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  Disease summary:

  
  
  
  
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    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.

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

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

    
    
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    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.

    
    
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    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%.

    
    
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    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.

  
  

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  Hereditary basis:

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

    
    
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    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.

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

    
    
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    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.

  
  

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  Differential diagnosis:

  
  
  
  
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    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

WHO histologic classification of PNETs

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

  
  
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  Well-differentiated endocrine carcinomas (low-grade malignancy)

  
  
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  Poorly differentiated carcinomas (high-grade malignancy)

  
  
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  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:

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

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

  
  
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  Grade III (Ki67 <20% or <20 mitoses per HPF)—high proliferative index

The TNM staging system was subdivided into specific areas of the gastrointestinal (GI) system and takes into account tumor size, nodal and metastatic dissemination of these tumors. PNETs are frequently sporadic but they may be associated with genetic syndromes such as MEN1, VHL disease, NF1, or tuberous sclerosis. A recent study has shown that there is a different genetic expression between PNETs and pancreatic ductal adenocarcinomas. Genes most commonly affected by mutation in ductal adenocarcinomas are rarely affected in PNETs suggesting a different genetic mechanism involved in their pathogenesis.

PNETs are predominantly (50%) nonfunctional and have an indolent clinical course being diagnosed in an advanced stage.

An essential diagnostic approach of PNETs has to consider the specific clinical presentation of the disease (see the associated clinical findings in Table 46-1), personal medical and family history. The diagnosis of PNETs is complex and may include biochemical diagnosis, histopathology, and tumor imaging. PNETs can be identified using general and specific neuroendocrine markers. Common neuroendocrine markers in the diagnosis of PNETs and non-PNETs are:

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  CgA (all different types of endocrine tumors)

  
  
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  Neuron-specific enolase (NSE)

  
  
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  Synaptophysin (P38)

  
  
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  Protein gene product (PGP) 9.5

  
  
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  CD56

  
  
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  MAP18

  
  
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  CDX2 (intestinal NETs)

  
  
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  Neuroendocrine secretory protein 55 (only in PNETs)

Determination of anterior pituitary hormones, ionized calcium, parathyroid hormone (PTH), and analyzing the menin gene are included in MEN1 screening. Symptoms arising from secreted hormones may lead to measurement of these hormones in the blood or tumor tissue for the initial diagnosis. Hormone-specific markers used in functioning PNETs are (see Table 46-2):

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  Adrenocorticotropic hormone (ACTH)

  
  
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  Calcitonin

  
  
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  Insulin

  
  
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  Growth hormone

  
  
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  Growth hormone-releasing hormone (GHRH)

  
  
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  Glucagon

  
  
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  Gastrin

  
  
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  Neurotensin

  
  
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  Pancreatic polypeptide

  
  
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  Somatostatin

  
  
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  Serotonin

  
  
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  VIP

The next step in diagnosing PNETs is represented by tumor imaging. Anatomic imaging of PNETs is essential for proper diagnosis and surgical management of the disease. Various imaging techniques have been employed in detection of PNETs. The most sensitive and specific imaging modalities considered are computed tomography (CT) and magnetic resonance imaging (MRI) followed by ultrasound.

Transabdominal ultrasound plays a limited role in evaluating these tumors because of difficulties related to imagining of the body and the tail region of the pancreas. Detection rates of ultrasound for pancreatic neuroendocrine tumor (NET) range from 0% to 66%.

Transhepatic venous sampling has a sensitivity of approximately 55%.

Endoscopic ultrasound has a sensitivity rate of 80% to 90%for PNETs.

CT—the use of multiphasic contrast-enhanced CT has improved its sensitivity up to 94.4%. A CT examination is recommended for detection of nodal and metastatic disease.

MRI is very useful for assessment of solid visceral organ lesions with a positive prediction value of 96%. The most typical MRI signs for these lesions are a T2 hyperintensity and T1 hypointensity. Gadolinium-enhanced MRI has a 40% sensitivity.

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  Functional imaging of PNETs is utilized for targeted detection of specific cell receptors leading to the localization of these tumors.

  
  
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  The most common means of detection are somatostatin receptor scintigraphy, F18-fluorodeoxyglucose positron emission tomography (PET)/CT and F18-dihydroxyphenylalanine PET/CT.

Somatostatin receptor scintigraphy (SRS) is considered the gold standard for diagnosis, staging, and follow-up of these tumors.

An octreoscan has an overall sensitivity of approximately 80% to 90%, although it is lower for insulinomas (~40%). Ga-DOTATOC PET carries a sensitivity of 92% to 97%.

Fluorodeoxyglucose (FDG) PET imaging is a molecular imaging technique used for diagnosis of malignant tumors which are avid of glucose and necessitate higher levels of glucose to maintain their metabolism. FDG tumor uptake increases probably in relation to overexpression of glucose transporters GLUT-1, 3, and 5 and hexokinase. The sensitivities are around 50% for this imaging modality which may be more useful for prognostic purposes of PNETs.

F18-dihydroxyphenylalanine PET/CT test rests on the ability of neuroendocrine type cells to take up radiolabeled decarboxylate amino acid precursors and transport them into PNETs via the sodium independent system L. This test seems to be better in detection of PNET lesions compared with SRS. The overall sensitivities reported are in the range of 65% to 96% for the detection of individual lesions. Some authors have found better sensitivities rates for F18-dihydroxyphenylalanine PET/CT compared with conventional CT or SRS.