Neuroendocrine Tumour of Small BowelKai-Hong Yue, Ivan

Kwong Wah Hospital

Outline

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

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

1. 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.

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 742-756

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.

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

Modlin, I.M., Kidd, M., Latich, I., et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128: 1717-1751.

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

Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:377-385

Evers BM, Townsend CM Jr, ThompsonJC. Small intestine. In Schwartz SI, ed. Principles of Surgery.New York: McGraw-Hill, 1999, pp 1217–1263.http://www.webpathology.com/image.asp?case=209&n=2

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

Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:377-385

Distant Metastases

Most common: liver Bilateral, diffusely spread; 10%

dominant lesion Carcinoid syndrome

Skeleton (spine, orbital framing) Lungs, CNS, peripheral

lymphnodes, ovaries, breast, skin

Surgical treatment of midgut carcinoid tumours. World J Surg 1990;14:377-385

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: 1717-1751.

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: 1717-1751.

Diagnosis

Biochemistry Radiology Histology

Biochemistry

Sensitive, reflect tumour load, as indicator of treatment response, non specific

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

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

Midgut Neuroendocrine Tumors: Imaging Assessment for Surgical ResectionWoodbridge et al. RadioGraphics 2014 34:2, 413-426

Woolbridge et al. Midgut Neuroendocrine Tumors: Imaging Assessment for Surgical Resection. RadioGraphics 2014 34:2, 413-426

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%

Treatment

Surgery Primary tumour and mesenteric

metastases Resection

Medical treatment and prophylaxis against carcinoid crisis

Primary tumour

Surgical resection 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

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

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

Prophylaxis Against Carcinoid Crisis

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

ENETS Consensus guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology 2009;90: 203-208.

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

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