1. MALIGNANT CARCINOID SYNDROME
Prof. Brij B Agarwal, Dip Yoga
Inputs from Dr. Kamran Ali & Karan Goel

2. Background Malignant carcinoid driven symptom complex
Excessive circulating bioactive molecules
Serotonin predominated the list initially
Bioactive molecules have to escape liver barrier for symptom complex
* Warrell et al. (2010). Oxford Textbook of Medicine (8th ed.). Oxford University Press

3. Background Thought to be paradoxical in site of origin
? the appendix, Meckel's & small bowel,
? lung, colon, breast, and stomach

4. Incidence
The incidence of carcinoid tumors has been estimated to be 1 to 2 per 100,000 population.
Because carcinoids often pursue an indolent clinical course, their true incidence is likely much higher.
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.

5. INCIDENCE
Within the gastrointestinal tract, small intestine carcinoids were most common (29%) and were followed in incidence by tumors of the rectum (14%), stomach (5%), and appendix (5%)

7. History

8. History
1888 Lubarsch first described what is now known as carcinoid tumor.(*)
1907 Oberndorfer used nomenclature karzinoide tumoren (carcinoid) (#)
1950s Erspamer and Asero described malignant potential of carcinoids (^)
* Lubarsch O. Ueber den primaren Krebs des Ileum, nebst Bemerhunge uber das gleichzeitge Vorkommen von Krebs und Tuberculose. Virchows Arch. 1888;111:
# Oberndorfer S. Uber die "kleinen Dunndarm Carcinome". Verh Dtsch Ges Pathol. 1907;11:113—6.
^ Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-Hydroxytryptamine. Nature. 1952;169:800-1.

9. History
1914, Gosset and Masson carcinoid tumors arise from enterochromaffin cells (Kulchitsky cell) within glands of Lieberkühn [*]
1928, Masson carcinoids are argentaffin cell tumors.[^]
1980, the WHO, carcinoid are tumors of the diffuse endocrine system (amine precursor uptake & decarboxylation [APUD] cells + neuroendocrine cell system).
* Gosset A, Masson P. Tumeurs endocinne de l'appendice. Presse Med. 1914;22:
^ Masson, P. Carcinoids (argentaffin-cell tumors) and nerve hyperplasia of appendicular mucosa. Am J Patholol. 1928;4:

10. Introduction

11. Introduction Highly vascularized tumors “rule of one third”
one third of the tumors are multiple
one third of those in the gastrointestinal (GI) tract are located in the small bowel
one third of patients have a second malignancy
one third of these tumors metastasize.
one third of metastatic cause syndrome

12. Introduction This syndrome is characterized by
- hot, red flushing of the face
- severe and debilitating diarrhea
- asthma like attacks

13. Introduction
Most of these tumors produce 5-hydroxytryptamine, which, in physiologic conditions, is taken up and stored in the platelets while the excesses are inactivated in the liver and lung and transformed into 5-hydroxyindoleacetic acid (5-HIAA).

14. Introduction .
Carcinoids do not produce the malignant carcinoid syndrome until they JUMP THE LIVER BARRIER.
After spreading to the liver, carcinoids can metastasize to the lungs,bone, skin, or almost any organ.

15. Pathophysiology

16. Pathophysiology
As many as 40 secretory products have been identified in various carcinoid tumors. The most prominent of these are serotonin, histamine, tachykinins, kallikrein and prostaglandins.

17. Secretory products of carcinoid
Amines
Tachykinins
Peptides
Other
5HT
Kallikrein
Pancreatic polypeptide
Prostaglandins
5-HIAA
Substance P
Chromogranins
5-HTP
Neuropeptide K
Neurotensin
Histamine
HCGα
HCGβ
Dopamine
Motilin
HCG, Human chorionic gonadotropin; 5-HIAA, 5-Hydroxyinoleacetic acid; 5-HT, 5-Hydroxytryptamine; 5-HTP, 5-Hydroxytryptophan

18. Pathophysiology
The flushing results from  kallikrein, which catalyzes kininogen to lysyl-bradykinin to bradykinin, a powerful vasodilators
Diarrhea (? caused by serotonin+ VIP+ Motilin )
A pellagra-like syndrome (? caused by staelin tryptophan from synthesis of the vitamin B3, niacin, to synthesize 5-hydroxyindoles including serotonin).
Only 1% of dietary tryptophan is converted to serotonin; in patients with carcinoid syndrome, this may go to 70%.

19. Pathophysiology
Carcinoid tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized
Similarly ovarian carcinoid

20. Clinical presentation

21. 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.

22. History Diarrhea : is common in carcinoid syndrome.
Watery but not copious (<1Litre/day of diarrhoea), frequency upto/> 20 episodes / day leading to debility / fluid, electrolyte, and protein depletion.
Transit time through the intestine extremely short
It persists with fasting, fails to disappear despite parentral feeding
Steatorrhea is present in 2/3rd and abdominal pain in 1/3rd patients.
von der Ohe MR, Camilleri M, Kvols LK, Thomforde GM. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med 1993; 329:1073

23. History
Flushing : ( vasodilation of sudden onset causing a deep red or violaceous erythema of the upper body, especially the neck and face, often associated with a feeling of warmth).
It is the most frequent symptom and may be brief (eg, 2-5 min) or may last for several hours, usually in later disease stages.
Flushes may be precipitated by stress, alcohol, exercise, certain foods such as cheese or drugs like SSRIs.

25. History
Cardiac manifestations : occur in ~11% initially and 14-41% at some time in disease course.
It is due to fibrosis involving the endocardium, primarily on the right side, although left side lesions can occur also.
The dense fibrous deposits are most commonly on the venticular aspect of tricuspid valve (TR) , and less commonly on pulmonary valve cusps (PS).
Upto 80% patients with cardiac lesions develop heart failure.

26. History Other common problems include the following: Asthma Wheezing
Dyspnea
Palpitations
Low blood pressure
Fatigue
Dizziness
Asthenia
Warner RRP. Carcinoid tumors. In: Gastroenterology, Berk JE (Ed), WB Saunders, Philadelphia 1985.

27. History Uncommon symptoms include the following: Myopathy Arthritis
Arthralgias
Irritability, aggression, and lack of impulse control; these have been linked with low levels of plasma tryptophan and presumably with low brain serotonin

28. History
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.

29. Physical examination General examination
Facial telangiectasis with cyanosis and edema
Pallor
Flushing
Macular erythema
Periorbital edema
Pellagralike skin lesions

30. Physical examination Systemic examination
CHEST & CVS :
TR/ PS, a pulmonary systolic and diastolic heart murmur as Cardiac involvement cause pulmonic valve stenosis and/or tricuspid insufficiency.(*)
Bronchospasms, most pronounced during flushing attacks.
* Monsegu J, Algayres JP, Ciribilli JM, et al. [Tricuspid insufficiency disclosing carcinoid syndrome]. Rev Med Interne. 1994;15(9):593-6

31. Physical examination Systemic examination
ABDOMEN :
Hepatomegaly from metastases
Abdominal borborygmi may be present

33. Causes

34. Causes As with many other cancers, the exact cause is unknown.
Malignant carcinoid syndrome does not generally appear to be hereditary.
A study of genetic alterations in small bowel carcinoid tumors found that loss of all or most of chromosome 18 was the most common finding. Heterozygosity was also lost on chromosome arms 9p and 16q. (*)
* Kulke MH, Freed E, Chiang DY, Philips J, Zahrieh D, Glickman JN, et al. High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes Cancer. Jul 2008;47(7):

35. Differential Diagnoses

36. Differential Diagnoses
Anaphylaxis
Angioedema
Intestinal Motility Disorders
Irritable Bowel Syndrome
Ogilvie Syndrome
Tumor Lysis Syndrome
Urticaria

37. Work up

38. Laboratory Studies
Hormones in blood and urine are measured to monitor the growth, activity, and eventual recurrence of the primary tumor.
Urinary excretion of 5-HIAA — 
A useful initial diagnostic test for the carcinoid syndrome is to measure 24-hour urinary excretion of 5-hydroxyindoleacetic acid, which is the end product of serotonin metabolism. This test has a sensitivity of over 90 percent and specificity of 90 percent for the carcinoid syndrome.
Sjöblom SM. Clinical presentation and prognosis of gastrointestinal carcinoid tumours. Scand J Gastroenterol 1988; 23:779.

39. Laboratory Studies
If dietary (or pharmaceutical) 5-hydroxyindoles are excluded, a urinary excretion of 5-HIAA of 25 mg/d is diagnostic of carcinoid.
The measurement of other bioactive amines (eg, serotonin, catecholamines, histamine, histamine metabolites) in the platelets, plasma, and urine of patients with carcinoid tumors is of interest but has less diagnostic value than an assay of the major metabolite of serotonin in the urine.

40. Laboratory Studies Serum Chromogranin A (CgA) :
Levels are elevated correlate with tumor bulk.
Levels of CgA vary on a day by day basis in healthy subjects and those with NETs. Food intake also affects CgA levels.
Hence CgA is a sensitive but nonspecific marker for neuroendocrine tumors / carcinoids

41. 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 with radioimmunoassay of tumor products [^]
Sinzinger H, Renner F, Granegger S. Unsuccessful iodine-131 MIBG imaging of carcinoid tumors and apudomas. J Nucl Med. Jul 1986;27(7):
Garg S, Bourantas CV, Nair RK, Alamgir F. Carcinoid syndrome diagnosed by echocardiography. Int J Cardiol. Feb

42. 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.

43. Imaging studies Somatostatin receptor scintigraphy
The accuracy of SRS enhanced by single photon emission computed tomography (SPECT) due to differentiation between areas of pathologic and physiologic uptake in the abdomen.
Advancements in CT and MRI have led some to question whether SRS is still a necessary component of the staging workup for carcinoid and other neuroendocrine tumors:
* Schirmer WJ, Melvin WS, Rush RM, et al. Indium-111-pentetreotide scanning versus conventional imaging techniques for the localization of gastrinoma. Surgery 1995; 118:1105.

47. Imaging studies Somatostatin receptor scintigraphy
In a series of 121 patients, 107 detected with metastatic disease by multiphase contrast-enhanced CT or MRI as against 85 by SPECT-SRS [^].
SPECT-SRS did identify clinically unsuspected bone metastases that were not identified on CT or MRI. The authors concluded that the routine use of octreotide scanning as an adjunct for tumor staging was not justified unless the finding of asymptomatic bone lesions would change patient management and the treatment plan.
^ Reidy-Lagunes DL, Gollub MJ, Saltz LB. Addition of octreotide functional imaging to cross-sectional computed tomography or magnetic resonance imaging for the detection of neuroendocrine tumors: added value or an anachronism? J Clin Oncol 2011; 29:e74.

48. Imaging studies Radiography
Barium examination is rarely diagnostic but may show a benign-appearing submucosal lesion or a large bulky ulcerating mass with bowel deformity.
A smooth polyp observed in the terminal ileum should always be considered a probable carcinoid tumor.
The importance of angiography for carcinoid diagnosis has been decreased by the availability of more recent imaging methods.

49. Imaging studies CT scanning
CT scanning may be used to find the primary tumor or to check for any disease spread.
Primary carcinoids of the bowel are usually not observed on CT scanning; otherwise, 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.
CT scanning typically shows a homogeneous, ill-defined mesenteric mass with calcifications.

50. Imaging studies CT scanning
Most carcinoid tumors are highly vascular, and liver metastases may appear isodense with the liver on a noncontrasted study.
Following the injection of intravenous (IV) contrast, carcinoids often enhance with iodinated contrast during the early arterial phase (approximately 20 seconds after contrast injection), with washout during the portal venous imaging phase (approximately 70 seconds after contrast injection)

53. Imaging studies PET
Experience with PET scanning to detect carcinoids is very limited.
Either tryptophan or its metabolite 5-hydroxytryptophan (5-HTP) has 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.
According to initial reports, only C11-5-HTP is taken up by serotonin-producing tumors

54. Other tests
Several provocative tests have been developed for carcinoid syndrome.
The most recent test uses pentagastrin.
The traditional test uses alcohol (10 mL PO), calcium (10 mg/kg of calcium gluconate in 4 h), or catecholamines (norepinephrine 1-20 mcg).
These tests must be performed with caution because they can trigger crises.

55. Treatment

56. 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.

57. Treatment Serotonin reuptake inhibitors
5HT1 and 5HT2 antagonists (Methysergide, Cyproheptadine, Ketanserin) : control the diarrhoea, but do not decrease flushing.
Ketanserin diminishes diarhhoea
* Methysergide causes retroperitoneal fibrosis so its use is limited.

58. Treatment Serotonin reuptake inhibitors , H1&H2 blockers
5HT3 receptor antagonists ( Ondansetron, Tropisetron, Alosetron ) :
Control diarhhoea 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.

59. 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.
Octreotide has demonstrated the ability to relieve symptoms in most patients, but tumor reduction is rarely observed

60. Treatment Somatostatin analogues
The PROMID Study Group evaluated the ability of somatostatin analogs to control the growth of well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors (NETs).[*] 
The phase IIIB study randomized 85 treatment-naive patients with mid-gut NETs to receive either placebo or octreotide LAR 30 mg IM monthly until tumor progression or death.
* Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. Oct ;27(28):

61. Treatment Somatostatin analogues
The primary efficacy endpoint was median time to tumor progression, which was found to be significantly longer in treatment with octreotide LAR compared with placebo (14.3 months vs 6 months, p = ).
Secondary endpoints included tumor response and survival time. At 6 months of treatment, more patients had stable disease in the octreotide LAR group compared with placebo (66.7% vs 37.2%) with similar responses in functionally active and inactive tumors.

62. Treatment Somatostatin analogues
Octreotide LAR significantly extends the time to tumor progression compared with placebo for patients with midgut NETs.
A randomized, placebo-controlled phase 3 trial found that everolimus plus octreotide LAR improved progression-free survival in patients with advanced NETs associated with carcinoid syndrome.[*]
* Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. Dec ;378(9808):

63. Chemotherapy
Radiotherapy or chemotherapy with streptozotocin, cisplatin, etoposide, and doxorubicin, either alone or in combination, has been used, and reports show some success; a good response occurs in only 20-30% of cases.
The role of radiation therapy in the management of carcinoid tumors with distant metastasis is restricted to symptomatic palliation of the painful bone metastases.
This therapy is not useful for treating liver metastases or for other nonskeletal tissues.

64. Surgical care

65. Surgery
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 embolization is possible.
Cytoreductive surgery has been reported to have the best impact on symptom regression and overall survival. (*)
* Hodul P, Malafa M, Choi J, et al. The role of cytoreductive hepatic surgery as an adjunct to the management of metastatic neuroendocrine carcinomas. Cancer Control. Jan 2006;13(1):61-71.

66. Surgery
An extensive surgical excision, including the adjacent mesentery, must be performed.
Surgery should always be considered in patients with large or extensive hepatic metastases involving surgically accessible areas of the liver.
For lesions in the distal ileum, a right hemicolectomy is necessary to remove the lymphatic drainage adequately.

67. Surgery
For tumors located in the appendix that are smaller than 1.5 cm in diameter, appendectomy is suitable and curative in 100% of patients.
The involvement of the mesoappendix does not alter the patient's prognosis, but invasion of the cecum mandates more radical surgery (eg, right hemicolectomy with regional lymphadenectomy).
Carcinoids in children usually occur in the appendix, and the appendectomy results in a complete cure.

68. Surgery
Rectal carcinoids, if smaller than 1.5 cm in diameter, should be treated with local excision.
If rectal carcinoids are larger than 1.5 cm, treated like other rectal malignancies

69. MANAGEMENT OF REFRACTORY SYMPTOMS
Interferon
Liver-targeted therapies
Antidiarrheal therapy
Systemic therapies
- Cytotoxic chemotherapy
- Molecularly targeted agents
Peptide receptor radioligand therapy

70. MANAGEMENT OF REFRACTORY SYMPTOMS Interferon
Interferon-alpha helpful if octreotide treatment has failed; 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

71. MANAGEMENT OF REFRACTORY SYMPTOMS Interferon
The liver is the predominant site of metastases in patients with metastatic carcinoid.
Liver-directed treatments, such as surgical resection, transarterial embolization, and local tumor ablation, play an important role in the management of patients with advanced carcinoid tumors.

72. MANAGEMENT OF REFRACTORY SYMPTOMS Chemoembolization
Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy is useful as a palliative technique in patients with symptomatic hepatic metastases who are not candidates for surgical resection.
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.(*)
* Farndon JR. The carcinoid syndrome: methods of treatment and recent experience with hepatic artery ligation and infusion. Clin Oncol. Dec 1977;3(4):365-75

73. MANAGEMENT OF REFRACTORY SYMPTOMS Chemoembolization
Early studies noted a significant incidence of severe postembolization complications, including renal failure, hepatic necrosis, and sepsis.
But improvements in technique have reduced the incidence of such complications, making embolization an important and generally safe treatment option for patients with metastatic neuroendocrine tumors, including carcinoids

74. MANAGEMENT OF REFRACTORY SYMPTOMS Anti-diarrhoeal agents
Anti-diarrheal agents such as loperamide and/or diphenoxylate/atropine (lomotil) can be used for control of refractory diarrhea.
For more severe diarrhea, the opiates paregoric and tincture of opium may be prescribed.
Several studies demonstrate that serotonin receptor antagonists, such as ondansetron, can alleviate diarrhea in patients with the carcinoid syndrome
Wymenga AN, de Vries EG, Leijsma MK, et al. Effects of ondansetron on gastrointestinal symptoms in carcinoid syndrome. Eur J Cancer 1998; 34:1293.

75. MANAGEMENT OF REFRACTORY SYMPTOMS Cytotoxic chemotherapy
Most well-differentiated carcinoid tumors appear to be refractory to conventional cytotoxic agents with response rates of <10 percent in modern studies.
Conventional cytotoxic chemotherapy is generally not helpful for control of symptoms in patients with carcinoid syndrome from well-differentiated carcinoid tumors. Its use should be restricted primarily to patients with poorly-differentiated (high-grade) carcinoid tumors, where objective response rates are higher.

76. MANAGEMENT OF REFRACTORY SYMPTOMS Molecularly targeted agents
The limited efficacy of conventional cytotoxic chemotherapy has prompted the development of novel therapeutic approaches for patients with advanced carcinoid tumors.
These include therapies targeting the vascular endothelial growth factor receptor (eg, bevacizumab, sorafenib, sunitinib, pazopanib) and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).
In particular, whether or not any of these treatments helps to control symptoms of refractory carcinoid syndrome is not yet known.

77. MANAGEMENT OF REFRACTORY SYMPTOMS Peptide receptor radioligand therapy
Radiolabeled somatostatin analogs (eg, 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

78. Liver transplant
Hepatic transplantation has also been attempted in selected patients, with promising results; however, generalization for this treatment option, is not possible without more long-term studies.

79. Thankyou
Acknowlegements- Pooja & Ramneek