keratinization or a solid growth pattern with at least the positivity of two of the three abovementioned markers. The rate of squamous differentiation in iCCA was determined to be 12.9 % (19/147). p40 demonstrates the highest sensitivity and specificity for identifying squamous differentiation in iCCA, recorded at 94.7 % and 87.5 %, respectively. Squamous differentiation in iCCA was found to be associated with large tumor size, large bile duct subtype, poorly differentiated adenocarcinoma component, activated tumor microenvironment, tumor necrosis, high tumor budding, increased invasiveness, and advanced pT stages. Patients with greater than 30 % squamous differentiation had significantly shorter median overall survival and disease-free survival than controls. These results suggest that squamous differentiation serves as an unfavorable prognosis factor in iCCA, and a threshold of 30 % for the squamous differentiation component can be considered to classify a tumor as adenosquamous carcinoma in iCCA. [Display omitted] •p40 shows highest sensitivity/specificity for squamous differentiation iniCCA.•Squamous differentiation serves as an unfavorable prognosis factor in iCCA.•A 30% squamous differentiation threshold may help classify adenosquamous carcinoma in iCCA.