Aetiology

Neuroendocrine tumours (NETs) of the gut are thought to arise from cells of the diffuse endocrine system. These cells are characterised by the production of a wide variety of hormonal peptides and other bioactive substances.[10] Midgut tumours that lead to carcinoid syndrome vary from benign, well-differentiated endocrine tumours to low-grade malignant endocrine tumours.[11] Occasionally, some midgut tumours can be poorly differentiated endocrine carcinomas.

Approximately 40% of NETs are functional. Carcinoid syndrome occurs in 20% to 30% of patients with midgut carcinoid tumours and approximately 5% of bronchial carcinoids. Other foregut tumours (e.g., pancreatic NETs) can cause carcinoid syndrome, although this is uncommon (1%). Hindgut tumours are generally non-functional and only occasionally cause carcinoid syndrome. Carcinoid syndrome is usually seen in patients with liver metastases (95% of patients), but excess tachykinins, serotonin (5-hydroxytryptamine) production from retroperitoneal metastases, or ovarian tumours can bypass the liver and systemic circulation.

Pathophysiology

Neuroendocrine tumours normally secrete biogenic amines into the circulation. However, when the primary site is within the gut, the secreted amines are degraded by the liver and symptoms do not generally occur.[12] When liver metastases are present, these amines drain into the circulation prior to being broken down and, hence, cause carcinoid syndrome.[13] The most prominent secretory products of carcinoid tumours are amines, kallikrein, and prostaglandins. One of these amines is serotonin. Normally serotonin is synthesised from tryptophan and is subsequently metabolised by monoamine oxidase to 5-hydroxyindoleacetic acid, which is subsequently secreted in the urine.[14] In healthy people, approximately 99% of tryptophan is used for the synthesis of nicotinic acid and <1% is converted to serotonin. However, in patients with carcinoid tumours there is a shift towards the production of serotonin. The increased production of serotonin and other products and their direct release into the systemic circulation, due to liver metastases, leads to the development of carcinoid syndrome.[15]

Classification

Functional/non-functional

Tumours can be either non-functional or functional, depending on whether or not they secrete peptides leading to syndromes (e.g., serotonin and kinins released from neuroendocrine tumours [NETs] leading to carcinoid syndrome).

Foregut/midgut/hindgut

Tumours can be separated depending on embryological origin:

  • Foregut: from mouth to duodenum

  • Midgut: from jejunum to ascending colon

  • Hindgut: the remaining colon and rectum

Typical/atypical bronchial NETs

Typical carcinoid tumours generally are slower growing and less likely to metastasise than atypical tumours. Atypical carcinoid tumours are more aggressive than typical tumours, with a higher rate of metastases.

Histopathological[1]​​

The WHO has updated the histological classification of neuroendocrine neoplasms (NENs). These tumours are now collectively referred to as NENs and are divided into two categories based on differentiation:[2]

  • Well-differentiated tumours, referred to as NETs

  • Poorly differentiated cancers, termed Neuroendocrine Carcinomas (NECs)

The grading system for NENs remains largely the same, with well-differentiated NETs being graded into Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3) based on their Ki-67 proliferation index. Poorly differentiated NECs are always classified as high-grade (G3) tumours due to their aggressive nature.

Well-differentiated NEN

  • Grade 1

  • Grade 2

  • Grade 3

Poorly-differentiated NEN

  • NEC (high grade)

    • Small cell type (SCNEC)

    • Large cell type (LCNEC)

  • Mixed endocrine non-endocrine neoplasm (MiNEN) (grade 1-3)

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