Small bowel tumours

Section: Small bowel Curriculum: Curriculum, page 59

Background

• Despite accounting for 75% of length and 90% of surface area, small bowel accounts for only 2% of GI malignancy

Benign

1. Stromal Tumours
2. Adenoma
3. Lipoma
4. Harmartomas
5. Haemangiomas

Stromal tumurs

• Mesenchymal tumours
  • Leiomyoma

Adenoma

• Account for 15% of Benign SB tumours
  • Three types
    • True Adenomas
    • Villous Adenoma (Malignant potential 35-55%)
    • Brunner Gland Adenoma (Hyperplastic lesions with no malignant potential)
      • Arise from Brunner Glands in proximal Duodenum
• Location
  • Duodenum – 20%
  • Jejunum – 30%
  • Ileum – 50%
• Aetiology
  • Familial adenomatous polyposis major risk factor for Duodenal Polyps
    • Spigelman staging
    • 5% lifetime risk of Duo Adenoca
• Management varies
  • Endoscopic mucosal resection
  • Local excision
  • Formal resection

Lipoma

• Most commonly occur in ileum
• < 1/3 are symptomatic
• No malignant potential
• Excise if symptomatic

Hamartomas

• Peutz-Jeghers syndrome
  • Hamartomas of SB associated with mucocutaneous pigmentation
  • Most common in jejunum and ileum, 50% also have colonic/rectal polyps, 25% have gastric
• Treatment of complications (obstruction or bleeding)
• Resection of symptomatic lesion only

Haemangiomas

• Developmental malformation consisting of submucosal proliferation of blood vessels
• Occur anywhere throughout GI tract, most commonly in jejunum
• Most common presentation is bleeding
• Site can be identified with angiography or labelled red cell scan

Malignant

1. GIST
2. Small bowel neuroendocrine tumours
3. Small bowel adenocarcinoams
4. Small bowel sarcomas

Gastrointestinal stromal tumor

• Overview
  • Arise from interstitial cells of Cajal (Pacemaker cell of mesodermal origin)
  • Most commonly found in stomach (60%) and jejunum/ileum (30%). Rare in duodenum (5%)
  • 3 - 4 x more common than malignant GIST
  • Can grow intramurally causing obstruction or extramurally causing bleeding
• Management
  • Medical management with Gleevec (Imatinib)
  • Surgical resection often needed, peri-ampullary tumours may require pancreaticoduodenectomy
• Most benign tumours have low mitotic index
• Predictors of recurrence
  • Size > 5cm
  • Mitoses > 5/50 hpf
    • Location – Stomach better than Colon/rectum

Small bowel neuroendocrine tumours

Definition

• Small bowel tumour originating from enterochromaffin cells (neuroendocrine cells) in the gut epithelium. These tumors may produce: Serotonin, histamine, bradykinin, or tachykinins.

Epidemiology

• 9.3/1,000,000 (increasing – possibly due to better diagnosis)
• Account for 37% of small bowel malignant tumours
• Median age 67

Aetiology

Arise from Enterochromaffin cells (Kulchitsky cells) located in the Crypts of Lieberkühn

Clinical

• Clinical symptoms
  • Episodic abdominal pain or borborygmi
  • Carcinoid syndrome
  • Intestinal bleeding is rare
  • Bowel obstruction
• Carcinoid syndrome
  • Term applied to a constellation of symptoms mediated by various humoral factor released from well-differentiated NETs.
  • More than 90% of patients with carcinoid syndrome have metastatic disease from a small bowel primary NET - typically to the liver.
  • Monoamine oxidase in the liver can generally detoxify substances - thus if patient symptomatic = liver metastasis.
  • Can occur with very large retroperitoneal tumours
  • Symptoms of carcinoid occur due to serotonin, tachykinins (substance P), prostaglandins, PDGF.
  • Symptoms of carcinoid syndrome
    • Secretory diarrhoea - often prevalent in the morning and often meal related.
    • Cutaneous flushing - often provoked by stress, ETOH, certain food, cheese or coffee.
    • Heart valve fibrosis - right side valvular fibrosis, can result in carcinoid heart disease - RHF.
  • Other sections
    • NETs can produce a number of different peptides
    • Foregut – Low levels of serotonin but can produce 5-hydroxytryptophan and ACTH
    • Midgut – High levels of serotonin
    • Hindgut – Rarely produce serotonin but produce somatostatin and peptide YY
    • Also produce corticotropin, histamine, dopamine, neurotensin, prostaglandins, kinins, gastrin, calcitonin
    • 70-80% asymptomatic

Pathophysiology

• WHO classifies NENs

Terminology	Differentiation	Grade	Mitotic rate* (mitoses/2 mm2)	Ki-67 index* (%)
NET, G1	Well differentiated	Low	<2	<3
NET, G2	Well differentiated	Intermediate	2 to 20	3 to 20
NET, G3	Well differentiated	High	>20	>20
NEC, small cell type (SCNEC)	Poorly differentiated	HighΔ	>20	>20 (often >70)
NEC, large cell type (LCNEC)	Poorly differentiated	HighΔ	>20	>20 (often >70)
MiNEN	Well or poorly differentiated¶	Variable¶	Variable¶	Variable¶
LCNEC: large cell neuroendocrine carcinoma; MiNEN: mixed neuroendocrine-non-neuroendocrine neoplasm; NEC: neuroendocrine carcinoma; NET: neuroendocrine tumor; SCNEC: small cell neuroendocrine carcinoma.

Mitotic rates are the number of mitoses/2 mm2 (ie, 10 high-power fields at 40× magnification and an ocular field diameter of 0.5 mm). To assess the mitotic rate, count in 50 fields of 0.2 mm2 (over a total area of 10 mm2). To assess the Ki-67 proliferation index, count at least 500 cells in the regions of highest labeling (using scanning magnification). The final grade is determined by the value (mitotic rate or Ki-67 proliferation index) that places the tumor in the category with the higher grade.

¶ In most MiNENs, both the neuroendocrine and non-neuroendocrine components are poorly differentiated. Additionally, the mitotic rate and Ki-67 proliferation index of the neuroendocrine component usually fall into the same range as an NEC. However, in some MiNENs, either (or both) components could be well-differentiated so they should be graded separately, if possible.

Δ Poorly differentiated NECs are not formally graded but are considered high grade by definition.

Location

• 90% are found in one of 5 sites
  • 38% Appendix
  • 29% Small bowel (usually within 2 feet of Ileocaecal valve)
  • 13% Colon
  • 12% Stomach
  • 8% Rectum
• Metastasie
  • Only 3% of Appendiceal NETs metastasise
  • 35% Ileal NETs associated with metastasis
  • Risk of metastasis also related to size
    • 2% NETs < 1cm
    • 50% NETs 1-2cm
    • 80-90% NETs > 2cm

Investigation

• Bloods
  • Chromogranin A – elevated in 80% of pts
    • Sensitivity: 55%, Specificity: 95%
• Urine
  • Elevated 5-HIAA (metabolic product of serotonin breakdown)
  • 24h urine test
  • When combined with serum chromogranin A, provides acceptable sensitivity and specificity
• Imaging
  • CT
    • Primaries often small and not seen on imaging
    • Mesenteric lesions are classically spiculated with spoke-like appearance within mesentery due to local desmoplastic reaction
  • CT-A useful for operative planning
  • MRI generally does not provide additional information
    • Can be used to look for liver lesions
  • Octreotide scintigraphy can be used
  • FDG PET only avid in high grade tumours
  • DOTATATE PET/CT- binds to somatostatin receptors
• Pre-op colonoscopy – 10-15% Synchronous Colorectal Adenoca
• ECHO to investigate for cardiac abnormalities

Management

Surgery

• Primary site
  • Surgery most effective therapy when possible
  • Small lesions (< 1cm) can be removed endoscopically or with segmental resection
  • Larger lesions need wide excision of bowel and mesentery
  • Significant anaesthetic issues
    • Can develop Carcinoid Crisis – flushing, hypotension, bronchospasm, tachycardia
    • Give octreotide intra-op if carcinoid crisis
  • In the context of mets
    • If symptomatic resect
    • Consider resecting if resectable metastatic disease
• Liver metastasis
  • Consider treating with metastectomy
    • Traditionally considered if >90% of disease can be resected although limited evidence - newer thinking is >70% disease
    • Improves symptoms
  • If unable to resect
    • Chemoembolization or radioembolization
    • Aggressive debulking may prolong survival but requires extensive debulking to improve symptoms.
    • High morbidity
• Surgical technique
  • The majority of metastasis originate from primary lesions in the terminal parts of the ileum, and tend to be deposited mainly on the right side of the mesenteric artery.
  • To remove - often require mobilisation of the right colon and small bowel up to the pancreas and horizontal duodenum - this posterior view allows the vessels to be easily identified and divide the fibrotic surrounds to the mesenteric root.
  • Generally the right colon requires removal.
  • Bypass should be avoided - ischaemia may still develop of disengaged segment.

Medical

• Somatostatin analogue
  • Long acting Octreotide or Lantreotide
    • Can be used to relieve symptoms if symptomatic patients
      • Decreases hormone release
    • In patients with a high tumour burden
      • Treats tumour growth
• Chemotherapy efficacy limited
• Peptide Receptor Radioligand Therapy (PRRT)
  • Indications:
    • Advanced (Metastatic) or Progressive disease despite long-acting somatostatin analog AND
    • Somatostatin Receptor-Positive Disease AND
    • No underlying Renal or Haematologic insufficiency
  • Most commonly used radionuclides: Yttrium-90 (90Y) and Lutetium-177 (177Lu)
  • Long-Term Adverse Effects:
    • Renal impairment
    • Pancytopaenia
    • Myelodysplastic Syndrome
    • Secondary Acute Leukaemia

Prognosis

• NETs best prognosis of all small bowel tumours
• Resection of localised tumour, close to 100% survival
• Regional disease 5 yr survival 65%
• Distant mets 5 yr survival 25-35%
• Metastases present in 20-50% at presentation
• Recurrence in 40-60%

Small bowel adenocarcinoma

Definition

• Adenocarcinoma affecting small intestine

Epidemiology

• Account for 37% of malignant small bowel lesions
• Peak 7th decade
• Most located in duodenum

Aetiology

• Major risk factor is Crohn’s
• Also FAP, Lynch Syndrome, Peutz-Jegher

Clinical presentation

• Depends on site and extent of disease
• Possible symptoms include obstruction, pain, biliary obstruction

• 50% have advanced disease at presentation

• 25% have metastatic disease

Investigation

• Imaging with CT (Enterography), MRE
• Endoscopy with push Enteroscopy or Pillcam (unable to biopsy)

Management

• Surgery
  • Surgical resection with 10cm margins and resection of associated mesentery
  • Duodenal (peri-ampullary) tumours often require pancreaticoduodenectomy
  • Distal duodenal tumours treated with duodenal resection and lymphadenectomy
  • TI tumours treated with Right Hemicolectomy
• Chemotherapy
  • Neoadjuvant
    • Appropriate to attempt downstaging tumour
  • Adjuvant
    • Treatment is extrapolated from colon cancer treatment i.e. node positive or patients with high risk features should be given chemotherapy (tumour perforation, high grade, tumour budding, LVI etc.
      • Regimes include CAPOX or FOLFOX

Prognosis

• Poor due to delayed presentation and advanced disease at presentation
• 5 yr survival 14-33% (duodenal up to 50% as earlier symptoms)

Metastatic tumours

• Metastatic tumours are much more common than primary tumours
• Can be intra-abdominal source – Ovaries, Cervix, Colon, Stomach, Pancreas
• Most common extra-abdominal source is Melanoma
• Present in 50% of patients with palliative melanoma
• Palliative options include
  • Medical/conservative
  • Palliative resection/bypass if limited disease