Panfolliculoma ( PF ) is a rare benign tumor with signs of differentiation toward all components of the hair follicle ( HF ). Cystic panfolliculoma ( CPF ) is a subset of PF with histological similarity to trichofolliculoma making the differential diagnosis difficult in some cases. Immunohistopathological investigations of PF have been reported; however, previous studies focused mostly on the expression profile of the outer root sheath markers. Herein, we report a case of CPF. A panel of antibodies was developed and used for the detection of the expression of cytokeratin ( CK ) 10, CK13 , CK14 , CK15 , hair‐hard keratin ( AE13 ) and EpCAM within the lesion, supporting the differentiation of all epithelial lineages of the HF and the diagnosis of CPF . Immunohistopathological examinations... clearly showed the spatial distribution pattern of each subset of tumor cells with distinct HF differentiation marker expression. Intriguingly, fibroblastic dermal cells were distributed preferentially near CK15 ‐negative epithelium or CK13 ‐positive HF ‐like structures, suggesting a role for epithelial‐mesenchymal interactions ( EMIs ) in CPF pathogenesis. Further characterization of EMIs between the tumor and surrounding mesenchymal cells in CPF may provide an explanation for immature HF differentiation. These findings suggest that the more intense and coordinated EMI in the analogous tumorigenesis gives rise to mature HF structures, resulting in trichofolliculoma, which may explain their histological resemblance.