Immunohistochemically, all ACTH-producing pancreatic neuroendocrine tumors react with general neuroendocrine markers (synaptophysin, neuron-specific enolase, chromogranin A, CD56). These tumors are also immunoreactive for ACTH and/or other ACTH-related peptide hormones, such as pro-opiomelanocortin (POMC), melanotropin (MSH), β-endorphin, and met-enkephalin, all identifiable using specific antibodies in at least a fraction of tumor cells [93] (Figs. 13.5 and 13.6). Intriguingly, several neuroendocrine tumors of the pancreas have been reported to show ACTH expression and clinical features of CS only in recurrences or in metastatic localization, while the primary neoplasm was ACTH negative [63, 74]. As it is also clinically evident, plurihormonality is not an infrequent feature of CS-associated PanNETs. Interestingly, a few of these neoplasms have been found to be immunoreactive also for corticotropin-releasing hormone (CRH), including malignant plurihormonal neuroendocrine tumors associated with ZES [74]. In addition, a case of CRH-immunoreactive PanNET associated with ECS, with no expression of ACTH or other hormones, has also been described [69]. All ZES-associated tumors show positive immunostaining for gastrin (Fig. 13.7), whereas insulin was detected in tumors associated with insulinoma syndrome. It has been recently reported that ACTH-producing neuroendocrine tumors of the pancreas can be immunoreactive for CD117 and galectin-3, although the meaning of the expression of these molecules is still unclear [92]. Finally, ACTH-secreting PanNETs show a weak expression of SSRT2A, possibly due to the downregulation of the SSTR by high levels of glucocorticoids, as reported in ACTH-secreting pituitary adenomas [95–97]. However, octreotide therapy has been shown to suppress ACTH and cortisol secretion in several patients with ectopic ACTH production from PanNETs, bronchial carcinoids, and medullary carcinoma of the thyroid [1].

ACTH-producing PanNETs have a high metastatic rate, with 79 % of all cases presenting with systemic disease or developing distant metastases during the history of the disease [91]. As a consequence, the majority of these tumors have a high stage at diagnosis, according to the ENETS system [98]. The liver is the most frequent site of hematogenous localization, and it is almost invariably involved in metastatic disease. Less frequently, distant metastases may occur in the lung, in the bones, and in pelvic organs, i.e., ovaries [91].