By special stains, tumor cells are uniformly non-argentaffin and show argyrophilia only with the Hellerstrom-Hellman technique which is selective for somatostatin-producing cells [8].

Immunohistochemically, tumor cells are strongly positive for synaptophysin and with varying degree of immunoreactivity for somatostatin [43] (Figs. 10.1 and 10.2). Immunolabeling for chromogranin A, however, may be negative [23]. More than half of the tumors additionally exhibit scattered cells with immunoreactivity for other peptides such as pancreatic polypeptide (PP), insulin, glucagon, gastrin, adrenocorticotropin, and calcitonin [23, 43, 47]. As in other types of pancreatic neuroendocrine tumors, the transcription factor islet 1 gene product (ISL1) is also expressed in somatostatin-producing tumors [48]. In the series of Garbrecht et al., tumors with a gangliocytic appearance typically showed immunohistochemical positivity for somatostatin, VIP, and PP [23].

By electron microscopy, tumor cells contain two distinct populations of intracytoplasmic membrane-bound neurosecretory granules (Fig. 10.3). The majority of the secretory granules are large (range of diameter 250–450 nm), round, and moderately electron dense, resembling those of normal D cells. The second subset consists of smaller granules (range of diameter 150–300 nm), with dense cores surrounded by a thin peripheral halo [43].

Because of the rarity of these tumors, there are only very few molecular data on somatostatinomas available in the literature. Recently, somatic and germline mutations in the HIF2A gene of patients with pheochromocytomas/paragangliomas associated with polycythemia, and in some of them also with somatostatinomas were described [49].