title: Molecular pathology and CXCR4 expression in surgically excised retinal hemangioblastomas associated with von Hippel-Lindau disease.
abstract: OBJECTIVE
  The surgical excision of retinal vascular lesions including hemangioblastomas is rarely practiced. This study investigates the pathological characteristics of 4 patients (3 with von Hippel-Lindau [VHL] disease and 1 with a vasoproliferative retinal tumor) who underwent ocular tumor resection. von Hippel-Lindau is an autosomal dominant disease caused by a defect of the VHL tumor suppressor gene. The VHL protein is required for oxygen-dependent degradation of hypoxia-inducible factor 1alpha. This factor regulates vascular endothelial growth factor (VEGF) and the chemokine receptor CXCR4. Retinal hemangioblastoma is the most common tumor observed in VHL disease. We investigated the expression of CXCR4; its ligand, CXCL12/SDF-1alpha; VEGF; and the VHL gene in VHL disease-associated retinal hemangioblastomas.
  
  
  METHODS
  Interventional case series with immunohistological and molecular pathological analyses.
  
  
  METHODS
  Immunohistochemistry and molecular pathology of the surgically excised retinal lesions were performed.
  
  
  METHODS
  Large retinal hemangioblastomas (1-3 disc diameters) and vasoproliferative tumors were resected surgically after laser photocoagulation in 4 patients. The excised tissues were snap frozen and evaluated by histology. Molecular pathology was performed for the VHL gene, and immunohistochemistry and molecular detection (reverse transcription polymerase chain reaction) were carried out for VEGF, CXCR4, and CXCL12.
  
  
  METHODS
  Evaluation of clinical presentations and molecular pathology of the excised retinal lesions.
  
  
  RESULTS
  Large retinal hemangioblastomas were resected successfully from the 3 VHL cases. Postoperatively, all patients were stable. Molecular analyses disclosed the loss of heterozygosity at the VHL allele locus in the VHL retinal hemangioblastomas but not in the vasoproliferative tumor. High levels of transcript and protein were found for VEGF and CXCR4, whereas low levels of CXCL12 mRNA were expressed in the retinal hemangioblastomas associated with VHL disease. In contrast, very low levels of VEGF and CXCR4 mRNA were detected in the vasoproliferative tumor. Furthermore, increased expression of VEGF and CXCR4 was detected in more active hemangioblastomas.
  
  
  CONCLUSIONS
  Surgical resection of large retinal hemangioblastomas may be useful for therapy in selected VHL patients. Activated VHL lesions produce more VEGF. This is the first demonstration of CXCR4 expression in VHL disease-associated retinal hemangioblastomas. We suggest targeting CXCR4 as an additional therapeutic strategy for VHL disease-associated retinal hemangioblastomas.
authors.affiliation: Key Laboratory of Ophthalmology of the Ministry of Education, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liang
authors.forename: Defen
authors.initials: D
authors.lastname: Shen
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Chunyue
authors.initials: C
authors.lastname: Yin
authors.forename: Christine M
authors.initials: CM
authors.lastname: Bojanowski
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
mesh_terms: D000293:Adolescent; D000328:Adult; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018325:Hemangioblastoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008967:Molecular Biology; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D019572:Retinal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human