title: Intraocular tumor-associated lymphangiogenesis a novel prognostic factor for ciliary body melanomas with extraocular extension?
abstract: OBJECTIVE
  To evaluate whether intraocular tumor-associated lymphangiogenesis contributes to prognosis of ciliary body melanomas with extraocular extension and to study its association with other tumor characteristics.
  
  
  METHODS
  Nonrandomized, retrospective case series.
  
  
  METHODS
  Twenty consecutive patients enucleated for a malignant melanoma of the ciliary body with extraocular extension.
  
  
  METHODS
  Lymphatic vessels were identified using lymphatic vascular endothelial-specific hyaluronic acid receptor-1 (LYVE-1) and podoplanin as specific immunohistochemical markers for lymphatic vascular endothelium. Baseline tumor characteristics included intra- and extraocular tumor size, 2009 tumor, node, metastasis (TNM) classification, route of extraocular spread, tumor cell type, mitotic rate, Ki-67 proliferation-index, microvascular patterns and density, tumor-infiltrating lymphocytes and macrophages, and expression of human leukocyte antigen (HLA) class I and insulin-like growth factor-1 receptor. Kaplan-Meier and Cox regression analyses of melanoma-specific survival were performed.
  
  
  METHODS
  Prevalence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels and association with intraocular tumor characteristics and metastasis-free survival.
  
  
  RESULTS
  Intraocular LYVE-1(+) and podoplanin(+) lymphatic vessels could be detected in 12 (60%) of 20 ciliary body melanomas with extraocular extension. Presence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels was significantly associated with larger intra- (P = 0.002) and extraocular tumor size (P<0.001), higher TNM categories (P = 0.004), epithelioid cellularity (P = 0.016), higher mitotic rate (P = 0.003), higher Ki-67 proliferation-index (P = 0.049), microvascular networks (P = 0.005), higher microvascular density (P = 0.003), more tumor-infiltrating macrophages (P = 0.002), higher expression of HLA class I (P = 0.046), and insulin-like growth factor-1 receptor (P = 0.033), but not significantly with route of extraocular spread (P = 0.803), and tumor-infiltrating lymphocytes (P = 0.069). Melanoma-specific mortality rates increased significantly with the presence of intraocular LYVE-1(+)/podoplanin(+) lymphatic vessels (P = 0.008). By multivariate Cox regression, tumor size (hazard ratio, 14.40; P = 0.002), and presence of intraocular lymphatic vessels (hazard ratio, 8.09; P = 0.04) were strong prognostic predictors of mortality.
  
  
  CONCLUSIONS
  Intraocular peritumoral lymphangiogenesis seems to be associated with an increased mortality risk in patients with ciliary body melanomas and extraocular extension. This association may be primarily because of an association of intraocular lymphangiogenesis with greater tumor size and increased malignancy.
authors.affiliation: Department of Ophthalmology and Eye Hospital, Ophthalmic Pathology Laboratory, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. ludwig.heindl@uk-erlangen.de
authors.forename: Ludwig M
authors.initials: LM
authors.lastname: Heindl
authors.forename: Tanja N
authors.initials: TN
authors.lastname: Hofmann
authors.forename: Werner
authors.initials: W
authors.lastname: Adler
authors.forename: Harald L J
authors.initials: HL
authors.lastname: Knorr
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Holbach
authors.forename: Gottfried O H
authors.initials: GO
authors.lastname: Naumann
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Kruse
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate; D014604:Uveal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D014408:Biomarkers, Tumor; D015395:Histocompatibility Antigens Class I; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D017526:Receptor, IGF Type 1; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin