Pancreatic neuroendocrine neoplasms – diagnosis and staging

The clinical manifestations in functional neoplasms very often result from the distinctive metabolic effects of the hormones secreted by the neoplastic cells, rather than from tumor bulk or metastatic disease. Therefore, functional neoplasms are usually diagnosed at an early stage, and may even be too small to be detected by cross-sectional imaging techniques. On the contrary, non-functional neoplasms do not produce specific clinical syndromes (although they may secrete inactive amine and peptide products), and tend to present at later clinical stages with symptoms attributable to mass effect or metastases. However, thanks to the widespread application of cross-sectional imaging, such as CT-scan and magnetic resonance imaging, the number of small incidentally discovered non-functional pancreatic neuroendocrine neoplasms is dramatically increasing. To learn more about the specific symptoms of neuroendocrine neoplasms, visit the sections on functional neoplasms and non-funcional neoplasms. 

Pancreatic neuroendocrine neoplasms in most cases appear as ovalar, well circumscribed masses rich in blood vessels. In a minority of cases their morphologic characteristics might be atypical, making the differential diagnosis with ductal adenocarcinoma difficult. Pancreatic neuroendocrine neoplasms may occasionally present as cystic neoplasms.

If a pancreatic neuroendocrine neoplasm is suspected, high-quality cross-sectional imaging is necessary to confirm the diagnosis and to stage the neoplasm. A staging system is a standardized way in which the cancer care team describes the extent that a cancer has spread, and contains different pieces of information, including:

  • The size of the primary tumor
  • Whether the tumor has spread to nearby organs or vessels
  • Whether the tumor has spread to nearby lymph nodes
  • Whether the tumor has spread (metastasized) to distant organs 

Here are described the imaging tests to diagnose and stage pancreatic neuroendocrine neoplasms.

  • Contrast-enhanced computed tomography (CT). The CT scan is an x-ray test (it uses ionizing radiations) that produces detailed cross-sectional images of the body. 3D reconstruction softwares allow detailed tumor characterization. CT scans show the pancreas fairly clearly and often can confirm the location of the tumor, which appears hyso-hyperdense and richly enhanced. CT scans can also show the organs near the pancreas, as well as lymph nodes and the liver, where the cancer might have spread. 
  • Magnetic resonance imaging (MRI). MRI scan use radio waves and strong magnets instead of x-rays. It is a multiplanar imaging modality. MRI is a complementary imaging modality for the staging of pancreatic neuroendocrine neoplasms. In particular, it may be very useful to localize small lesions, thanks to the high contrast resolution. Furthermore, the use of hepato-specific contrast agents (Gd-BOPTA) allows better detection of small liver metastases.
  • Contrast-enhanced ultrasonography (CEUS). This is an new imaging technique that involves the use of microbubble contrast agents to show real-time tissue perfusion information. In CEUS examination, pancreatic neuroendocrine neoplasms shows an early and rich enhancement during the dynamic phases. Both margins and size of the lesion are more visible, improving the detection of vascular infiltration. In addition, CEUS improves hepatic staging. 
  • Ecoendoscopic ultrasound (EUS). Endoscopic ultrasound is performed using an ultrasound probe that is attached on the tip of an endoscope. This allows direct vision of the duodenum and of the papillary region as well as a very detailed ultrasonography of the pancreas, which sits next to the duodenum. It is particularly useful, and probably better than CT-scan, for spotting small tumors (such as incidentally diagnosed non-functional neoplasms or functional neoplasms of the duodeno-pancreatic area). If a tumor is seen, a trans-gastric or a trans-duodenal biopsy can be performed during this procedure. 

  • Somatostatin receptor scintigraphy (OCTREOSCAN™). It is a nuclear medicine test using a somatostatin analogue (octreotide) that has been bound to a radioactive substance (indium-111). Octreotide attaches somatostatin receptors that may be expressed by neoplastic cells of many neuroendocrine neoplasms. After a while from the octreotide injection, a gamma-camera is used to show where the radioactivity has collected in the body. More scans may be done on the following few days as well. This scan can help diagnose neuroendocrine neoplasms, but it can also help decide on a treatment. If a neuroendocrine neoplasm shows up on a OCTREOSCAN™, it often means that the tumor will stop growing if treated with octreotide. This test is less frequently used because of the introduction of PET radio tracers.

  • Gallium-68 positron emission tomography (68-Ga PET-CT). PET-scan involves the use of a very small dose of a intravenous radio tracer that is absorbed by neoplastic cells and detected by the scanner. The Gallium-68 PET scan is based on similar technology to OCTREOSCAN™. In particular, the Gallium-68 labeled compound DOTATATE binds very strongly to the somatostatin receptors expressed by many neuroendocrine neoplastic cells. PET scan is combined with CT-scan to provide detailed images. The Gallium-68 PET/CT scan offers higher spatial resolution than octreotide scans (3-6 mm versus 10-15 mm), and results more effective at detecting very small neoplasms and metastases. 

Once the radiologic characterization has been obtained (tumor size, relation with peripancreatic vessels, lymph node status, presence of metastases), this information is combined to assign a stage. Two staging systems based on TNM (tumor/node/metastasis) are currently in use. The former has been proposed by the American Joint Commitee on Cancer (AJCC, www.cancerstaging.org), the latter by the European Neuroendocrine Tumor Society (ENETS, click here for more information). Tumor stage is expressed in Roman numerals I through IV. Here are the ENETS stage groups of pancreatic neuroendocrine neoplasms:

  • Stage I: The tumor is confined to the pancreas and is less than 2 cm in size. It has not spread to nearby lymph nodes or distant sites.
  • Stage IIA: The tumor is confined to the pancreas and is between 2-4 cm in size. It has not spread to nearby lymph nodes or distant sites.
  • Stage IIB: The tumor is > 4cm  growing into the common bile duct or the duodenum. It has not spread to nearby lymph nodes or distant sites.
  • Stage IIIA: The tumor is growing outside the pancreas (stomach, spleen, colon, kidney, adrenal) and/or into superior mesenteric artery or celiac trunk. It has not spread to nearby lymph nodes or distant sites.
  • Stage IIIB: The tumor has spread to nearby lymph nodes but not to distant sites.
  • Stage IV: The cancer has spread to distant sites.

Radiologic staging divides pancreatic neuroendocrine neoplasms into groups, based on whether the neoplasm is confined to the pancreas, has spread to nearby organs, or has spread to distant organs. Click on the following links to learn more.