Carcinoid syndrome

1. CARCINOID SYNDROME
PRESENTATION
BY
DR. AJAO O.E

2. OUTLINE
• INTRODUCTION
• EPIDEMIOLOGY
• PATHOPHYSIOLOGY
• CLINICAL PRESENTATION
• DIFFERENTIAL DIAGNOSIS
• INVESTIGATION
• TREATMENT
• COMPLICATION
• PROGNOSIS
• CONCLUSION
• REFERENCES

3. INTRODUCTION
• Carcinoid syndrome(CS) is a paraneoplastic syndrome comprising of
signs and symptoms that occur secondary to metastases of carcinoid
tumors.
• Carcinoid tumors are slow growing well differentiated
neuroendocrine tumors(NETs)
• They can arise anywhere from the primitive gut but are mostly found
in the gastrointestinal tract(commonly small intestine, rectum and
appendix) as well as the lungs

4. • Gastrointestinal NETs(also referred to as carcinoids) are derived from
the diffuse neuroendocrine system in the GI tract that is composed of
enterochromaffin cells (amine and acid producing cells) with different
hormonal profile depending on the site of origin.
• They were originally classified as APUDomas (for amine precursor
uptake and decarboxylation) due to the ability of the
enterochromaffin cells to take up and decarboxylate precursors of
biogenic amines

5. • In most instances they are discovered incidentally at the time of
surgery for other abdominal disorders and their presence may be
undetectable for years without signs or symptoms. This evidence is
supported by their relatively high incidence in autopsy series.
• Symptoms of carcinoids occur either due to local mass effect, the
effects due to tumor engendered fibrosis or the secreted bioactive
products from the neoplasm

6. • Carcinoid syndrome is predominantly associated with neuroendocrine
tumors(NETs) that arise from the midgut in the setting of extensive
liver metastases
• In patients with extensive liver metastases, a large amount the
bioactive substances are not completely metabolized by hepatic or
pulmonary cells and enter the systemic circulation causing carcinoid
symptoms.

7. • Rarely, primary GI-NETs with nodal metastases with extensive
retroperitoneal invasion, pancreatic NETs with retroperitoneal lymph
nodes, or NETs of the lung or ovary with direct access to the systemic
circulation can cause the carcinoid syndrome without hepatic
metastases
• Ovarian carcinoids may also be considered an exception as a patient
with ovarian teratomas whose secretory product enters the systemic
circulation may present with this syndrome without liver metastases

9. EPIDEMIOLOGY
• In 1888, Lubarsch first described a patient with multiple carcinoids of
the ileum but regarded them as carcinomas.(Lubarsch et al; Virchows
Arch 1888)
• In 1890 Ransom WB first described the classical symptomatology of
the carcinoid syndrome in a patient with an ileal carcinoid tumor and
hepatic metastases.(Ranson WB;The Lancet oncology 1890)
• However Oberndorfer in 1907 coined the term “karzinoide” to
describe these tumors (Oberndorfer et al; Zeitschrift fur Pathologie
1907)

10. • Thorson et al described in 1954 described a series of 16 patients
with a new syndrome where patients had symptoms of diarrhea, skin
flushing, edema and ascites. (Thorson et al; American Heart Journal
1954)
• A Swedish series, in which the incidence of carcinoid tumors was
evaluated in surgical specimens and autopsies in a single geographic
location showed an incidence of 8.4/100,000. (Berge T et al; Acta
Pathol Microbiol 1976)

11. • A study from Netherlands found an incidence of carcinoid tumors to
be 1.95 per 100,000.(Quaedvlig et al; Ann oncol 2001).
• In the most updated series of 29,664 patients with GEP-NETs
reported to the Surveillance, Epidemiology and End Results (SEER)
program of the National Cancer Institute, an incidence of
3.65/100,000 individuals per year was reported. (Lawrence B et al;
Endocrinol Metab Clin North Am, 2011)

12. • The prevalence of carcinoid syndrome within all neuroendocrine
neoplasms(NEN) was reported between 18% (J Soga, Journal of
Experimental and Clinical cancer research 2003) and 72% (Janson et
al; Annals of oncology, 1997) based on older series from a UK data
• More recent European data show a prevalence of carcinoid syndrome
in 25% of 837 patients with GEP-NENs (Garcia et al, Annals of
Oncology 2010) and 20% of all 1263 NEN patients (Ploeckinger et al;
Neuroendocrinology, 2009)

13. • A recent article by Halperin et al analyzed the Surveillance,
Epidemiology and End results(SEER) database in USA which
demonstrated that 19% of patients with neuroendocrine neoplasm
had carcinoid syndrome giving an overall prevalence of 1:100,000
population (Halperin et al; The lancet oncology, 2017)
• Patients with carcinoid syndrome have an overall survival of 4.7years
compared with 7.1 years in patients without symptoms of carcinoid
syndrome (Halperin et al, 2017)

14. • A review of carcinoid tumors seen in a tertiary northern institution
showed a slight female preponderance of 1.5:1 and a peak age of
occurrence in the 6th decade. Umar et al; West African Journal of
Medicine 2013
• Sokunle et al from the Department of Pathology and Forensic
Medicine in LUTH reported a case of ileal carcinoid in a patient with
features of intestinal obstruction. Sokunle et al; Arch Int Surg,2017

15. • Obateru et al from the Gastroenterology Unit in FMC Lokoja
documented a case report of a man with cecal carcinoid tumor
(Obateru et al, Nigerian journal of clinical practice, 2017)

16. PATHOPHYSIOLOGY
• GI-NETs(carcinoids) are highly vascularized tumors and have varied
propensity to metastasize and cause the carcinoid syndrome.
• Midgut carcinoids account for 57–67% of cases, foregut NETs for 33%
and hindgut NETs for 8%
• Carcinoid tumors secrete several factors such as polypeptides,
vasoactive amines and prostaglandins.

17. • More than 40 substances have been identified as being potentially
related to carcinoid syndrome of which the main secretory product
include 5-hydroxytryptamine(5-HT)
• Other substances secreted by these tumors include numerous GI
peptides: gastrin, insulin, somatostatin, motilin, neurotensin,
tachykinins (substance K, substance P, neuropeptide K), glucagon,
gastrin-releasing peptide, vasoactive intestinal peptide (VIP),
polypeptide, other biologically active peptides (ACTH, calcitonin,
growth hormone) and prostaglandins

18. Amines Tackykinins Peptides 0thers
5HT Kallikrein Pancreatic polypeptide Prostaglandins
5-HIAA Substance P Chromogranins
5-HTP Neuropeptide K Neurotensin
Histamine HCGα
HCGβ
Dopamine Motilin

19. • One of the main characteristics of enterochromaffin cells is the synthesis,
storage and secretion of serotonin
• Serotonin (5-hydroxytrypamine, 5-HT) is synthesized from tryptophan
through its precursor, 5-hydroxytryptophan (5-HTP), and is subsequently
metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in
the urine.
• In normal subjects, approximately 99% of tryptophan is used for the
synthesis of nicotinic acid (niacin), and 1% or less is converted to 5-HT.

20. • Serotonin is taken up and stored in the platelets while the excesses are
inactivated in the liver and lung and transformed into 5-HIAA.
• In 90–100% of patients with the carcinoid syndrome, there is evidence of
serotonin overproduction
• This is because of the shift toward the production of 5-HT (which are
stored in platelets and tumor secretory granules)and eventually 5-HIAA.
This may lead to tryptophan deficiency and pellagra might ensue as a result
of nicotinic acid deficiency

21. • When 5-HT and other products like kallikrien are secreted into the
portal circulation, they are efficiently metabolized by the liver and do
not usually cause any systemic signs or symptoms.
• However, when liver metastases is present or when the primary
lesions are found in the bronchus and/or ovaries, the systemic
features of the carcinoid syndrome become more evident.

22. • Serotonin has numerous biologic effects including increasing
intestinal secretion with inhibition of absorption, stimulating increase
in intestinal motility and stimulating fibrogenesis.
• It is thought to be predominantly responsible for the diarrhea
patients with the CS have as actions of serotonin in the gut increase
colonic motility with a shortened transit time
• Prostaglandins also mediate increased intestinal motility and fluid
secretion in the gastrointestinal tract.

23. • Kallikrein, which catalyzes the conversion of kininogen to lysyl-
bradykinin and in turn is converted to bradykinin is a strong
vasodilator that results in flushing in patients together with the
vasoactive effect of serotonin
• 5-HT may also stimulate fibroblast growth and fibrogenesis. These
effects can lead to retroperitoneal and mesenteric fibrosis as well as
cardiac valvular fibrosis.

24. Complications of mesenteric fibrosis may include intra-abdominal
vessel ischemia and intestinal obstruction as well as ureteral
obstruction and renal failure
CS may cause fibrotic lesions of the endocardium, particularly on the
right side of the heart, resulting in an insufficiency of the tricuspid valve
and, less frequently, the pulmonary valve

28. CLINICAL PRESENTATION
• Carcinoid tumors grow slowly and symptoms may not occur for
several years. Symptoms are ill defined and given the rarity may be
neglected for a long time
• Onset of symptoms may be spontaneous or may be precipitated by
certain foods and beverages (e.g., alcohol), pharmacologic agents,
and physical or emotional stress.

29. • The main symptoms of CS are episodic facial flushing , diarrhea,
bronchoconstriction, dyspnea and ultimately fibrotic complications
such as mesenteric retroperitoneal fibrosis and carcinoid heart
disease
• Some GI-NETS(carcinoids) cause an atypical carcinoid syndrome that
is thought to be due to deficiency in the enzyme dopa decarboxylase
thus 5HTP cannot be converted to 5HT and 5HTP is secreted into the
blood stream

30. • In these patients plasma serotonin levels are normal but urinary
levels may be increased because some 5HTP cannot be converted to
5HT in the kidney. Characteristically urinary 5HT and 5HT are
increased but urinary 5-HIAA levels are only slightly elevated.
• Foregut carcinoids are the most likely to cause an atypical carcinoid
syndrome; however, they also can cause a typical carcinoid syndrome

31. • Flushing
• Vasodilation of sudden onset causes a deep red or violaceous
erythema of the upper body, especially the neck and face, often
associated with a feeling of warmth and occasionally associated with
pruritus, lacrimation, diarrhoea and facial oedema
• In patients with gastric carcinoids, the characteristic red, patchy
pruritic flush is thought to be due to release of vasoactive substances
such as 5-HT, histamine, caines, tacchykinins as well as from kallikrein
a powerful vasodilator

32. • It is the most frequent symptom and may be brief or may last for
several hours, usually in later disease stages.
• Flushes may be precipitated by increase in adrenergic activity such as
stress and physical exercise as well as alcohol, certain amine rich
foods( such as cheese, chocolate, banana, avocado, nuts )or drugs like
selective serotonin reuptake inhibitors(SSRIs).

33. • Flushing usually is associated with metastatic midgut NETs but can
also occur with foregut NETs. Foregut tumours tend to produce
pruritic wheals that are reddish brown and occur all over the entire
body
• With bronchial NETs (carcinoids), the flushes frequently are
prolonged for hours to days, reddish in color, and associated with
salivation, lacrimation, diaphoresis, diarrhea, and hypotension.

34. • Diarrhea
• The prevalence of CS-associated diarrhea among NET patients with
elevated urinary 5-HIAA is as high as 60-80% .
• However, this type of diarrhea is not typical but rather unspecific,
usually described as intermittent and sporadic and often
accompanied by mild abdominal cramping, and it may become
continuous when complicated by bacterial overgrowth

35. • This somewhat atypical course may explain the delayed diagnosis of
NETs , which can sometimes be after many years of uncomplicated
and mild symptoms that result in many patients being diagnosed with
advanced incurable disease
• Diarrhea usually occurs with flushing (85% of cases). The diarrhea
usually is described as watery. Steatorrhea may be present and
abdominal pain may be occur with the diarrhea or independently

36. • Bronchospasm
• The underlying mechanism is not clear however, patients who
complain about bronchospasm tend to report concurrent flushing,
sneezing and dyspnea.
• Secretion of histamine and 5-HT by the tumor are probably linked to
the mechanisms of bronchospasm.

37. • Pellagra
• Pellagra is a clinical condition caused by niacin deficiency (vitamin B3)
characterized by dermatitis, diarrhea and dementia in severe cases.
• The actual prevalence of pellagra in patients with CS is unknown,
although some report that approximately 5% of CS patients
experience pellagra

38. • Neuropsychological symptoms
• It has been estimated that extreme tryptophan deprivation can lead
to an 87% to 97% reduction in the levels of 5-HT synthesized in the
brain
• Supporting the concept that CS induces neurocognitive dysfunction
through tryptophan depletion, studies with drugs that inhibit 5-HT
synthesis have reported associated depressive symptoms.

39. Carcinoid heart disease
• CHD is part of the CS spectrum and is associated with high mortality
and morbidity.
• Its incidence varies, ranging from 19% to 60%, depending on the
patient population, access to somatostatin analogues, definition of
CHD and methods used for diagnosis

40. • CHD is characterized by deposition of fibrous tissues on the valves
primarily affecting the right heart chambers, particularly the tricuspid
valve, because circulating 5-HT is inactivated in the lungs.
• Therefore, left valve involvement is rare and is usually associated with
a higher risk of interatrial shunt that may be present in these patients
due to overload of the right atrium.

41. • Despite the strong evidence of 5-HT involvement in the development
of CHD, a significant proportion of patients with elevated plasma
levels of 5-HT do not develop this condition, which suggests that
there are other biochemical or genetic mechanisms involved.
• For example, other potential contributing factors are bradykinins,
tachykinins, activin A and tissue growth factor (CTGF).

42. • Bradykinins are associated with endocardium injury that results in
fibrosis as a response mechanism of the endocardium .
• In addition, tachykinins have been described as endocardial
fibroblast pro-proliferative agents that induce plaque formation.

43. • While the initial disease of CHD is usually asymptomatic, symptoms of
right heart failure, such as peripheral edema, abdominal discomfort
and indigestion, early satiety and cachexia, appear during the course
of its evolution.
• As the condition worsens, fatigue, dyspnea upon exertion, jugular
swelling, and ascites are observed. If these symptoms are not treated,
progression of the manifestations leads to death from heart failure.

44. • Patients with heart disease have higher plasma levels of neurokinin
A, substance P, plasma atrial natriuretic peptide (ANP), pro-brain
natriuretic peptide, chromogranin A, and Activin A as well as higher
urinary 5-HIAA excretion
• Serotonin overproduction by GI-NETs (carcinoids) is important in
mediating the valvular changes, possibly by activating 5-HT2B
receptors in the endocardium

45. • The cardiac disease is due to the formation of fibrotic plaques
(composed of smooth-muscle cells, myofibroblasts, and elastic tissue)
involving the endocardium, primarily on the right side, although
lesions on the left side also occur occasionally, especially if a patent
foramen ovale exists.
• The dense fibrous deposits are most commonly on the ventricular
aspect of the tricuspid valve

46. • Mesenteric fibrosis
• Mesenteric fibrosis (MF) is another complication of uncontrolled CS
which occurs in approximately 50% of CS patients, consequent to a
fibrotic and desmoplastic reaction around metastatic mesenteric
lymph nodes.
• MF can lead to ischemia of vessels and intestinal obstruction. This
vascular ischemia can lead to bowel congestion and result in
decreased absorption of nutrients and can also cause ascites and
more severe cases of mesenteric ischemia.

47. • Another rare complication of MF is ureteral obstruction, which may
cause renal failure
• Historyof Intestinal obstruction may result from the primary tumor or
from the sclerosing reaction in the surrounding mesentery.
• Necrosis of hepatic tumor masses may produce a typical acute
syndrome with fever, abdominal pain, tenderness, and leukocytosis

51. Differential Diagnosis
• Systemic Mastocytosis
• Medullary thyroid carcinoma
• Irritable Bowel Syndrome
• Malignant Neoplasm of the small intestine
• Benign Cutaneous flushing
• Recurrent idiopathic anaphylaxis

53. DIAGNOSIS
• Laboratory studies
• Hormones in blood and urine are measured to monitor the growth,
activity, and eventual recurrence of the primary tumor.
• The diagnosis of CS requires the combination of carcinoid symptoms
and the evidence of elevated levels of 5-HIAA in a 24-h urine sample.
• The sensitivity and specificity of this test for CS are higher than 90% in
patients with characteristic symptoms.

54. • However, false positive findings could be due to the use of
serotoninergic drugs (antidepressants, tramadol, acetaminophen,
salicylates, L-DOPA) and patients' consumption of foods rich in 5-HT.
• Therefore, to increase the accuracy of the diagnosis, it is advisable to
avoid using serotonergic drugs and avoid foods such as banana, kiwi,
avocado, pineapple, nuts, coffee for 2 days before and during the 24-
h urine collection.

55. • Platelet serotonin levels are more sensitive than urinary 5-HIAA but
are not generally available. . .
• A single plasma 5-HIAA determination is found to correlate with the
24-h urinary values, raising the possibility that this could replace the
standard urinary collection because of its greater convenience and
avoidance of incomplete or improper collections.

56. • Patients with foregut NETs (carcinoids) may produce an atypical
carcinoid syndrome and if this syndrome is suspected, the urinary 5-
HIAA maybe minimally elevated or normal and other urinary
metabolites of tryptophan, such as 5-HTP and 5-HT, should be
measured .

57. • Levels are elevated serum chromogranin A (CgA) are elevated in 56-
100% of patients and this correlates with tumor bulk and it varies on
a day by day basis in healthy subjects and those with NETs.
• Serum chromogranin A levels are not specific for GI-NETs (carcinoids)
because they are also elevated in patients with pNETs and other NETs.
Use of potent acid antisecretory drugs such as proton pump inhibitors
(omeprazole and related drugs) cause elevation of plasma
chromogranin A levels

58. • Plasma neuron-specific enolase levels are also used as a marker of GI-NETs
(carcinoids) but are less sensitive than chromogranin A, being increased in
only 17–47% of patients.
• Newer markers have been proposed including pancreastatin (a
chromogranin A breakdown product) and activin A.
• Activin A is not affected by proton pump inhibitors however, its sensitivity
and specificity are not established. Plasma activin A elevations are reported
to correlate with the presence of cardiac disease with a sensitivity of 87%
and specificity of 57%.

59. • Imaging studies
• For the diagnosis of carcinoids, several diagnostic methods have been
evaluated, including barium examinations, Iodine-131
metaiodobenzylguanidine (MIBG) scanning , Octreotide scanning CT
scan, angiography, and venous blood sampling wit radioimmunoassay
of tumor products

60. • Imaging studies Somatostatin receptor scintigraphy
Many carcinoid tumors express high levels of somatostatin receptors
and can therefore be imaged with a radiolabeled form of the
somatostatin analog octreotide (111-indium pentetreotide) using
somatostatin receptor scintigraphy (SRS, OctreoScan).
• The 3-day half-life of this radionuclide allows for a scan after 24, 48,
and 72 hours. This technique has the advantage of instantaneous
whole body scanning, which also allows detection of metastases
outside of the abdominal region.

61. • Imaging studies CT scanning
CT scanning may be used to find the primary tumor or to check for any
disease spread.
• This study allows the assessment of the extent of tumor spread to the
mesentery and bowel wall and metastases to the lymph nodes and liver. It
typically shows a homogeneous, ill-defined mesenteric mass with
calcifications.
• Most carcinoid tumors are highly vascular, and liver metastases may
appear isodense with the liver on a noncontrasted study.

62. Imaging studies with PET scan
• Either tryptophan or its metabolite 5-hydroxytryptophan (5-HTP)
have been used as a tracer substance.
• PET scanning seems to be capable of identifying carcinoid metastases
to various sites and it may be valuable in the follow-up care of treated
patients.

63. • The diagnosis of CHD is performed by transthoracic echocardiography,
which shows valve thickening with retraction and reduction in the
mobility of the tricuspid valve in patients with CS
• Nuclear magnetic resonance imaging of the heart also allows analysis
of ventricular anatomy and function, thereby contributing to a better
assessment of valvular changes when the echocardiogram is not
conclusive.
• N- terminal proBNP a marker of heart failure is also a useful serum
biomarker in the screening of heart disease in patients with CS.

64. • Mesenteric fibrosis is diagnosed with an abdominal imaging exam
usually a computed tomography or NMR
• It shows at least a spiculated mass with attenuation in the soft tissue
range, with fibrotic bands that radiate outward from the mesenteric
fat tissue with a star pattern around a metastatic lymph node

66. TREATMENT
• Treatment includes avoiding conditions that precipitate flushing,
dietary supplementation with nicotinamide, treatment of heart
failure with diuretics, treatment of wheezing with oral
bronchodilators, controlling diarrhea with antidiarrheal agents such
as loperamide or diphenoxylate.
• If patients still have symptoms , serotonin receptor antagonists or
somatostatin analogues are the drugs of choice.

67. • Treatment with Serotonin reuptake inhibitors
5HT1 and 5HT2 antagonists (Methysergide, Cyproheptadine,
Ketanserin) control the diarrhoea, but do not decrease flushing.
Ketanserin diminishes diarhhoea
• 5HT3 receptor antagonists ( ondansetron, tropisetron, alosetron )
control diarrhea and nausea effectively and occasionally ameliorate
the flushing.
• A combination of H1 and H2 receptor antagonists ( diphenhydramine
and cimetidine/ranitidine ) control flushing in patients with foregut
carcinoids

68. • Treatment Somatostatin analogues
Synthetic analogues of somatostatin (octreotide, lanreotide ) are the
most widely used agents to control the symptoms of patients with
carcinoid syndrome. These drugs are effective at relieving symptoms
and decreasing urinary 5-HIAA levels in patients with carcinoid
syndrome
• Octreotide-LAR and lanreotide-SR/autogel (Somatuline) (sustained-
release formulations) control symptoms of patients with carcinoid
syndrome

69. • Complete surgical removal of all tumor tissues, when feasible, is the
best treatment because it may result in a complete and permanent
cure. The aim of surgical therapy is to reduce the tumor mass and
obtain symptom remission.
• Performing a curative resection, mass debulking, or hepatic artery
embolization either alone or with chemotherapy can be used to
control the symptoms of carcinoid syndrome

70. • Chemoembolization with hepatic artery infusion of 5-FU or
doxorubicin, combined with embolization of the hepatic artery with
collagen fibers, leads to substantial tumor necrosis. This procedure
reportedly decreases tumor bulk of liver metastases from carcinoid
tumors by more than 50% in vast majority of patients.
• .

71. • Somatostatin analogues (octreotide and lanreotide) are the standard
treatment for CS and have excellent efficacy.
• Unfortunately, when the disease progresses, and patients experience
carcinoid symptoms that are refractory to label doses to somatostatin
analogue treatment, locoregional therapies and systemic treatments
can be helpful

72. • Interferon-alpha is helpful if octreotide treatment has failed however
benefits are transient and accompanied by adverse effects.
• Interferons exert antitumor effects via stimulation of T cells, induction
of cell cycle arrest, and inhibition of angiogenesis
• Molecularly targeted agents that target the vascular endothelial
growth factor receptor ( bevacizumab, sorafenib, sunitinib,
pazopanib) have been developed

73. • Peptide receptor radioligand therapy such as radiolabeled
somatostatin analogs (90-Y-DOTA tyr3-octreotide, 90Y-edotreotide)
can be used to deliver targeted radiation to somatostatin-receptor
expressing tumors.
• Objective radiographic response rates vary widely, but symptomatic
responses have been observed in the majority of patients with
carcinoid syndrome who were refractory to octreotide

74. • In mesenteric fibrosis, once present, there is no specific treatment to
alleviate the symptoms associated with this CS complication.
• However, its development can be prevented by resection of the
primary midgut 5-HT-producing NET

76. • CARCINOID HEART DISEASE
• The treatment of CHD includes the management of volemia and heart
failure, treatment of the NET itself, reduction in the production of
related hormones (with the use of somatostatin analogues), and
heart valve repair surgery.
• The use of somatostatin analogues, such as octreotide and lanreotide,
improves CS symptoms and reduces urinary levels of 5-HIAA.

77. • Telotristat ethyl (a tryptophan hydroxylase inhibitor) reduces the
levels of 5-HIAA in 24-h urine tests, it is may be a promising treatment
to prevent or delay the onset of CHD.
• The treatment that best controls CHD is heart valve repair surgery;
however, it is associated with a high rate of mortality
• Repair surgery is indicated only for symptomatic patients who are
refractory to clinical treatment or who have right ventricular
dysfunction.

79. Carcinoid crisis
• Carcinoid crisis is a serious and potentially life-threatening
exacerbation of CS due to the release of large amounts of amines in
the circulation.
• Carcinoid crisis is characterized by hypotension, arrhythmias,
tachycardia, flushing and bronchospasm, and it can be lethal.

80. • This is more common in patients who have intense symptoms or have
greatly increased urinary 5-HIAA levels ( >200 mg/d).
• The crisis may occur spontaneously; however, it is usually provoked
by procedures such as anesthesia, chemotherapy, surgery, biopsy,
endoscopy, or radiologic examinations such as during biopsies,
hepatic artery embolization, and vessel catheterization.

81. • Given the life-threatening consequences of carcinoid crisis
recommend that prophylactic and intraoperative octreotide be
administered to all patients with CS and/or elevated urinary 5-HIAA
levels when they are treated with invasive interventions such as
hepatic embolization and liver biopsy as well as during surgical
procedures .

82. PROGNOSIS
• For patients with GI-NETs (carcinoids), worse prognosis include the
development of the carcinoid syndrome (especially the development
of carcinoid heart disease), male sex, the presence of a symptomatic
tumor or greater increases in a number of tumor markers (5-HIAA,
neuropeptide K, chromogranin A) and the presence of various
molecular features.

83. • Location of primary: appendix < lung, rectum < small intestine <
pancreas
• Presence of carcinoid syndrome
• Laboratory results (urinary 5-HIAA levels , plasma neuropeptide,
serum chromogranin A)
• Presence of a second malignancy
• Male sex
• Molecular findings (TGF-α expression, chr 16q LOH or gain chr 4p)

84. CONCLUSION
• Carcinoid syndrome can develop in patients with hormone producing
neuroendocrine neoplasm involved in the development of dymptoms
and fibrotic complications
• Newer treatment such as telotristat and PPRT to reduce hormone
levels have becone available however there ability to reduce fibrotic
complication is still under research

85. • Depression, anxiety as well as cognitive impairment are reported
symptoms of Carcinoid syndrome and Carcinoid crisis is a life
threatening complication
• Despite being recognized however for over 65years, Carcinoid
Syndrome is still not well understood and more studies are needed to
understand the various devastating effects on the body system

86. REFERENCES
• 1.Carcinoid syndrome: update on the pathophysiology and treatment.
Rubin de Celis Ferrari AC, Glasberg J, RiechelmannII RP. Clinics (Sao
Paulo) 2018;73:0
• 2.Rare disease database. Carcinoid syndrome. [Jan;2020 ] 2012
• 3. Carcinoid tumors [Article in Hungarian] Tóth M, Prónai L, Németh
AM, Tulassay Z. Orv Hetil. 2002;143:1087–1092.
• 4. Carcinoid syndrome. Pinchot SN, Holen K, Sippel RS, Chen H.
Oncologist. 2008;13:1255–1269.
• 5. Yao JC, Hassan M, Phan A, et al. One hundred years after
“carcinoid”: epidemiology of and prognostic factors for
neuroendocrine tumors in 35,825 cases in the United States. J Clin
Oncol. 2008;26:3063-72.

87. THANK YOU