1. Neuroendocrine Tumour of Small Bowel
Kai-Hong Yue, Ivan
Kwong Wah Hospital

2. Outline Neuroendocrine tumour Distribution and Classification
Morphology
Presentation and Diagnosis
Treatment and survival
Take home message

3. Neuroendocrine Tumour
Oberndorfer, 1907: used Karzinoide to represent the carcinoma-like appearance and the relative indolent nature
Neuroendocrine cells throughout the entire GI tract, bronchopulmonary systems, and urogenital tract
Secrets vasoactive substances
Controversies about terminology and staging
WHO 2010 classification
Lubarsch O. Uber den pimaeren krebs des ileum nebst Bemerkungen ueber das gleichzeitige Vorkommen von krebs und Tuberculos. Virchows Arch 1888;11:280–317.
2. Oberndorfer S. Karzinoide tumoren des dunndarms. Frankf Z Pathol 1907;1:425–429.
Lubarsch O. Uber den pimaeren krebs des ileum nebst Bemerkungen ueber das gleichzeitige Vorkommen von krebs und Tuberculos. Virchows Arch 1888;11:280–317.
Oberndorfer S. Karzinoide tumoren des dunndarms. Frankf Z Pathol 1907;1:425–429.

4. Distribution Site Occurrence (%)
Extragastrointestinal (Lung, ovary, uterus)
~30
Oesophagus
<1
Stomach
4-8
Duodenum/ pancreas
< 2
Small intestine
25-30
Appendix 6
Colon 10
Rectum 15
Kenneth J. . Current management of gastrointestinal carcinoid tumors .Journal of Gastrointestinal Surgery. 2004, Volume 8, Issue 6, pp
Kenneth J. . Current management of gastrointestinal carcinoid tumors .Journal of Gastrointestinal Surgery. 2004, Volume 8, Issue 6, pp

5. Highly differentiated neuroendocrine tumor Neuroendocrine tumor
WHO 1980
WHO 2000
WHO 2010
Carcinoid
Highly differentiated neuroendocrine tumor
Neuroendocrine tumor
Grade 1 (carcinoid)
Grade 2
Highly differentiated neuroendocrine carcinoma
Poorly differentiated (small-cell) neuroendocrine carcinoma
Neuroendocrine carcinoma
Grade 3
(Small- or large-cell)
Mucocarcinoid mixed carcinoid-adenocarcinoma
Mixed endocrine-exocrine carcinoma
Mixed adenoneuroendocrine carcinoma
Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.
WHO grade was classified with Ki-67 index; grade 1 = B 2%, grade 2 = 3–20%, and grade 3 > 20%
Well-differentiated NETs can be classified as either grade 1 or grade 2 depending on proliferation and histology (see comparison table below). Well-differentiated grade 1 and grade 2 NETs traditionally have been referred to as carcinoids, regardless of grade or site of origin.2,9,10 The WHO 2010 guidelines apply the term "carcinoid" to grade 1 NETs only2
Poorly differentiated grade 3 neuroendocrine carcinomas are characterized by rapid dissemination, resistance to therapeutic interventions, and a highly aggressive course
Basically, NEN is classified into tumors of low- and high-grade malignancy, which has made the classification concept clearer than the previous versions. The former entity is neuroendocrine tumor (NET), corresponding to carcinoid tumor, which can be further classified into NET grade 1 with very low malignancy and grade 2 NET with metastatic potential. High-grade tumors are classified into neuroendocrine carcinoma (NEC) and mixed adeno-neuroendocrine carcinoma (MANEC).
Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

6. Small Bowel Neuroendocrine Tumours
Midgut/ Jejuno-ileal NETs
“classical” midgut carcinoids
serotonin (5-hydroxytryptamine [5-HT]) immunoreactivity
30% of NETs
25% of small-bowel neoplasms
Average age of diagnosis: 65 year-old
Slight male predominance 11
Modlin, I.M., Kidd, M., Latich, I., et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128:
Modlin, I.M., Kidd, M., Latich, I., et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128:

7. Morphological Features
Most common: terminal ileum
Small (usually <1cm), flat and fibrotic submucosal tumour, central navelling
Mesenteric metastases
Typically conspicuously larger than primary tumour
Incidence: 70-90% in patient subjected to surgery
Marked desmoplastic reaction with fibrosis
Conglomerate of mesenteric lymph gland metastases
Fibrosis might result from local effects of serotonin, growth factors and substances secreted 61
Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:
Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:

8. A, Carcinoid tumor of the distal ileum with an
intense desmoplastic reaction and fibrosis of the bowel wall.
B, Mesenteric metastases from a carcinoid tumor of the
small bowel.
Evers BM, Townsend CM Jr, Thompson
JC. Small intestine. In Schwartz SI, ed. Principles of Surgery.
New York: McGraw-Hill, 1999, pp 1217–1263.

9. Mesenteric metastases
Partial or complete small-intestinal obstruction by kinking and fibrotic entrapment
Fibrosis may tether the mesenteric root to the retroperitoneum/ duodenum
Mesenteric vessels encased or occluded
Venous stasis/ congestion, or arterial deficiency
Vascular elastosis: specific angiopathy
marked thickening of mesenteric vessel walls due to elastic tissue proliferation in the adventitia 61
Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:
Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:

10. Distant Metastases Most common: liver
Bilateral, diffusely spread; 10% dominant lesion
Carcinoid syndrome
Skeleton (spine, orbital framing)
Lungs, CNS, peripheral lymphnodes, ovaries, breast, skin 61
Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:
Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:

11. Clinical Presentation
Slow growing tumour
Long periods of prodromal symptoms
Episodic abdominal pain; features of carcinoid syndrome
Intestinal bleeding: rare, late
Moderate size, submucosal location
Mesenteric metastases invasion
Venous stasis
Modlin, I.M., Kidd, M., Latich, I., et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128:

13. Carcinoid Syndrome 20% of patient with jejuno-ileal NETs
Release of vasoactive peptides:
Serotonin, bradykinin, tachykinins (substance P, neuropeptide K), prostaglandins and growth factors, e.g. platelet-derived growth factor (PDGF), noradrenaline
Implication: Hepatic metastasis
Impaired monoamine oxidase activity for detoxification
Symptoms: Secretory Diarrhoea, Cutaneous Flushing, Heart valve fibrosis, Bronchial constriction
Modlin, I.M., Kidd, M., Latich, I., et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128:

14. Diagnosis
Biochemistry
Radiology
Histology

15. Biochemistry
Serotonin metabolite: (5-hydroxyindoleacetic acid ) 5-HIAA
Chromogranin A
24-hour urine sample
Plasma
Specific
Sensitive
advanced disease, liver metastases
Reflect tumour load, Indicator of treatment response, non specific
Sensitive, reflect tumour load, as indicator of treatment response, non specific
Chromogranin A is a very sensitive but relatively nonspecific serum marker of GEP-NENs. False high values are found, for instance, in patients with renal insufficiency or severe malabsorption syndrome. Chromogranin A determination is useful for staging and prognosis, since the serum concentration correlates to the tumor mass
Chromogranin A or parathyroid secretory protein 1 (gene name CHGA) is a member of the granin family of neuroendocrine secretory proteins, i.e., it is located in secretory vesicles of neurons and endocrine cells such as islet beta cell secretory granules in pancreas
enterochromaffin-like cells 
Chromogranin A is the precursor to several functional peptides including vasostatin-1, vasostatin-2, pancreastatin, catestatin and parastatin.

16. Radiology Contrast CT Sensitivity 50-100%
“circumscribed mesenteric mass with radiating densities”
Somatostatin receptor scintigraphy - OctreoScan
Sensitivity 43%–86%
indium-111. Somatostain receptors type 2 and 5
PET
Sensitivity 90% - 97%
fluorine 18 (18F) FDG is less useful . Low proliferative rate
Gallium; 68Ga DOTA octreotate
Mesenteric lymph node metastases, retroperitoneal extension, liver metastases
Iodine 123 (123I) MIBG scintigraphy has a lower sensitivity than does 111In octreotide scintigraphy for MNETs (12,19) but can sometimes demonstrate tumors that were not seen at 111In octreotide scintigraphy.
Standard PET using fluorine 18 (18F) FDG is less useful for imaging well-differentiated MNETs because they generally have lower proliferative activity than other solid tumors. It can be used to detect poorly differentiated SSTR-negative MNETs (3). Newer agents have been developed for use with PET to assess SSTR-positive tumors, such as 68Ga DOTA octreotate (GaTate), which is more sensitive than 111In octreotide scintigraphy and has the benefit of assessing suitability for PRRT (10,11,16,24) (Fig 7). Carbon 11 (11C) 5-HTP PET is another newer agent that is trapped by
Midgut Neuroendocrine Tumors: Imaging Assessment for Surgical Resection
Woodbridge et al. RadioGraphics :2,

17. Coronal (b) and axial (c) portal venous phase CT images show the primary mass (black arrowhead in c), as well as desmoplasia (white arrow in b), mesenteric nodes (white arrowhead in b and c), and liver metastases (black arrow in b).
Woolbridge et al. Midgut Neuroendocrine Tumors: Imaging Assessment for Surgical Resection. RadioGraphics :2,

18. Histology Insular, glandular, mixed growth pattern
Immunocytochemistry staining
Chromogranin A
Synaptophysin
Ki67 antibody: proliferation rate
grade 1 < 3%, grade 2 = 3–20%, and grade 3 > 20%
The protein is a synaptic vesicle glycoprotein with four transmembrane domains weighing 38kDa. It is present inneuroendocrine cells and in virtually all neurons in the brain and spinal cord that participate in synaptic transmission. It acts as a marker for neuroendocrine tumors, and its ubiquity at the synapse has led to the use of synaptophysin immunostaining for quantification of synapses.

19. Treatment
Surgery
Primary tumour and mesenteric metastases
Resection
Medical treatment and prophylaxis against carcinoid crisis
Liver metastases
Medical treatment, surgery, radiofrequency/ microwave ablation, embolisation, transplantation

20. Primary tumour Surgical resection Inoperable
Active strategy with early prophylactic locoregional tumor removal
to prevent or delay abdominal complications from the growth of the mesenteric tumor disease
Resection of the primary tumor reduces symptoms and improves survival, even though inoperable mesenteric lymph node and liver metastases are present
Inoperable
Involvement of origins of proximal jejunal arteries, median colic artery or extending retroperitoneally
Long-term palliation following surgery
Even in the presence of liver metastases
Recurrence up to >80% with liver metastases if follow-up is long enough, clinically overt recurrence occurs after median of 10 years to 25 years
Early diagnosis of recurrence by serum chromogranin A estimates, not urine 5-HIAA

21. Effect of Surgery on the Outcome of Midgut Carcinoid Disease with Lymph Node and Liver Metastases. World J. Surg. 26, 991–997, 2002
Hellman et al. Effect of Surgery on the Outcome of Midgut Carcinoid Disease with Lymph Node and Liver Metastases. World J. Surg. 26, 991–997, 2002

22. Medical Treatment Palliation of symptoms Somatostatin analogues
Octreotide, lanreotide
Binding to somatostatin receptors types 2 and 5
Reduce the release of bioactive peptides Inhibit tumour growth, induce apoptosis
Long-acting formulations (Monthly)
Octreotide-LAR, lanreotide-PR
Interferon-α (IFN - α)
Reduces hormone secretion and stimulates natural killer cells

23. Prophylaxis Against Carcinoid Crisis
Hyperthermia, shock, arrhythmia, excessive flush or bronchial obstruction
Octreotide
500 microgram in 500ml NS,
50 microgram/hr infusion for prophylaxis
100 microgram/ hr infusion for carcinoid crisis
Octreotide, histamine blockade and cortisone, avoidance of histamine-releasing agents eg morphine and tubocurarine
ENETS Consensus guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology 2009;90:
ENETS Consensus guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology 2009;90:

24. Survival Age-adjusted overall 5-year survival: 67%
Median survival 8.4 year
Inoperable liver metastases: 50% 5-year survival
Inoperable liver and mesenteric lymph node metastases: 42% 5-year survival
Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center. World J Surg (2012) 36:1419–1431
Long-Term Results of Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center. World J Surg (2012) 36:1419–1431

25. Take Home Message
Rare, Slow growing tumour, long periods of prodromal symptoms
Intestinal obstruction
Carcinoid syndrome uncommon
Locoregional resection improves survival even in presence of liver metastases
Medical treatment improves symptoms