title: Increased epidermal thickness and abnormal epidermal differentiation in keloid scars.
abstract: BACKGROUND
  The pathogenesis underlying keloid formation is still poorly understood. Research has focused mostly on dermal abnormalities, while the epidermis has not yet been studied.
  
  
  OBJECTIVE
  To identify differences within the epidermis of mature keloid scars compared with normal skin and mature normotrophic and hypertrophic scars.
  
  
  METHODS
  Rete ridge formation and epidermal thickness were evaluated in tissue sections. Epidermal proliferation was assessed using immunohistochemistry (Ki67, keratins 6, 16 and 17) and with an in vitro proliferation assay. Epidermal differentiation was evaluated using immunohistochemistry (keratin 10, involucrin, loricrin, filaggrin, SPRR2, SKALP), reverse-transcriptase polymerase chain reaction (involucrin) and transmission electron microscopy (stratum corneum).
  
  
  RESULTS
  All scars showed flattening of the epidermis. A trend of increasing epidermal thickness correlating to increasing scar abnormality was observed when comparing normal skin, normotrophic scars, hypertrophic scars and keloids. No difference in epidermal proliferation was observed. Only the early differentiation marker involucrin showed abnormal expression in scars. Involucrin was restricted to the granular layer in healthy skin, but showed panepidermal expression in keloids. Normotrophic scars expressed involucrin in the granular and upper spinous layers, while hypertrophic scars resembled normotrophic scars or keloids. Abnormal differentiation was associated with ultrastructural disorganization of the stratum corneum in keloids compared with normal skin.
  
  
  CONCLUSIONS
  Keloids showed increased epidermal thickness compared with normal skin and normotrophic and hypertrophic scars. This was not due to hyperproliferation, but possibly caused by abnormal early terminal differentiation, which affects stratum corneum formation. Our findings indicate that the epidermis is associated with keloid pathogenesis and identify involucrin as a potential diagnostic marker for abnormal scarring.
authors.affiliation: Department of Dermatology, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: G C
authors.initials: GC
authors.lastname: Limandjaja
authors.affiliation: Department of Dermatology, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: van den Broek
authors.affiliation: Department of Dermatology, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Waaijman
authors.affiliation: Van Leeuwenhoek Centre for Advanced Microscopy, Amsterdam Medical Centre, Amsterdam, the Netherlands.
authors.forename: H A
authors.initials: HA
authors.lastname: van Veen
authors.affiliation: Van Leeuwenhoek Centre for Advanced Microscopy, Amsterdam Medical Centre, Amsterdam, the Netherlands.|Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University, Amsterdam, the Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Everts
authors.affiliation: Department of Plastic Surgery, University of Ghent, Ghent, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Monstrey
authors.affiliation: Department of Pathology, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: F B
authors.initials: FB
authors.lastname: Niessen
authors.affiliation: Department of Dermatology, VU Medical Centre, Amsterdam, the Netherlands.|Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University, Amsterdam, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Gibbs
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002454:Cell Differentiation; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000473:pathology*; D004817:Epidermis / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D007150:Immunohistochemistry; D007627:Keloid / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; C032253:involucrin