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Key Points

  • Disease summary:

    • Pancreatic neuroendocrine tumors (PNETs) are uncommon and represent only 1% to 2% of pancreatic neoplasms, about 85% of these tumors occur in the pancreas and 15% are extrapancreatic tumors.

    • Based on their clinical expression these tumors are categorized as either functional or nonfunctional.

    • Functional tumors (~50%) are characterized by abnormal secretion of (often) biologically active peptides mostly insulin, gastrin, glucagon, somatostatin, or vasoactive intestinal polypeptide (VIP).

    • Nonfunctional tumors are clinically silent although they can secrete neurotensin, pancreatic polypeptide or chromogranin A (CgA), but these peptide-like substances are not biologically active. Most nonfunctional PNETs have a malignant course. They are discovered usually when their size is large, have already invaded adjacent organs or metastasized.

    • Among functional tumors, insulinomas and gastrinomas account for 25% and 15% of the cases, respectively. The other functional PNETs are responsible for the remaining 15%.

    • Negative prognostic factors for PNETs are considered: metastasis, tumor diameter, angioinvasion, proliferative index Ki-67, lymph nodes, and mitoses. Localized disease has a 5-year survival rate of 60% to 100%, whereas regional and metastatic PNETs have a 40% and 29% survival rate, respectively.

  • Hereditary basis:

    • Multiple endocrine neoplasia type 1 (MEN1): autosomal dominant trait with greater than 95% penetrance.

    • von Hippel-Lindau (VHL) syndrome: autosomal dominant pattern (80%); 20% due to a new mutation that occurred during the formation of reproductive cells or early in embryogenesis.

    • Neurofibromatosis type 1 (NF1): autosomal dominant (50%) or spontaneous mutations (50%).

    • Tuberous sclerosis: autosomal dominant pattern of inheritance; one-third of cases are inherited and two-thirds of people with tuberous sclerosis complex (TSC) are considered as sporadic; TSC1 mutations–more frequent in familial cases while mutations in the TSC2–more often in sporadic cases.

  • Differential diagnosis:

    • PNETs can be divided into functional and nonfunctional varieties. The functional PNETs lead to a recognizable clinical entity in which one or more hormones are secreted into the bloodstream. Nonfunctioning PNETs are initially asymptomatic and difficult to diagnose. Their diagnosis is more evident later in the disease course. Apart from that, a small number of PNETs are associated to four major genetic syndromes which can be recognized by their specific clinical features. Differential diagnosis has to take the family history (going back three generations) into consideration.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

WHO histologic classification of PNETs

  • Well-differentiated endocrine tumors (benign or uncertain malignant potential)

  • Well-differentiated endocrine carcinomas (low-grade malignancy)

  • Poorly differentiated carcinomas (high-grade malignancy)

  • Mixed endocrine-exocrine carcinomas

The European Neuroendocrine Tumor Society has adopted a staging system of PNETs considering cell characteristics or proliferation capacity of the tumor, and specific tumor node metastasis (TNM) staging system.

Three tumor grade categories were assigned to describe their proliferative behavior:

  • Grade I (Ki67 ≤2% or <2 mitoses per high-power field [HPF])—low proliferative index

  • Grade II (Ki67 3%-20% or 2-20 mitoses per HPF)—moderate proliferative index

  • Grade ...

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