title: p16 is consistently expressed in endometrial tubal metaplasia.
abstract: BACKGROUND
  Cell cycle proteins and HIF-1alpha with downstream factors are often abberrantly expressed in (pre)neoplastic tissue.
  
  
  METHODS
  Paraffin-embedded specimens of inactive endometrium with TM (n=15), ovarian inclusion cysts (n=6), cervix with TM (tubal metaplasia) (n=3), Fallopian tubes (n=7), cycling endometrium (n=9) and a ciliated cell tumor of the ovary were stained for p16 and LhS28. 39 Endometrioid endometrial carcinomas and 5 serous endometrial carcinomas were stained for p16. Additionally, inactive endometrium (n=15) was immunohistochemically stained for p21, p27, p53, cyclin A, cyclin D1, cyclin E, HIF-1alpha, CAIX, Glut-1 and MIB-1.
  
  
  RESULTS
  A mosaic pattern of expression of p16 was seen throughout in all cases of endometrial TM (15/15), in 2/6 of the ovarian inclusion cysts with TM, in all (3/3) cervical TM and focal in 5/7 of Fallopian tube cases. Mosaic expression was also seen in a ciliated cell tumor of the ovary and in 18/39 of endometrioid endometrial carcinomas, and diffuse p16 expression was seen in 5/5 serous carcinomas. In comparison with normal endometrium, TM areas in the endometrium showed significantly increased expression of HIF-1alpha, cyclin E, p21 and cyclin A, and decreased expression of p27. Membranous expression of CAIX and Glut-1 was only seen in TM areas, pointing to functional HIF-1alpha.
  
  
  CONCLUSIONS
  As p16 is consistently expressed in TM, less and only patchy expressed in the normal Fallopian tube, is paralleled by aberrant expression of cell cycle proteins, HIF-1alpha, CAIX and Glut-1 and resembles the pattern of p16 expression frequently seen in endometrial carcinomas, we propose endometrial TM to be a potential premalignant endometrial lesion.
authors.affiliation: Department of Surgical Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Horree
authors.forename: A P M
authors.initials: AP
authors.lastname: Heintz
authors.forename: D M D S
authors.initials: DM
authors.lastname: Sie-Go
authors.forename: P J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D018269:Carcinoma, Endometrioid / Q000378:metabolism / Q000473:pathology; D002584:Cervix Uteri / Q000737:chemistry / Q000473:pathology; D019925:Cyclin A / Q000032:analysis; D019938:Cyclin D1 / Q000032:analysis; D019927:Cyclin E / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000737:chemistry / Q000473:pathology*; D005187:Fallopian Tubes / Q000737:chemistry / Q000473:pathology*; D005260:Female; D051272:Glucose Transporter Type 1 / Q000032:analysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D008679:Metaplasia
chemical_list: D019925:Cyclin A; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27