Functioning GHRH– and GH–producing pancreatic neuroendocrine tumors represent <1 % of cases of acromegaly, giving rise to a syndrome known as ectopic or extrapituitary acromegaly [8, 9, 11, 19]. From a clinical perspective, the overt acromegalic features associated with these tumors are indistinguishable from those of pituitary-dependent or classical acromegaly; patients exhibit acral overgrowth, soft tissue swelling, arthralgia, jaw prognathism, fasting hyperglycemia, hyperhidrosis, osteoarthritis, frontal bone bossing, diabetes mellitus, and hypertension [9, 11, 16, 19]. As is the case with pituitary disease, the acromegalic features can be subtle and insidious, leading to a delay in diagnosis of 5–6 years from retrospective recognition of onset of symptoms [1–4, 8, 54]. Once acromegaly is suspected clinically, the diagnosis is confirmed biochemically on the basis of elevated insulin-like growth factor 1 (IGF-1), as well as the lack of suppression of GH during oral glucose tolerance testing (Table 15.3) [1, 9, 11, 15]. However, confirmation of an ectopic source requires clinical acumen, and unfortunately, many patients are only diagnosed after pituitary surgery fails to identify a pituitary adenoma, and instead, pituitary hyperplasia is diagnosed. The diagnosis can be made on MRI of the pituitary, which shows diffuse enlargement with no enhancing rim of normal adenohypophysis [55–57]. In some cases, the distinction between hyperplastic and adenomatous pituitary lesions can be challenging clinically and radiologically [9, 11, 19]. When the possibility of an ectopic source of GHRH is suspected, measurement of plasma GHRH using a threshold of 250–300 ng/L has been shown to have excellent specificity for the diagnosis of a GHRH-producing tumor and is also a biomarker for follow-up of patients after treatment [9, 11]. A recent review of 55 cases of functioning GHRH-producing tumors reported a median GHRH value of 860 ng/L (range 100–145,000 ng/L), with only three patients between 100 and 250 ng/L [11]. Lack of GH response to exogenous GHRH 1–44 has been proposed by some investigators as a mean to distinguish GHRH excess from a primary GH-producing pituitary tumor, as there is usually no response in ectopic acromegaly [11]. Moreover, an elevation of serum GH after thyrotropin releasing hormone (TRH) stimulation test has been described in ectopic acromegaly [19]. Elevated serum prolactin levels have also been frequently reported (up to 70 % in some studies), and in cases where pituitary pathology has been carefully investigated, this is attributed to mammosomatotroph hyperplasia, consistent with the findings in mice overexpressing GHRH [1, 9, 11, 58, 59]. Furthermore, GHRH-producing pancreatic tumors occasionally secrete multiple hormones (gastrin, ACTH), leading to concomitant clinical syndromes (Zollinger-Ellison or Cushing’s syndrome) [1, 2, 8, 11, 54]. Radiographically, GHRH-producing tumors are typically large and easy to localize on computed tomography (CT) or somatostatin receptor scintigraphy, with a reported median diameter of 5.5 cm (range, 1–25 cm), and over 65 % of cases presented with liver metastases in recent series [9, 11].

A single case of GH–producing pancreatic neuroendocrine neoplasm has been reported in a 63-year-old man, presenting with classic features of acromegaly and elevated serum GH and IGF-1 levels; CT scan of the pituitary was unremarkable, while that of the abdomen revealed a 8.1 × 6.6 cm mass in the head of the pancreas [17, 18]. Dynamic GH responses confirmed the functional autonomy of the GH-producing pancreatic tumor: serial GH sampling showed slight fluctuations with no discrete episodes of absent GH secretion, which is unlike pituitary acromegaly [18].

Ghrelin–producing pancreatic neuroendocrine tumors are nearly impossible to detect on clinical grounds alone, due to the absence of distinct functional symptoms. Recently, a putative ghrelin syndrome has been proposed on the basis of vague clinical symptoms with body mass index (BMI) preservation despite widely disseminated disease, likely secondary to the orexigenic effect of extremely elevated serum ghrelin levels [5, 22–25]. A single case of ghrelin-producing pancreatic tumor was described in a 66-year-old woman, with a BMI of 29.9 kg/m [2], who was referred initially for an episode of intestinal subocclusion [27]. On further investigations, a pancreatic tumor with multiple hepatic metastases was detected on imaging; her circulating ghrelin levels were reported at 12 000 pM, with normal GH and IGF-1 serum levels (Table 15.3) [27]. A second case of gastric ghrelinoma was described in a 46-year-old Caucasian male, referred for occult gastrointestinal bleeding [26]. Similar to the first case, no evidence of acromegaly was found; the patient had a circulating ghrelin levels of 2,100 ug/L, with normal GH and IGF-1 serum levels [26]. Despite advanced disease with radiographic evidence of liver metastases, the patient maintained a stable BMI of 32 kg/m², and his appetite remained good even at his last follow-up appointment 1 year after diagnosis [26]. Recently, Walter and colleagues described three additional cases of metastatic neuroendocrine tumors (one pancreas, one rectum, one gallbladder) with elevated circulating ghrelin levels (respectively, 49 028, 63 711, and 101 996 pg/mL) [28]. However, no evidence of clinical or biological effects of ghrelin was reported in these cases [28].

Functioning PTHrP– and PTH–producing pancreatic neuroendocrine tumors give rise to hypercalcemia of malignancy, a paraneoplastic syndrome that encompasses a constellation of symptoms including anorexia, dehydration, nausea, vomiting, poor appetite, obstipation, polyuria, polydipsia, fatigue, muscle weakness, cerebral symptoms, and palpitations (Table 15.3) [10, 33, 34, 37]. In advanced stages, malignant hypercalcemia can lead to progressive mental impairment and renal failure [36]. The majority of cases (80 %) are attributed to PTHrP overproduction, causing a clinical syndrome known as humoral hypercalcemia of malignancy [36]. PTHrP-producing neuroendocrine tumors usually have an insidious onset, with hypercalcemia seen in late stages of the disease [4, 10, 33, 34, 38]. As a result, almost all cases of PTHrP-producing pancreatic tumors presenting with hypercalcemia have metastatic disease at the time of diagnosis [1, 4, 10, 33, 34, 38]. Given its nonspecific clinical findings, hypercalcemia is typically detected on routine biochemical testing. The diagnosis of humoral hypercalcemia of malignancy is typically confirmed biochemically in conjunction with radiographic findings of malignancy, by demonstrating elevated serum calcium, ionized calcium, and PTHrP levels, as well as low PTH levels [10, 33, 37, 38]. In patients with elevated PTH serum levels, primary hyperparathyroidism as part of MEN1 syndrome should be considered [10, 34, 37]. Serum 25(OH)D and 1,25(OH)₂D levels, bone scan, skeletal survey, and parathyroid imaging may also be indicated to exclude alternative etiologies of hypercalcemia when appropriate [10, 36, 37].