Clinicopathologic and Genetic Analysis of Inverted Follicular Keratosis With Emphasis on Its Similarity to Seborrheic Keratosis

The classification of inverted follicular keratosis (IFK) remains controversial, with debate on whether it represents a variant of seborrheic keratosis, a follicular poroma (folliculosebaceous poroma), or a distinct tumor type. To clarify, we conducted genetic analyses to detect FGFR3 and PIK3CA mutations, as well as PAK1/2/3 rearrangements, in IFK cases. IFK was diagnosed based on exo-endophytic or endophytic growth; biphasic basaloid and squamoid keratinocytes with acantholysis and squamous eddies; and absence of adnexal differentiation. Using these histopathological criteria, 12 IFK cases were identified in our two hospitals. The cohort comprised 10 male and 2 female patients, with a median age of 59.5 years (range: 42-89). Most tumors were located on the face (n = 11, 92%) and were small in size (median: 6.5 mm; range: 2-13 mm). No cases demonstrated local recurrence or metastasis. Histologically, tumor architecture was classified into three patterns: papillomatous wart-like (n = 5), keratoacanthoma-like (n = 3), and solid nodular (n = 4). Sanger sequencing revealed the presence of FGFR3 p.R248C (n = 1/10, 10%), PIK3CA p.E545K (n = 1/10, 10%), and PIK3CA p.H1047Y (n = 1/10, 10%), although analysis failed in the two oldest cases owing to degraded DNA. PAK1/2/3 break-apart fluorescence in situ hybridization (FISH) showed no split signals in any case; PAK3 FISH also failed in the same two older specimens. Thus, IFK may represent a distinct clinicopathologic variant of seborrheic keratosis under our proposed diagnostic criteria.