The distribution of the sst2A receptor was investigated, using immunohistochemistry, with the specific antipeptide antibody R2-88, in a total of 120 tumors of the nervous and the neuroendocrine systems, including small-cell lung carcinomas, medulloblastomas, neuroblastomas, pheochromocytomas, and paragangliomas. The great majority of the tumor samples, frozen or formalin-fixed, showed a positive immunohistochemical staining with R2-88, and an excellent correlation with receptor autoradiography using 125I[Tyr3]-octreotide. Whereas small-cell lung carcinomas and medulloblastomas had a predominantly plasma membrane staining, pheochromocytomas and neuroblastomas had variable ratios of cell surface and intracellular staining. Strikingly, a preferentially cytoplasmic staining was seen in tumors with a high level of somatostatin gene expression, whereas a more plasma membranous staining was seen in tumors lacking somatostatin messenger RNA. Specificity of both the plasma membrane and the cytoplasmic staining pattern was confirmed in immunoblots, which showed the immunoreactive receptor migrating as a characteristic 70-kDa broad band. In both immunohistochemical and immunoblotting experiments, staining was abolished by antibody blockade with 100 nM antigen peptide. These results describe, for the first time, the localization of the sst2A receptor protein in human small-cell lung carcinomas, medulloblastomas, neuroblastomas, and paragangliomas. Moreover, it is the first report investigating possible causes for distinct subcellular localizations of sst2A in human tissues. We show that the subcellular distribution of the receptor may be dependent on the surrounding somatostatin concentration, consistent with both the known effect of somatostatin to cause sst2A receptor internalization and an autocrine regulation of tumors by the peptide they produce. Moreover, our demonstration that the sst2A receptor can be identified in this group of tumors using simple immunohistochemical methods in formalin-fixed, paraffin-embedded material opens numerous diagnostic, therapeutic, and prognostic opportunities.