title: Immunohistochemical investigation of angiogenic factors in parathyroid proliferative lesions.
abstract: OBJECTIVE
  The pathological distinction between parathyroid neoplasms and hyperplasias remains difficult in several cases. Endoglin (CD105) is a proliferation-associated and hypoxia-inducible protein abundantly expressed in angiogenic endothelial cells. Vascular endothelial growth factor (VEGF) induces angiogenesis and VEGF-R2 is a tyrosine kinase receptor expressed early in development by endothelial cell precursors. We attempted to examine whether immunohistochemical expression of CD105, VEGF and VEGF-R2 may be useful in distinguishing between parathyroid hyperplasia and neoplasia as well as to elucidate, to some extent, the mechanism of neovascularization in proliferative lesions of the parathyroid gland.
  
  
  METHODS
  Tissue specimens were taken from 38 patients with primary hyperparathyroidism (HPT) (17 adenomas and 21 primary hyperplasias) and from 30 patients with secondary HPT. Normal glands served as controls.
  
  
  METHODS
  In a standard immunohistochemical procedure, monoclonal antibodies to endoglin, VEGF and VEGF-R2 were applied to detect angiogenic endothelial cells. Immunostaining was estimated by image analysis and statistical analysis was subsequently performed.
  
  
  RESULTS
  Positive CD105 immunoreaction was significantly increased in parathyroid adenomas by comparison with primary hyperplasias (P = 0.033) and with secondary hyperplasias (P = 0.033). When parathyroid adenomas, primary hyperplasia and secondary hyperplasia specimens were comparatively evaluated, VEGF immunoreaction was much more common in adenomas (P = 0.018). In addition, in samples with secondary hyperplasia, VEGF-R2 immunoreactivity was positively linked with VEGF expression as well as with the apoptotic index of parathyroid cells (P = 0.038 and 0.010 respectively). In secondary hyperplasia specimens, an inverse correlation between cyclin D1 immunoexpression and angiogenic indexes, such as CD105 and VEGF, was noticed (P = 0.007 and 0.0017 respectively).
  
  
  CONCLUSIONS
  This study shows increased angiogenesis in parathyroid adenomas compared with parathyroid proliferative lesions. In secondarily hyperplastic glands increased angiogenesis and increased apoptosis occur simultaneously; in the latter glands, the overexpression of cyclin D1 does not appear to be the genetic abnormality responsible for increased angiogenesis.
authors.affiliation: 1st Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Lazaris
authors.forename: Sofia
authors.initials: S
authors.lastname: Tseleni-Balafouta
authors.forename: Thomas
authors.initials: T
authors.lastname: Papathomas
authors.forename: Theodore
authors.initials: T
authors.lastname: Brousalis
authors.forename: Georgia
authors.initials: G
authors.lastname: Thomopoulou
authors.forename: George
authors.initials: G
authors.lastname: Agrogiannis
authors.forename: Efstratios S
authors.initials: ES
authors.lastname: Patsouris
mesh_terms: D000236:Adenoma / Q000737:chemistry* / Q000175:diagnosis; D015703:Antigens, CD / Q000032:analysis*; D000071063:Endoglin; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000175:diagnosis* / Q000378:metabolism; D006965:Hyperplasia / Q000175:diagnosis; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010282:Parathyroid Neoplasms / Q000737:chemistry / Q000175:diagnosis*; D011956:Receptors, Cell Surface / Q000032:analysis*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2