Introduction: Up to 80% of von Hippel-Lindau disease (VHL) patients develop central nervous system hemangioblastomas (HB) during the disease course. Treatment of choice for symptomatic HBs remains surgery. VHL-related HBs show avid DOTATATE uptake on PET imaging, suggesting the presence of somatostatin receptors (SSTRs). Neuroendocrine tumors and renal cell carcinoma expressing SSTRs have shown clinical response to somatostatin analogues. For the first time, we describe the presence of SSTRs on VHL HBs and demonstrate a possible tumoral response to somatostatin analogues.
Methods: Immunohistochemistry (IHC) for SSTRs 1, 2a, 3, 4, and 5 was performed on 18 formalin fixed, paraffin embedded (FFPE) HBs from VHL patients. Western Blotting was performed on six HBs (OTC-embedded flash-frozen) for SSTRs. HB stromal-cells were harvested and cultured from three freshly resected tumors, proven by using flow-cytometry labeled for the stromal-cell marker CA-9, and plated for cell viability with increasing doses of the somatostatin-analogue Octreotide for XTT assay.
Results: Seventeen of 18 (94%) FFPE tumors showed staining of HB stromal cells on IHC for SSTR2a. Sixteen of 18 (89%) HBs showed staining for SSTR4 and 17 of 18 (94%) stained for SSTR5. IHC for SSTR1 and 3 did not stain HBs. Western blot confirmed positive SSTR presence of SSTR 2 and 5 in VHL HBs. Primary culture of HBs demonstrated dose-dependent decreased survival with Octreotide treatment for 24 hours of 87.8% of control survival at 1ug/ml, 79.29% at 4ug/ml, and 60.5% at 8ug/ml.
Conclusions: VHL-associated HBs consistently show stromal-cell expression of SSTR2a, SSTR4, and SSTR5. Activation of these receptors using Octreotide leads to decreased stromal-cell survival. Further work is necessary to elucidate the mechanism of this response, possibly mediated by the SSTR downstream targets SHP-1 or HIF-2. This study is suggestive of the potential use of Octreotide in the management of VHL HBs.
Patient Care: This work raises the possibility of using Octreotide or other somatostatin analogues to target and reduce the growth of VHL-associated HBs.
Learning Objectives: 1. Understand the potential utility of somatostatin receptor in VHL-associated hemangioblastomas
2. Appreciate the somatostatin receptor expression profile of hemangioblastomas
3. Become aware of the potential utility of using therapeutic somatostatin analogues in hemangioblastomas
References: Böhling et al: Von Hippel-Lindau disease and capillary haemangioblastoma, in pathology and genetics of tumors of the nervous system. World Health Organization classification of tumors. Lyon, France: IARC Press, 2000, pp 223-226
Caplin M et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine. 371(3) 224-33. 2014.
Cives M. et al. Phase II clinical trial of pasireotide LAR in patients with metastatic neuroendocrine tumors. Endocrine Related Cancer. 22(1) 1-9. 2015.
Lonser R et al. von Hippel-Lindau disease. Lancet. 361:2059-2067, 2003.
Lonser R et al. Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurgery. 1055-1062. 2014.
Park D et al. von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med. 4:e60, 2007.
Plonowski, A et al. Inhibition of metastatic renal cell carcinomas expressing somatostatin receptors by a targeted cytotoxic analogue of somatostatin AN-238. Cancer Research 60(11) 2996-3001. 2000.