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INTRODUCTION

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Epidemiology

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Epidemiology
Incidence: 1/100,000
~85% sporadic; ~15% hereditary, for example, multiple endocrine neoplasia (MEN1), von Hippel-Lindau disease
Median age: 53–57 years
Male to female ratio: 0.8–1.3:1

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Hochwald SN et al. J Clin Oncol 2002;20:2633–2642

Öberg K, Eriksson B. Best Pract Res Clin Gastroenterol 2005;19:753–781

Tomassetti PD et al. Ann Oncol 2005;16:1806–1810

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Pathology

WHO classification: Pancreatic endocrine tumors

  1. Well-differentiated neuroendocrine tumor (20–35%): no gross invasion

    • Benign: no angio- or perineural invasion, size <2 cm, <2 mitoses/10 high-power fields (HPF), <2% of cells Ki67-positive

    • Of uncertain behavior: angio- and/or perineural invasion and/or >2 cm and/or 2–10 mitoses/10 HPF and/or >2% of cells Ki67-positive

  2. Well-differentiated neuroendocrine carcinoma (51–71%): gross local invasion and/or metastases

  3. Poorly differentiated neuroendocrine carcinoma (9–21%): >10 mitoses/10 HPF

 

Functional status:

Nonfunctioning: 59–76%

Insulinoma: 8–17%

Gastrinoma: 10–14%

Glucagonoma: 1–6%

VIPoma: 2–5%

 

Ekeblad SB et al. Clin Cancer Res 2008;14:7798–7803

Fischer L et al. Br J Surg 2008;95:627–635

Pape U-F et al. Cancer 2008;113:256–265

Rindi G, Klöppel G. Neuroendocrinology 2004;80 (Suppl 1):12–15

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Work-up

Radiology

  1. Body CT or MRI

  2. Somatostatin receptor scintigraphy: Uses radioactive octreotide, a drug similar to somatostatin that attaches to tumor cells that have somatostatin receptors

  3. Positron emission tomography (PET) scan (in selected cases)

    • [11C]5-hydroxy-l-tryptophan (5-HTP) PET for well-differentiated tumors

    • Fluorodeoxyglucose (FDG) PET for poorly differentiated tumors

  4. Endoscopic ultrasound

  5. Intraoperative ultrasound

    • To localize small tumors not visualized by other modalities but suspected because of biochemical findings

    • To localize multiple tumors in MEN1 patients

 

Biochemistry

  1. In all patients with suspected pancreatic endocrine tumor

    • Fasting levels of:

      • insulin, proinsulin, blood glucose

      • gastrin

      • glucagon

      • pancreatic polypeptide

      • vasoactive intestinal peptide (VIP)

      • chromogranin A

  2. If insulinoma is suspected (high fasting insulin or symptoms of hypoglycemia):

    • 72-hour fast with measurements of insulin, proinsulin, and plasma glucose

    • Consider differential diagnoses, for example, measurement of sulfonylurea in blood to exclude abuse of oral hypoglycemic drugs

  3. If gastrinoma is suspected (high fasting gastrin in the absence of treatment with proton pump inhibitors, multiple ulcers, and/or steatorrhea):

    • Measure gastrin after secretin stimulation test (after withdrawal of proton pump inhibitors, ideally for 1 week)

    • Measure gastric pH together with fasting gastrin

  4. If ectopic Cushing syndrome is suspected to be caused by a pancreatic tumor:

    • Measure 24-hour urine free cortisol excretion, or free cortisol to creatinine ratio

      A ratio of cortisol >95 mcg per gram of creatinine helps confirm hypercortisolism

    • Measure adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor (CRF)

 

Biopsies

  1. If possible, radiologically verified tumors should be biopsied under ultrasound guidance

  2. Ideally, biopsy specimens should be evaluated by pathologists knowledgeable in endocrine pathology and stained for:

    • General markers for pancreatic endocrine tumors: Chromogranin A, synaptophysin

    • Specific hormones: Insulin, gastrin, glucagon, VIP, pancreatic polypeptide

    • Markers of proliferation: Ki67

MEN1 investigation

  1. If MEN1 is suspected (family history, hyperparathyroidism)

    • Measure serum calcium, PTH, prolactin

    • Perform genetic testing

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Staging

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