1) Carcinoid tumors are rare neuroendocrine tumors that originate from enterochromaffin cells in the small intestine. 2) Symptoms can include flushing, diarrhea and heart disease due to secreted hormones. 3) Treatment involves surgical removal of the primary tumor and metastases. Octreotide can help control symptoms.

1. DR. OBIORA NWAFULUME
UNIVERSITY OF NIGERIA TEACHING HOSPITAL, ITUKU-OZALLA.
PATHOLOGY AND MANAGEMENT OF SMALL
INTESTINAL CANCERS WITH EMPHASIS ON
CARCINOID TUMOURS

2. INTRODUCTION:
• The small intestine makes up 75% of the length of the digestive tract but cancer of the
small bowel is rare and accounts for 2% of gastro-intestinal malignancies.1–3
• Nonetheless, incidence has been increasing owing to the widespread use of endoscopy.1
• Explanation for the low incidence of cancer is unknown. Possibilities:2,4

3. INTRODUCTION:
 The fluidy chyme cause less mucosal irritation, and dilutes the carcinogens in the lumen.
 Rapid transit time of intestinal contents reduce contact time to carcinogens
 The low bacterial count result in decreased conversion of bile-acids into carcinogens

4. INTRODUCTION:
 The carcinogen benzpyrene is converted to less toxic metabolites by benzpyrene
hydroxylase, present in high concentrations in the small intestine.
 IgA: Lymphoid accumulations within the small bowel wall may be protective.
 Efficient epithelial cellular apoptotic mechanisms: Eliminates clones harbouring genetic
mutation5

6. INTRODUCTION:
• The 4 major subtypes of cancer of the small intestine:
 adenocarcinomas
 neuroendocrine tumours,
 gastrointestinal stromal tumours (GISTs)
 lymphomas.3,6,4

7. CARCINOID TUMOURS
• The most common neuroendocrine tumors
• Are of neuroendocrine origin and derived from primitive stem cells
• Arise from enterochromaffin cells (Kulchitsky cells) in the crypts of Lieberkuhn.

8. • GIT is the most common site:
 Appendix (45%)
 Ileum (28%; almost always last 2 feet of ileum)
 Rectum (16%)
 Stomach
• Other sites: lungs, tracheobronchial tree, pancreas, biliary tract, and liver.

9.  20-30% multicentric
 10% associated with other malignancy (adenoca)
 10% associated with MEN 1
 Composed of multipotential cells able to secrete numerous humoral agents such as
serotonin, substance P.

10. EPIDEMIOLOGY
• Relatively rare tumours
• Most common NEC tumour
• Incidence is 1.5-1.9 :100,000
• Median age: 63 years
• Incidence has increased 4 fold from 1985 to 2005
• Incidence of the carcinoid syndrome is about 0.5/100,000

11. PATHOGENESIS
• Carcinoid tumours are associated with a variety of genetic alterations
 MEN type 1: autosomal dominant disorder with loss of the tumor suppressor gene MEN1
 Mutations of the p53 tumor suppressor gene
 bcl-2 overexpression

12. CLASSIFICATION
• 3 types according to the origin
 Foregut: lung, bronchus, stomach, proximal duodenum, pancreas
 Midgut: second portion of the duodenum, the jejunum, the ileum, and the right colon
 Hindgut: transverse colon, descending colon, and rectum ?genitourinary, ovarian

13. • Unlike foregut and hindgut carcinoids, midgut carcinoids known for high serotonin
production and with a higher incidence of classic carcinoid syndrome.

14. CLASSIFICATION
 “Non functioning" presenting as a tumor mass
 "functioning" i.e. producing several biopeptides causing carcinoid syndrome.

15. MALIGNANT CARCINOID SYNDROME
• Occurs in < 10% with carcinoid tumors
• Most often associated with SB carcinoid
• Due to hepatic replacement by metastatic disease or large retroperitoneal disease burden
 Serotonin, 5-hydroxytryptophan, histamine, dopamine, kallikrein, substance P,
prostaglandin, neuropeptide K

16. MALIGNANT CARCINOID SYNDROME:
SYMPTOMS
 Cutaneous flushing
 Palpitations
 Diarrhea
 Hepatomegaly
 Neoplastic infiltrative cardiomyopathy:
 Pulmonic stenosis (90%)
 Tricuspid insufficiency (47%)
 Tricuspid stenosis (42%)
 Bronchoconstriction/Bronchospasm

17. PATHOLOGIC CHARACTERISTICS
• Small, firm, submucosal tumors
• White, yellow, or gray
• Slow growing but with a high potential for metastasis
• Overlying mucosa may be intact or ulcerated
• Cause intense desmoplastic reaction – mesenteric fibrosis

18. HISTOLOGY
 5 distinctive patterns exist
• Solid/ insular
• trabecular pattern with anastomosing features
• tubules and glands
• poorly differentiated or atypical patterns
• mixed patterns.
 Cells are uniformly round or polygonal with a central nucleus and small nucleoli
 IHC: strong positive reaction to neuroendocrine markers eg. chromogranin and
synaptophysin.

20. PATHOPHYSIOLOGY
Nicotinic acid
• Tryptophan
(in diet) 5-HTP, 5-HT MAO 5-HIAA ( Urine)
• Tryptophan shunt to the tumor instead of the brain, depletes nicotinic acid levels resulting
in pellagra (dermatitis, diarrhea, and dementia)
• Serotonin concentrations within the tumor correlate with frequency of carcinoid syndrome.

21. PATHOPHYSIOLOGY
 The clinical features also depends on
• the tumor location,
• size as well as on
• the presence of metastases.
• In the GIT, these tumors develop deep in the
mucosa, grow slowly and extend into the
underlying submucosa and mucosal surface.
• They form small firm nodules which bulge into
the intestinal lumen and could ulcerate.

22. • With expansion and infiltration through the
submucosa into the muscularis propria and
serosa, they can involve the mesentery.
• Metastasis:
 Liver (larger and more yellow than primary)
 Mesentery, peritoneum, lymph nodes
• Complications: Metastasis, hemorrhage, carcinoid crises, pellagra

23. BIOCHEMICAL MARKERS
• 5-HIAA:
 normal range: 2-8 mg/24 hours
 Urinary 5-HIAA levels elevated in 50% of patients whether or not they have carcinoid
syndrome
 Levels correlate with tumor burden

24. BIOCHEMICAL MARKERS
• Chromogranin A:
 present in the neurosecretory vesicles of NEC tumor cells
 it does not rely on serotonin secretion
 serum CGA is a more sensitive marker than urinary 5-HIAA.
 Levels may be measured in bronchial and rectal carcinoid tumors in whom urinary 5-HIAA
levels are unlikely to be elevated.

25. STAGING: TNM CLASSIFICATION OF SMALL
INTESTINE CARCINOID

26. GRADING
• This is based on
• The mitotic count
• the level of the nuclear protein Ki-67
• assessment of necrosis.
• G1: well differentiated, low grade
• G2: well differentiated, intermediate grade
• G3: poorly differentiated, high grade

27. MANAGEMENT
• Clinical evaluation
• Investigation
• Treatment is multidisciplinary and may require multimodality.
• Mode of presentation:
 emergency vs clinically stable

28. MANAGEMENT
• Treatment of small intestinal carcinoid tumours is based on tumour size, site and
presence/absence of metastatic disease.
• Treatment can either be surgical, medical or radiological.
• Surgical removal of the primary tumour is the mainstay of treatment

29. MANAGEMENT
• The goal is to surgery:
 obtain tissue for diagnosis
 document the extent of disease
 remove tumour for potential cure
 palliate symptoms and to prolong survival

30. PRINCIPLES OF SURGERY
• Primary tumours <1cm in diameter without evidence of lymph node (LN) metastasis:
segmental resection is adequate
• Tumours >1cm / Multiple tumours / Tumours with regional lymph nodal metastasis
regardless of primary tumour size: wide excision of bowel and mesentery required.
• In addition to treating the primary tumour, abdomen must be explored for multicentric
lesions.

31. PRINCIPLES OF SURGERY
• Carcinoid crisis can occur during the induction of anaesthesia in patients with carcinoid
syndrome.
• Due to the bradykinergic effects associated with bronchospasm, hypotension and
electrolyte disturbances.
• Premedication with anti-5HT agents and a smooth non-traumatic induction may be helpful.
• IV octreotide reverse the life threatening hypotension and reduce intraoperative
complications in 11% of patients

32. DUODENAL CARCINOIDS
 <1cm: endoscopic resection if no evidence of LN involvement
 1-2 cm and peri-ampullar lesions: transduodenal excision
 >2cm and lesions with LN involvement: Pancreaticoduodenectomy

33. JEJUNAL/ILEAL CARCINOIDS
• < 1 cm with no evidence of nodal disease: Segmental resection
• > 1 cm, multiple tumors, or LN involvement: Wide excision of bowel and mesentery
• Terminal ileum: Right hemicolectomy

34. APPENDICEAL CARCINOIDS
• Usually well-differentiated
 metastatic risk related to size
• < 1 cm: 2% metastatic
• 1-2 cm: 50% metastatic
• > 2 cm: 80-90% metastatic

35. APPENDICEAL CARCINOIDS
 < 1 cm: simple appendectomy
 1-2 cm: debatable. simple appendectomy
 > 2 cm or Mesoappendix involvement or Tumour at base of the appendix : Right
hemicolectomy

36. COLONIC CARCINOIDS
• Caecum: right hemicolectomy
• Sigmoid: anterior resection
• Rectal:
• serotonin prod or carcinoid synd uncommon
• <1cm: endoscopic resection
• 1-2 cm without evidence of invasion (<5% metastasize): local excision
• > 2cm (20% metastasize): low anterior resection or abdominoperineal resection

37. METASTATIC DISEASE
• Surgical debulking
 Hepatic resection: wedge or lobe
• Hepatic chemoembolization
• Radiofrequency ablation
• Radionucleide Therapy with Iodine-131-labelled metaiodobenzylguanidine [131I-MIBG]

38. MEDICAL TREATMENT
• Primary treatment in metastatic carcinoid tumour in the absence of intestinal obstruction,
ischemia, or refractoriness to medical therapy.
• The aim of treatment:
 symptom relief by reducing hormone levels and tumour growth
 improve quality of life.
• No clear evidence that the particular treatment is superior to others.

39. CHEMOTHERAPY:
• Clear therapeutic advantage has not been demonstrated
• Due to this questionable efficacy and associated toxicity, chemo should be reserved for
those who have not responded to other therapies
• Response rate: 10-30%
• Streptozocin, 5-FU, doxorubicin, cisplatin, etoposide, cyclophosphamide

40. • Serotonin antagonists: with limited success
 5HT synthesis inhibitors eg parachlorphenylalanine
 peripheral 5HT antagonists eg Cyproheptadine, ketanserine
• Interferon α
 acts selectively on tumour cells to inhibit cell division by prolonging the cell cycle.
 significantly decreases the tumour markers in 40-55%
 reduce tumour size in 10-20% of the patients

41. • Octreotide: a somatostatin analogue
 the first line treatment for patients with low grade tumours and carcinoid syndrome
 effective in abolishing flushing and improving carcinoid syndrome in 88% of patients

42. RADIOTHERAPY
• This form of treatment has not been extensively studied.
• It may be effective in palliation of bone or central nervous system metastases

43. PROGNOSIS
• Good if localized (slow growing)
• Tumour size (>2cm), histologic features, distant metastasis are significant factors
predicting survival
• Variable malignant potential: Ileal much more likely to metastasize than appendiceal

44. PROGNOSIS
• 5 yr survival:
 65% if locoregional
 35-50% if distant disease
• Worst prognostic factors:
 Presence of liver mets and carcinoid heart disease
• Follow up with tumour marker (5-HIAA)/ 6-12 months

45. DIFFERENTIAL DIAGNOSIS
• Benign neoplasm of the small intestine
• Intestinal polypoid adenomas
• Small intestinal adenocarcinoma
• Lymphomas
• GISTs
• Metastatic cancers

46. CONCLUSION
• Carcinoid tumours are the most common neuroendocrine tumors commonly involving the
intestine.
• Most are asymptomatic but carcinoid syndrome can occur in functional tumours.
• 5-HIAA and chromogranin A helpful in screening , diagnosis and monitoring.
• Preferred form of treatment is surgery