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

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.