Specific immunohistochemical pattern of carbonic anhydrase IX is helpful for the diagnosis of CNS hemangioblastoma

Schaller, Tina; Bode, Markus; Berlis, Ansgar; Frühwald, Michael C.; Lichtmannegger, Ines; Endhardt, Katharina; Märkl, Bruno

doi:10.1016/j.prp.2015.03.003

Cited by 5 publications

(1 citation statement)

References 27 publications

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“…We performed flow cytometry to confirm the presence of viable HB stromal cells in our experimental substrates. HB stromal cells were gated for marker carbonic anhydrase-IX (CA-IX)23, and cC3/cPARP positive cells were marked as apoptotic cells. We found satisfactory proportions of viable HB stromal cells (CA-IX positive, cC3/cPARP negative) cells with the harvesting procedure (60 ± 16%) (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Somatostatin receptor expression on von Hippel-Lindau-associated hemangioblastomas offers novel therapeutic target

Sizdahkhani

Feldman

Piazza

et al. 2017

Sci Rep

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Von Hippel-Lindau (VHL)-associated hemangioblastomas (VHL-HB) arise in the central nervous system (CNS), and are a leading cause of morbidity and mortality in VHL disease. Currently, surgical resection is the most effective way to manage symptomatic VHL-HBs. Surgically unresectable VHLHBs or those in frail patients are challenging problems. Therapies targeting oncologic and vascular endothelial growth factor (VEGF) pathways have failed to demonstrate tumor control. Our experience and previous reports on VHL-HB avidity to somatostatin analogues suggested somatostatin receptor (SSTR) expression in VHL-HBs, offering an alternative therapeutic strategy. We explored this possibility by demonstrating consistent histologic expression of SSTR1, 2a, 4, and 5 in VHL-HBs. We found that somatostatin analogue octreotide induces apoptosis in VHL-HB stromal cells in a dose-dependent fashion by BAX -caspase-3 pathway unrelated to canonical VHL pathway. When administered to a patient with unresectable symptomatic suprasellar hemangioblastoma, octreotide resulted in tumor volume reduction, symptom stabilization, and tumor cytopenia on repeat 68 Ga-DOTA-TATE positron emission tomography (PET) within 6 months, suggesting tumor infarction. We conclude that VHL-HBs harbor multiple SSTR subtypes that offer actionable chemo-therapeutic strategy for management of symptomatic, unresectable tumors by somatostatin analogue therapy.Von Hippel-Lindau disease (VHL) is an autosomal-dominant tumor disorder affecting 1 in 36,000 live births 1 due to mutations in the tumor suppressor VHL gene 2 . Up to 80% of patients with VHL develop central nervous system (CNS) hemangioblastomas (HBs) in the infratentorial regions, including the cerebellum and spinal cord, due to somatic 'second hits' at the VHL locus 3,4 . Approximately half of the VHL associated HBs (VHL-HBs) will grow over time and lead to mass effect-related neurological symptoms 5 . Surgical resection of symptomatic VHL-HBs remains the standard-of-care, but even with optimal management VHL-HBs remain a leading cause of death in VHL patients 3,4 . In some cases, surgical resection of symptomatic VHL-HBs is not an option due to unresectable locations or due to extensive co-morbidities. Development of chemotherapy and anti-angiogenic therapy for such patients remains underdeveloped due to the indolent nature of VHL disease [6][7][8][9][10] . Due to relatively long life expectancy of VHL patients 11 , treatment with toxic chemotherapeutic agents is not feasible for extended periods of time. Alternative strategies for long term management of unresectable VHL-HBs may arise from observations that VHL-HBs originate from hematopoietic precursors 12,13 , and that hematopoietic stem cells are known to express somatostatin receptors 14 . Our experience with DOTA-TATE positron emission tomography (PET) imaging of VHL patients confirms previous reports of VHL-HB avidity to somatostatin analogues (Fig. 1A-D) [15][16][17] . However, the therapeutic

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Section: Resultsmentioning

confidence: 99%