Biliary adenofibroma and cholangiocarcinoma: neighbors or relatives? A systematic and critical review

Biliary adenofibroma (BAF) is currently classified as a benign intrahepatic biliary tumor. However, a growing body of literature has documented BAFs with invasive components or associated cholangiocarcinoma. To better characterize this challenging entity, we performed a systematic review of BAF. PubMed, SCOPUS, and Embase were searched through April 2025 to identify all studies on BAFs. Clinicopathological, immunohistochemical (IHC), and molecular data have been extracted and analyzed. A total of 55 cases of BAF were identified in the literature. Macroscopically, BAFs usually showed mixed features, ranging from cysts intermingled with solid nodules to spongy, non-capsulated lesions. Histologically, the lining epithelium consisted of non-mucin-secreting biliary cells (55/55, 100 %). BAFs with invasive components accounted for 52.7 % of the literature (29/55). In two cases, innocent-looking tubulocystic structures were present but showed frankly invasive components. Although most patients were alive and disease-free after resection (35/43, 81.4 %), two patients died of disease (2/43, 4.6 %) and six experienced relapses (6/43, 14 %). In 7 studies with a total of 13 cases, molecular investigations demonstrated gene alterations typically seen in small-duct cholangiocarcinoma, including mutations in ARID1A (2/13), BAP1, PBRM1, and TP53 (one per case), and FGFR2 fusion (1/13). Taken together, our findings reveal that BAF is frequently associated with invasive malignancy. The frequent presence of tubulocystic structures with invasive features warrants further investigation of this entity, particularly given the challenging spectrum of the lesions in the differential diagnoses, ranging from benign to malignant neoplasms.