title: Histologic variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis.
abstract: BACKGROUND
  Juvenile polyps are distinct hamartomatous malformations of the gastrointestinal tract that may occur in the heritable juvenile polyposis syndrome (JPS) or sporadically. Histologically, juvenile polyps are characterized by a marked increase of the stromal cell compartment, but an epithelial phenotype has also been reported. JPS has an increased risk of colorectal cancer but sporadic juvenile polyps do not. In 50% to 60% of patients with JPS, a germline mutation of the transforming growth factor-β/bone morphogenetic protein (BMP) pathway genes SMAD4 or BMPR1A is found. This study compares the histologic phenotype of juvenile polyps with a SMAD4 or BMPR1A germline mutation and sporadic juvenile polyps.
  
  
  METHODS
  Hematoxylin and Eosin-stained slides of 65 JPS polyps and 25 sporadic juvenile polyps were reviewed for histologic features and dysplasia. Systematic random crypt and stroma counts were obtained by count stereology, and a crypt-stroma ratio was determined. All polyps were subsequently categorized as type A (crypt-stroma ratio <1.00) or type B (crypt-stroma ratio ≥1.00), the latter referring to the epithelial phenotype. Cell cycle activity was assessed using immunohistochemistry ofthe proliferation marker Ki67, and mutation analysis was carried out for KRAS and APC to determine the involvement of the adenoma-carcinoma sequence.
  
  
  RESULTS
  Juvenile polyps with a SMAD4 germline mutation were predominantly type B, whereas type A was more common among juvenile polyps with a BMPR1A germline mutation. However, this distinction could not be ascribed to differences in cell cycle activity. Dysplasia was equally common in JPS polyps with either a SMAD4 or BMPR1A germline mutation, in which the involvement of the adenoma-carcinoma sequence does not seem to play a distinct role.
  
  
  CONCLUSIONS
  Juvenile polyps in the setting of JPS exhibit distinct phenotypes correlating with the underlying genetic defect.
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Willem Arnout
authors.initials: WA
authors.lastname: van Hattem
authors.forename: Danielle
authors.initials: D
authors.lastname: Langeveld
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: de Leng
authors.forename: Folkert H
authors.initials: FH
authors.lastname: Morsink
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.forename: Francis M
authors.initials: FM
authors.lastname: Giardiello
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Lodewijk A A
authors.initials: LA
authors.lastname: Brosens
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018256:Adenomatous Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D017491:Genes, APC; D011905:Genes, ras; D018095:Germ-Line Mutation; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D007834:Lasers; D042282:Microdissection; D010641:Phenotype; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I