This document summarizes intestinal carcinoid syndromes. It defines carcinoid tumors as neuroendocrine tumors most commonly occurring in the small intestine. It covers the epidemiology, pathology, presentation, diagnosis and treatment of carcinoid tumors. Carcinoid tumors are often asymptomatic but can cause abdominal pain, obstruction and flushing. Diagnosis involves urine and blood tests. Treatment depends on size and metastasis but often involves surgery and medication like octreotide to control symptoms. Prognosis is best for localized disease but poorer with metastasis.

1. Intestinal Carcinoid syndromes
Dr. Uttam Laudari
JR III
Department of Surgery
Kathmandu Medical college
19/07/2016

2. Objective
• Definition/ Classification
• Epidemiology/ Etiology
• Pathology/Pathogenesis
• Presentation/ diagnosis
• Treatment/ Prognosis

3. Definition
• Carcinoid of the small intestine, a well-differentiated
neuroendocrine tumor, is the most common distal small
bowel malignancy, with an occurrence rate of one case per
300 autopsies

4. Background
• First identified in ileum by Lubarsch >100 years ago
• term used by Oberndorfer in 1907 as it was carcinoma like
lesion but with much more indolent clinical course
• Derived from resident endocrine cells with GIT and lung as the
predominant sites of ocurrence

5. Classification
• Anatomic classification
1. Foregut
a) bronchus, stomach, pancreas, duodenum
2. Midgut
3. Hind gut
Based on secretion
1. secretors
2. nonsecretors

6. Classification
Midgut carcinoids Serotonin Elevated urinary 5 HIAA
Foregut carcinoids Low level of serotonin
high 5- hydroxytryptophan
secretes 5- HTP
Hind gut Rarely produce serotonin
But may secret other
hormones like peptide YY

8. • In small intestine carcinoids almost always
occur within the last 2 feet of ileum

9. Epidemiology/Etiology
• USA
– Carcinoid tumor-1/300 individuals
– Carcinoid syndromes- 1/300,000
– 8000 GI carcinoids diagnosed early per year
– Age - Hazard ratio (HR) for ≥ 65 vs. 50-55 years = 3.31
– Male sex - HR = 1.44
– Obesity - HR for body mass index ≥ 35 vs. 18.5 to < 25 kg/m 2 = 1.95
– Current menopausal hormone therapy use - HR = 1.94

10. Etiology
• Genetic syndromes associated with increased
risk for carcinoid include
– multiple endocrine neoplasia type 1 (MEN1)
– neurofibromatosis type 1
– tuberous sclerosis complex
– von Hippel-Lindau disease
MEN1 may be responsible for approximately 10% of
carcinoid tumors.

11. Pathology/ Pathogenesis
• Enterochromaffin cells stain yellow-brown after chromate fixation and are
diffusely distributed in the tissues derived from the primitive gut.
• Intestinal enterochromaffin cells are the Kulchitsky cells in the crypts of
Lieberkühn of the small intestine.

12. Pathology/ Pathogenesis
• Carcinoid tumors arise from the enterochromaffin cells.
• Tumor cells and Kulchitsky cells both reduce silver salts
(argentaffin reaction)
thus, the term argentaffinoma is used to describe carcinoid
tumors

13. Pathology/ Pathogenesis
• Endocrine cells in the
– pituitary gland, thyroid gland, lungs, pancreas, and
gastrointestinal tract
secrete polypeptides and share common cytochemical and
ultrastructural characteristics.

14. Pathology/ Pathogenesis
• AUPD
Pearse developed the concept of the amine precursor uptake
and decarboxylation (AUPD) system
because these cells take up and decarboxylate amino acid
precursors of biogenic amines such as serotonin and
catecholamines.

15. Pathology/ Pathogenesis
• This system of cells has a common embryonic origin from the
neuroectoderm.
• Related cells are present in the adrenal medulla, sympathetic ganglia,
paraganglia, and chemoreceptor system.
• Which explains the occurrence of multiple endocrine neoplasia and the
multipotentiality of neoplastic cells derived from this system to produce a
variety of peptide hormones.

16. Pathology/ Pathogenesis
• There are also histologic similarities among
– carcinoid tumors
– islet cell tumors
– and medullary carcinoma of the thyroid
Also may coexist with other endocrine tumors.

17. Pathology/ Pathogenesis
Tumors that histologically appear to be carcinoids
may also produce
Gastrin
calcitonin
Insulin
vasoactive intestinal peptide
neurotensin, catecholamines
corticotropin (adrenocorticotropin hormone)

18. Pathology/ Pathogenesis
• Carcinoid syndromes:
– Hormonal manifestations of carcinoid tumors.
• flushing, diarrhea, bronchoconstriction, and cardiac
disease
• Most patients with carcinoid tumors do not develop
carcinoid syndrome.
• The frequency of hormonal manifestations is greatest
for midgut primary tumors

19. Pathology/ Pathogenesis
• Carcinoid syndromes:
– Hormonal aspects
• 40-50% of small intestinal and proximal colon
• less frequently in patients with bronchial carcinoids
• rarely observed in association with appendiceal
carcinoids,
• does not occur in patients with rectal carcinoids ( even
in advanced and metastasis)

20. Pathology/ Pathogenesis
• Carcinoid syndromes:
• Hormonal aspects
• Directly proportional to tumor burden and metastasis
• Unusual in small tumor
• Patients with these syndrome invariably has liver
metastasis

21. Pathology/ Pathogenesis
• Carcinoid syndrome
– Non hormonal aspect
• Identification of non hormonal symptoms in early disease
enhances likelyhood of diagnosis before distant metastasis
• Rectal carcinoids usually asymptomatic in the absence of
advanced disease
• midgut carcinoids frequently have symptoms for long
periods (ie, 2-5 or more y) before a specific diagnosis is
made

22. Pathology/ Pathogenesis
• Carcinoid syndrome
– Non hormonal aspect
• The most common symptoms and signs of an
intestinal carcinoid are
– abdominal pain
– intermittent obstruction
– and a palpable abdominal mass
each of which occurs in nearly 50% of patients.

23. Pathology/ Pathogenesis
• Malignant potential is related to loction, size, depth of
invasion and growth pattern
• 3% appendiceal carcinoids- metastasize
• 35 % ileal metastasize

24. Pathology/ Pathogenesis
• 75% of GI carcinoids are <1cm diameter and 2 % associated
with metastasis
• Caricinoid of 1-2cm 50 % metastasis
• >2 cm 80-90% metastasis

25. Presentation/Diagnosis
• Asymptomatic- many/ incidentally/ autopsy
• Symptomatic- depends on location, size and metastasis
• Complications

26. Presentation/Diagnosis
Location nonhormonal
symptoms
Carcinoid
syndrome
Metastatic disease
Small intestine Pain
Intestinal
obstruction
up to 90% 5-7%
Appendix Appendicitis
Incidental findings
<5 <5
Colon Pain
Bleeding
<66 <5
Recutm Pain
Constipation
Bleeding
5 <5

27. Presentation/Diagnosis
• Partial intestinal obstruction- intense desmoplastic reaction
• LGI bleeding- ulceration of mucosa overlying tumor
• Intestinal ischemia/infarction- desmoplastic reaction/ agiopathy
• Constitutional symptoms-
– anorexia, weight loss, and fatigue
– related to disease metastasis to regional lymph nodes or the liver
– which is present in up to 90% of patients at the time of diagnosis

28. Presentation/Diagnosis
• Malignant carcinoid syndrome
– carcinoid of the small bowel only with massive hepatic replacement by
metastatic tumor
– Serotonin and other vasoactive substances secreted by the hepatic
metastases
escape hepatic degradation and enter the systemic circulation directly,
with resultant symptoms

29. Presentation/Diagnosis
• Malignant carcinoid syndrome
– hepatomegaly diarrhea, and flushing in 80% of patients
– right heart valvular disease in 50%
– asthma in 25%
– Malabsorption and pellagra (ie, dementia, dermatitis, and
diarrhea)

30. Presentation/Diagnosis
• Cutaneous flushing
– Earliest manifestation of syndrome
– 80% of cases
– Head and neck
– triggered by excitement, exercise, some types of food, or
alcohol
– Flushing is mediated by the vasoactive peptides secreted
by the tumor.

31. Presentation/Diagnosis
• Diarrhea is the most common feature of carcinoid syndrome,
affecting 80% of patients
• It is usually episodic, often occurring after meals.
• The elevated levels of serotonin stimulate the secretion of
small bowel fluid and electrolytes and increase intestinal
motility, resulting in diarrhea.

32. • Right sided valvular heart disease
– Serotonin stimulation induces irreversible endocardial
fibrosis of the tricuspid and pulmonary valves, resulting in
valvular dysfunction (stenosis or incompetence).
– The lungs metabolize serotonin and protect the left heart
from fibrosis.
– Carcinoid heart disease may ultimately result in cardiac
insufficiency, usually with right-sided heart failure.

33. Work up
• Laboratory
– Carcinoid  serotonin metabolized in liver and
the lung to 5HIAA, which is measured in 24 hour
urine
– Carcinoid syndrome
• Levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) are usually
greatly increased

34. Work up
• plasma chromogranin A (CgA)
– patients with pancreatic or gastrointestinal neoplasms
Median CgA levels were significantly higher
1. in functioning tumors compared with non-functioning
tumors
2. in patients with metastases compared with those
without metastases
3. Increased CgA levels predicted recurrence after radical
surgery

35. Work up
• Combination of 24 hour urine 5-HIAA and serum
chromogranin A level provides best biochemical diagnostic
accuracy
• Response to therapy / surviellience Serum Chromogranin A

36. Work up
• PCR
– sensitivity of 98.4%,
– specificity of 100%
– positive predictive value of 100%,
– negative predictive value of 97.8%

37. Imaging
1. Barium
2. CT scan
3. CT angio
4. In- labelled syntigrapghy
5. MRI hepatic mets
6. C-5-HTP/ F-DOPA PET- best of all
Localize and stage
Extrabdominal
metastasis

38. Work up
• Imaging
– Barium contrast
• Multiple filling defects as a result of kinking and fibrosis
of bowel

39. Work up
• Imaging
– Ultrasound has limited use, particularly in lesions smaller
than 1 cm
• NCCT
– investigation of choice for carcinoid tumors because
metastatic carcinoid tumors are usually extremely vascular
– consequently, they tend to become isodense in the
presence of contrast
– also detect mesenteric involvement with tumor in 50% of
patients with metastatic disease.

40. Work up
• MRI
– supplemental abdominal investigation of choice
– For hepatic metastasis
• Radionucleotide Scans
– octreotide labelled radioactive isotope injected
– For delineating and localizing carcinoids
– Test of choice to identify extraabdominal metastasis
– particularly useful when other routine modalities have failed to localize the
site of the carcinoid.
– less commonly is I131 MIBG.

41. Work up
• PET
– used to assess the function of different metabolic
pathways specific to the tissue being scanned.
– It is useful in those instances in which scintigraphy with
In111octreotide has been inconclusive
• Endoscopy
– For gastric and rectal carcinoids

42. Work up
• C-5-HTP and F-DOPA PET fused with CT
best modalited of all

43. Staging
• Classification based on spread is as follows:
– Localized - Limited to the organ of origin
– Regional spread - Limited infiltration into
surrounding tissues
– Distant metastasis

44. Anesthetic issues
– As anesthesia may precipitate carcinoid crisis
– Hypotension, bronchospasm, flushing,
tachycardia, arrythmia
– Treatment
• IV octreotide 50-100mcg blous , infusion at 50mcg/hr
• Iv antihistamine, hydrocortisone

45. Treatment
• Based upon tumor size, site and metastasis
• Primary tumor small than 1cm without evidence of regional
metastasis segmental resection

46. Treatment
Lesions >1cm
with multiple tumors
with multiple regional LN metastasis regardless size of
tumor
wide excision of bowel and mesentery

47. Treatment
• Lesion of terminal ileum right hemicolectomy
• Small duodenal tumor excise lovally
– More extensive lesion- Whipples

48. Treatment
• Mesenteric disease involving large portion of mesentery
dissection of tumor with mesenteric vessels, preserving blood
supply to unaffected bowel

49. Treatment
• Metastatic disease
– Surgical debulking symptomatic relief
– Hepatic involvement metastastectomy
– Most patient as have extensive disease, hepatic resection
may not be possible
– Recurrence after metaststectomy-75%
– Transarterial chemoembolization or radioembolization for
liver direted control of disease

50. Medical therapy
• Symptomatic relief
• Octreotide
– Symtom relief
– Tumor regression
– newer drugs- Sandostatin

51. Medical therapy
• Pasireotide
– Broad somatostatin receptor inhibitor
– 40 fold increase in binding affinity
– For patient who fail with octreotide/ Sandostatin
• Interferon alfa
– Symptomatic relief
– Decreased 5HIAA and tumor regression was seen
– Side effects- fever, fatigue, anorexia, weight loss

52. Medical therapy
• Methysergide
– Serortonin receptor antagonist
– Limited success
– No longer use retroperitoneal fibrosis
• Cyproheptadine/ondansetronsymptomaic

53. Medical therapy
• Cytotoxic chemotherapy
– Limited success as it’s a slow growing tumor
– Used for metastatic disease who are symptomatic
– Unresponsive to other therapies
– High tumor proliferation rates
– Streptozotocin plus 5- FU or cyclophosphamide
• Tumor regression

54. Medical therapy
• Antiangiogenesis therapy
– Bevacizumab with cytotoxic drug still being investigated
– Sunitinib under study

55. prognosis
• Best prognosis of all small bowel tumors whether
localized or metastatic
• resection of primary tumor locized to its primary
site 100% survival
• 5 year survival
– Regional disease- 65%
– Distant metastasis 25- 35%
• Serum Chromogranin A level is independenr
predictor of adverse prognosis

56. • Thank you

57. • Carcinoid abdominal crisis
• is a rare acute abdominal syndrome characterized by severe abdominal
cramping without a mechanical bowel obstruction
• The mechanism of the crisis
– intestinal ischemia caused by vasoactive substances elaborated by the
carcinoid tumor, combined with a decreased mesenteric blood supply
due to a perivascular fibrosis.
– continuous release of bioactive substances may also cause severe
hypotension and watery diarrhea.
– Edema of the face, rapid pulse, and pruritus may also be present.

58. • General examination- 61-66year old
– has face, neck, and upper chest flushing lasting for
hours to days, lacrimation
• Vitals- hypotension, fever, respiratory distress
• experiences flushing when performing a Valsalva
maneuver.

59. • Skin findings  facial telangiectasias, usually bimalar.
• Chest-wheezing
• CVS- TR,PS murmur
• P/A- distended and nontender. Bowel sounds may be
normal or high pitched. Hepatomegaly is possible.
• Examination of the extremities may demonstrate bilateral
lower extremity edema, rashes ( niacin deficiency)