Fibrosis and carcinoid syndrome: from causation to future therapy

Abstract

Carcinoid tumors are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete hormones, 5-hydroxytryptamine, tachykinins and other mediators. These substances are thought to be responsible for the collection of symptoms, which include diarrhea, flushing and wheezing, that is known as carcinoid syndrome. Fibrosis that occurs either local to or distant from the primary tumor is one of the hallmarks of carcinoid tumors that originate from the midgut. The fibrotic process can occur in the mesentery as a desmoplastic response and may lead to obstruction of the small bowel, but it can also occur in the lungs, skin or retroperitoneum. Importantly, up to one-third of patients develop cardiac valvulopathy. One or more products that are secreted by the tumor and enter into the circulation are likely to have a role in this process. This Review discusses the incidence and prevalence of fibrosis in carcinoid syndrome and explores evidence to date for causative agents, in particular the roles of 5-hydroxytryptamine and elements of the downstream signaling pathway. Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have.

Neuroendocrine tumors of the small bowels are on the rise: Early aspects and management

“…It occurs when the NET's secreted products (serotonin, tachykinins, prostaglandins) reach the systemic circulation and are not inactivated by the liver [13,32,56] . Abdominal pain due to the desmoplastic reaction that can occur from the ileal NET and metastases in the proximal lymph nodes is also a common feature of carcinoid syndrome [13,32,56] . Because carcinoid syndrome is almost invariably a feature of advanced small intestinal NETs, it is Scherübl H et al .…”

Jejunoileal Neuroendocrine Tumors Complicated by Intestinal Ischemic Necrosis Are Associated With Worse Overall Survival

“…They often spread to the mesentery and form bulky masses; thus, their growth is often close to the mesenteric vasculature. In addition, they elicit abundant stromal fibrosis by secretion of growth factors, 26 which can cause distortion of the mesentery and kinking of the blood vessels. The JINETs also produce serotonin, which is known to have a role in platelet aggregation and vasoconstriction, 27 among other roles.…”

Carcinoid heart disease: two clinical cases and a review

“…14 While it is still debated as to whether serotonin, or another co-secreted hormone or by-product, is causative in the pathogenesis of fibrosis, evidence is mounting in favour of serotonin itself as the causative agent. [14][15][16][17][18] The vast majority of serotonin (90%) originates from the gastrointestinal tract, predominantly from the intestinal enterochromaffin cells (95%), while only 10% is produced in the brain. 17 Indirect evidence of the role of serotonin in the pathogenesis of valvular damage is that patients with cardiac involvement tend to have higher levels of urinary 5-HIAA than those without cardiac involvement.…”

“…[14][15][16][17][18] The vast majority of serotonin (90%) originates from the gastrointestinal tract, predominantly from the intestinal enterochromaffin cells (95%), while only 10% is produced in the brain. 17 Indirect evidence of the role of serotonin in the pathogenesis of valvular damage is that patients with cardiac involvement tend to have higher levels of urinary 5-HIAA than those without cardiac involvement. 10,15,19,20 Drugs known to inhibit the metabolism of serotonin, e.g.…”