ACTH-secreting Pancreatic Neoplasms Associated With Cushing Syndrome

Abstract

Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, β-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs.

Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter study

“…Pancreatic NETs were the most frequent source of ECS among GEP-NETs; they were usually of great size with distant metastases. The majority of pNETs (9/13) were well differentiated (G2 and G1) as found in a recent report (20). These tumors did not have distinctive histological features compared with pNETs without ECS; however, they displayed signs of aggressiveness including vascular and perineural invasion.…”

Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology

“…Patients with metastatic disease rarely show symptoms due to lipase hypersecretion, which include subcutaneous fat necrosis and polyarthralgia (5–7). Occasionally, patients, especially when young, may present increased alpha-fetoprotein (AFP) blood levels that should be considered as a suspicious marker of ACC in the presence of a pancreatic mass (8–11). Although most ACCs arise sporadically, rare cases diagnosed in the context of Lynch syndrome or familial adenomatous polyposis (FAP) have been documented (4, 12–14).…”

“…Serum AFP levels were elevated in all pediatric cases of ACCs in which it was measured (10, 67) and it has been hypothesized that AFP production in pancreatic neoplasms is related to acinar differentiation (10). In 3 of 29 pediatric ACCs, the most significant clinical manifestation was Cushing’s syndrome due to ectopic production of ACTH by tumor cells (11, 68, 69). …”

“…Among the 29 cases reported in the literature, 22 were pure ACCs, 4 MANECs, 1 acinar cell cystoadenocarcinoma, 1 mixed acinar-ductal carcinoma, and 1 mixed acinar-neuroendocrine-ductal adenocarcinoma. The cases of ACCs associated with Cushing’s syndrome were characterized by a surprisingly scant neuroendocrine component weakly immunoreactive for ACTH and general neuroendocrine markers including chromogranin A and synaptophysin (11, 68, 69). …”

A retrospective analysis of postoperative hypokalemia in pituitary adenomas after transsphenoidal surgery

“…ACTH-pituitary adenomas are recognized as a more aggressive and invasive subtype of pituitary adenomas (Jesser, Schlamp & Bendszus, 2014; Lake, Krook & Cruz, 2013; Maragliano et al, 2015). Total-body potassium is predominantly present as an intracellular component.…”