title: Low expression of nuclear Toll-like receptor 4 in laryngeal papillomas transforming into squamous cell carcinoma.
abstract: OBJECTIVE
  The malignant transformation rate of recurrent respiratory papillomatosis (RRP), a disease caused by human papillomavirus (HPV), has varied significantly. Cells of the human immune system express toll-like receptors (TLRs) that recognize particles from viruses and bacteria; TLRs are also present on tumor cells, and down-regulation of TLRs has been shown during the progression of HPV-associated neoplasia. The aim of this study was to determine the malignant transformation rate of laryngeal papillomas (LPs) and analyze the potential of TLR2, TLR4, and TLR9 immunoexpression as indicators of the increased cancer risk.
  
  
  METHODS
  Retrospective case-control study.
  
  
  METHODS
  Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  
  
  METHODS
  We reviewed all patients with RRP treated for LPs between 1975 and 2011. Data from the Finnish Cancer Registry confirmed the number of patients diagnosed with laryngeal squamous cell carcinoma (LSCC). Laryngeal tissue specimens from patients developing LSCC were subjected to TLR2, TLR4, and TLR9 immunohistochemistry. Nine patients with RRP without malignant transformation and 19 patients with LSCC without a pre-existing LP served as controls.
  
  
  RESULTS
  Nine of 324 patients (2.8%) with RRP developed LSCC. The intensity of nuclear staining of TLR4 was significantly lower in LPs transforming into LSCC than in LPs without malignant transformation. The expression of cytoplasmic TLR4 in LSCC correlated with tumor grade and T stage. Cytoplasmic TLR9 expression was significantly lower in LPs than in LSCC.
  
  
  CONCLUSIONS
  The expression of TLR4 may serve as a predictive marker of malignant transformation in LPs. High immunoexpression of cytoplasmic TLR4 in LSCC was associated with a more aggressive disease.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland taru.ilmarinen@helsinki.fi.
authors.forename: Taru
authors.initials: T
authors.lastname: Ilmarinen
authors.affiliation: Department of Pathology, Haartman Institute, Helsinki University Hospital, University of Helsinki, Helsinki, Finland Helsinki University Hospital Laboratory, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Hagström
authors.affiliation: Department of Pathology, Haartman Institute, Helsinki University Hospital, University of Helsinki, Helsinki, Finland Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
authors.affiliation: Helsinki University Hospital Laboratory, Helsinki University Hospital, University of Helsinki, Helsinki, Finland Department of Virology, Haartman Institute, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Auvinen
authors.affiliation: Department of Pathology, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Ilmo
authors.initials: I
authors.lastname: Leivo
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Pitkäranta
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Leena-Maija
authors.initials: LM
authors.lastname: Aaltonen
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D016022:Case-Control Studies; D002467:Cell Nucleus; D002471:Cell Transformation, Neoplastic; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007822:Laryngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010212:Papilloma / Q000378:metabolism* / Q000473:pathology*; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: human papillomavirus; laryngeal papilloma; malignant transformation; recurrent respiratory papillomatosis; squamous cell carcinoma; toll-like receptor