Somatostatin Receptor Subtypes in Human Pheochromocytoma: Subcellular Expression Pattern and Functional Relevance for Octreotide Scintigraphy

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Abstract
The stable somatostatin analog octreotide has been successfully used for imaging and treatment of a variety of human tumors. In pheochromocytoma, data on somatostatin receptor subtyping have thus far been sparse. Pheochromocytomas often express more than one somatostatin receptor, and it is uncertain by which receptor subtype the functional responses of octreotide are mediated. Here, we have examined somatostatin receptor protein expression in a panel of 52 pheochromocytomas from 35 randomly selected patients by immunostaining with specific polyclonal anti-sst1–5 and monoclonal mouse anti-SS-14 antibodies. Staining pattern, distribution and subcellular localization of somatostatin receptor subtypes were investigated. Seventeen patients received 111In-octreotide scintigraphy. Although the vast majority of tumors (90%) showed positive immunohistochemical staining for sst3, immunoreactive sst2A receptors were only seen in 13 tumors (25%). All other somatostatin receptor subtypes were less frequently detected. Interestingly, among sst3-positive tumors strikingly different subcellular distributions of immunoreactive sst3 receptors were observed. In most cases, immunoreactive sst3 receptors were distributed throughout the cytosol. Scintigraphic localization of tumors larger than 1 cm in diameter was always successful in the presence of immunoreactive sst2A receptors. In the absence of sst2A, true-positive octreotide scintigraphy was only seen in the presence of membrane-associated sst3 immunoreactivity. Our findings suggest that selective expression of functional membrane-associated sst3 receptors is sufficient for high tracer uptake during octreotide scintigraphy in a subgroup of human pheochromocytomas. These tumors may represent a potential target treatment with somatostatin receptor agonists with improved sst3 activity.