title: Investigation of papulopustular eruptions caused by cetuximab treatment shows altered differentiation markers and increases in inflammatory cytokines.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) critically regulates tumour cell division, survival and metastasis. Agents that inhibit EGFR have been used in the treatment of advanced-stage malignancies, but cause variable cutaneous side-effects, most often papulopustular eruptions and xerosis.
  
  
  OBJECTIVE
  We assayed expression of inflammatory cytokines [interleukin (IL)-1alpha, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, human leucocyte antigen (HLA)-DR and intercellular adhesion molecule (ICAM)-1], differentiation markers (filaggrin, involucrin and loricrin) and phosphorylated EGFRs (pEGFRs) in papulopustular eruptions to determine the association between these markers and the eruptions caused by cetuximab.
  
  
  METHODS
  Twelve papulopustular lesion biopsies were selected from patients with colon cancer who had received cetuximab treatment. Immunohistochemistry and immunofluorescence with a confocal laser scanning microscopy were performed.
  
  
  RESULTS
  Filaggrin expression decreased and expression of involucrin, various inflammatory markers (IL-1alpha, TNF-alpha, ICAM-1 and HLA-DR) increased and the expression of pEGFR was markedly downregulated in papulopustular eruptions. In perilesions, decreased pEGFR expression was noted in hair follicles compared with interfollicular epidermis. The increase of IL-1alpha and TNF-alpha was observed in perilesions as in the lesions.
  
  
  CONCLUSIONS
  The early inflammatory events (IL-1alpha and TNF-alpha expression) seen, and the lack of pEGFR in perilesional follicles, indicate that inflammatory events induced by EGFR inhibition may initiate papulopustular eruptions along with the altered differentiations. The decrease of filaggrin may contribute to the pathogenesis of the xerosis caused by cetuximab.
authors.affiliation: Department of Dermatology, Asan Medical Center, SongPa-Gu PyongNab-Dong, Seoul 138-736, Korea.
authors.forename: S S
authors.initials: SS
authors.lastname: Han
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.forename: G H
authors.initials: GH
authors.lastname: Park
authors.forename: S H
authors.initials: SH
authors.lastname: Bang
authors.forename: Y K
authors.initials: YK
authors.lastname: Kang
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
authors.forename: J L
authors.initials: JL
authors.lastname: Lee
authors.forename: H M
authors.initials: HM
authors.lastname: Chang
authors.forename: M H
authors.initials: MH
authors.lastname: Ryu
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D000068818:Cetuximab; D016207:Cytokines / Q000378:metabolism*; D003875:Drug Eruptions / Q000276:immunology* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D006684:HLA-DR Antigens / Q000032:analysis / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D006684:HLA-DR Antigens; D053582:Interleukin-1alpha; D007381:Intermediate Filament Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000068818:Cetuximab