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Characterizing a challenging cancer

Neuroendocrine neoplasms can be characterized by their1,4,10

  • Anatomic site of origin
  • Histology
  • Grade
  • Stage (extent of disease)
  • Hormone secretion (functional or nonfunctional)

Anatomic site of origin

Many characteristics of NETs are site specific,11 and most NETs arise in these locations4,8:

Chart showing the Classification of Neuroendocrine Tumors (NETs)

Despite these varied tissues of origin, all NETs

  • Have similar pathologic features
  • Can secrete bioactive products (most commonly serotonin or peptides such as insulin, gastrin, and glucagons)
  • Express neuroendocrine markers including chromogranin A (CgA)5,10

It is important to note primary tumors are often small,3,12 which may contribute to diagnosis being delayed until after the tumor has metastasized.4,13

Even small NETs (<2 cm) have the potential to metastasize.14,15


The WHO 2010 guidelines divide neuroendocrine neoplasms into 2 clinically distinct pathologic classes: well- and poorly differentiated.

  • Well-differentiated NETs can be classified as either grade 1 or grade 2
  • Poorly differentiated neuroendocrine carcinomas are classified as grade 31


Some of the biological behavior exhibited by neuroendocrine neoplasms is highly correlated with neoplasm grade10,16:

  • Grade 1 NETs are relatively slow growing16
  • Grade 2 NETs have a less predictable, moderately aggressive course10
  • Grade 3 neuroendocrine carcinomas can be highly aggressive16
Current Grading System for Neuroendocrine Tumors (NETs)

Stage, or extent of disease

The Surveillance, Epidemiology, and End Results (SEER) program database uses a "localized," "regional," and "distant" system to stage disease. NETs are also staged using this system.16

The SEER database is a comprehensive cancer statistics program operated by the National Cancer Institute. SEER is widely used to establish the epidemiologic landscape for various types of cancer throughout the world.

Extent of disease as shown by computed tomography

Additionally, the Worldwide Health Organization (WHO), the Union for International Cancer Control (UICC), and the American Joint Committee on Cancer (AJCC) classification systems reflect the widespread recognition that NETs should be staged using tumor-node-metastasis (TNM) staging criteria. In TNM guidelines, the fundamental staging landmarks for NETs parallel those used for carcinomas of the corresponding organs.1,16

Secretory potential (functional or nonfunctional)

Finally, NETs can be classified by whether or not they are capable of producing hormonal substances. This is sometimes referred to as functional status.7,13,19

  • Functional NETs produce symptoms that can be attributed to the secretion of specific hormones or peptides
    (eg, diarrhea, hypoglycemia, flushing)
  • Nonfunctional NETs produce symptoms that are not related to hormonal hypersecretion but to increasing mass
    (eg, pain, obstruction, bleeding)2

Most NETs are nonfunctional, and some NETs remain asymptomatic indefinitely. Many of the symptoms and syndromes that NETs can cause do not occur until the tumor has metastasized.3,12 In fact, about 50% of patients with reported disease stage have either regional or distant metastases at diagnosis.4