Carcinoid Tumours / NET

DEFINITION

Tumours mostly of the GI tract, which secrete bioactive peptides resulting in a number of endocrine syndromes, including carcinoid Syndrome.
Carcinoid = "carcinoma-like"; this because of relatively indolent nature cf carcinoma.
Preferred term is now Neuroendocrine Tumours ("NET") (WHO)
Formerly also APUDoma
See also pancreatic neuroendocrine tumours
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EPIDEMIOLOGY

Peaks in 50s.
But can occur at any age.
Increasing; possibly due to better diagnosis.
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AETIOLOGY

Diverse range of slow-growing neoplasms from enterochromaffin cells.
- these cells are normally found throughout the crypts of Lieberkuhn.

Most commonly GI origin, occasionally in other organs, eg lungs, thymus, biliary tree, testicles or even liver.
- Of GI carcinoids, commonly in small intestine (45%), also appendix (>10%), less likelihood in stomach, colon and rectum
- 1/3 of intestinal ones are multi-centric, others tend to be solitary.


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BIOLOGICAL BEHAVIOUR

Pathophysiology
Cells making peptide and non-peptide bioactive hormones are found along the entire GI tract normally.
- are derived from endothelial cells, but called 'endocrine' because of their function and resemblance.
Synthesise and secrete a variety of bioactive peptides.
- serotonin is most common
- multiple factors may also be synthesised by a single tumour
- but more likely to produce a predominant clinical syndrome, eg gastrinoma, somatostanoma, insulinoma.
- with GI carcinoids, liver metabolises products, so hepatic mets must exist before symptoms.

Natural History
All are potentially malignant
- average size at presentation is <2cm
- and up to 50% have spread by diagnosis
Tendency for aggressive behaviour correlates to:
- site of origin
- depth of local penetration
- size
Eg appendiceal and rectal carcinoids less likely to metastasize (but may show extensive local spread)
Mesenteric nodal spread is otherwise common.
5-year survival is 90%
- >50% with small bowel tumours and hepatic mets
- widespread disease is however rarely curable

Pathology
In appendix, tend to be bulbous swellings of the tip
Elsewhere they can be polypoid elevations rarely over 3cm.
- characteristically yellow-tan on transection.
Visceral mets are usually small and dispersed.
Cells arranged in islands / glands or sheets etc, and are fairly regular in most cases.
Mets favour liver
- thereafter, bone, lungs, CNS, many possible locations.
Agarophilia; serotonin stains with silver

Complications
May induce stricturing or kinking sufficient to induce obstruction.
Fibrosis can cause shortening of mesentery, fixation of mesentery to retroperitoneum
- often a cause of the kinking
- this is because involvement of serosa causes an intense desmoplastic reaction.
- due to infiltration and local release of serotonin and other mediators
--> fibrosis may cause venous congestion and ischaemia

May encase retroperitoneal vessels if severe
- venous stasis and venous ischaemia

Endocrinopathy

Produce a variety of symptoms dependent on site and type of bioactive amine produced.
- zollinger-ellison syndrome from excess gastrin.
- cushing's syndrome
- hyperinsulinism

Carcinoid Syndrome

Presentation in 10% of patients
- or 20% of those with widespread mets
Most arise from excess 5-hydroxytryptamine (5-HTP) secretion
- also produce histamine, bradykinin, kallikrein, prostaglandins; virtually any vasoactive peptide.
Generally (not exclusively) requires liver mets; avoids clearance of tumour secretions by liver

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MANIFESTATIONS

Symptoms

Grow slowly in intestine wall so often asymptomatic at first.

Local

Can have a prolonged history of vague pains, cramping, distension, nausea and vomiting, diarrhoea and weight loss,
Possibly might obstruct, bleed or become ischaemic

Endocrine
Features of endocrinopathies above.

Carcinoid Syndrome
Vasomotor: flushing, cyanosis (most)
- may be provoked by stress, coffee, aged cheese, alcohol
Hypermotility: nausea, vomiting (most), diarrhoea, food / alcohol intolerances
Bronchoconstriction: cough, wheeze, dyspnoea (1/3)
Systemic fibrosis: heart, lung, retroperitoneal fibrosis, collagenous pleural / intimal plaques (some)
- heart disease (2/3 untreated) --> fibrous cardiac plaques, pulmonary stenosis or tricuspid regurge.
--> responsible for 50% deaths in these pts.

Carcinoid Crisis
Excessive flushing, hyperthermia, shock, arrhythmia, bronchial obstruction.

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INVESTIGATIONS

30-50% simply found at laparotomy as a cause of bowel obstruction &c.

Biochemistry

Elevated 5-HT

But its metabolite 5-HIAA (5-hydroxyindoleacetic acid) is measured
- 24 hr urinary collection
73% sensitive, 100% if liver mets; very specific.

Chromogranin A blood level
- chromogranins are neuroendocrine markers; glycoprotein released by tumours
- superior screening test.
- sensitivity >80%, but specificity decreased by atrophic gastritis, renal impairment, IBD, PPIs
- but currently requires pt consent as they have to pay in Aus.
- also used for disease monitoring and surveillance for recurrence.

Imaging
Ct, MRI
- primaries are often small and not readily seen; good for examination large masses and resectability
- mesenteric lesions highly suggestive, with calcification in 50%
- contrast can help inform extent and resectability
- role of MRI more restricted to assessing possibility of liver disease
--> tumour necrosis may give lesions a rim-pattern of enhancement 

Ocreatide scan;
sensitivity 80-90%
- ie ' somatostatin receptor scintigraphy'
Routine used to identify degree of metastatic spread
Also helps to predict response to treatment with somatostatin receptor analogs (ocreotide)

PET
Less of a role in well differentiated tumours
But can be used with special neuroendocrine markers eg labeled HTP

EUS
Feasible for duodenal carcinoids

Echo

Perform on all patients with carcinoid syndrome

Colonoscopy
To rule out synchronous disease, going well into TI if possible.
- increasingly, double-balloon enteroscopy being used to assess SB extent

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MANAGEMENT

MDT Consultation

Treatment depends on size, location and symptoms
Tumours <1cm are generally benign

Pre-Op Principles
1. Assess extent of local and distal disease
2. Identify synchronous and non-synchronous carcinoid tumours
- need to exclude concurrent adenoCa; 10-15% in this group
3. Fluid and electrolyte repletion
4. Pharmacologic treatments
5. Detect cardiac abnormalities

Prophylactic measures against carcinoid crisis
Can be precipitated by operative stress
All at risk, though much higher in carcinoid syndrome
1. Give peri-operative somatostatin analogs (ie ocreotide); 100ug subcut tds
2. Carcinoid crisis can be treated with bolus IV ocreotide (100ug IV push), followed by ocreotide infusion, antihistamines, hydrocortisone, and albuterol as reqd.

Operative
Surgery is most effective therapy when possible.
- relieves obstruction bleeding and secretory effects
Metastatic nodal spread is common
--> requires extensive lymphadenectomy and wide resection of the mesentery
--> carefully inspect abdomen for multicentric lesions and liver mets.
May be extremely difficult to find.

Duodenal tumours
Small lesions can be removed endoscopically. 
- ie <1cm unless there is evidence of lymph node mets by imaging and EUS
1-2 cm may require transduodenal excision (if no nodes)
Larger lesions should be surgically removed until short life expectancy or widespread metastatic disease.
- if close to ampulla, pancreaticoduodenectomy may be required.
- if localised resectable disease in liver, resect all.
- resection helps to minimize chance of complications such as uncontrollable bleeding

Jejunum / ileum
Many present with obstruction and should undergo limited bowel resection and wedge excision of mesentery.
May be a small mass with large mass in mesentery and fibrosis
Want to take nodes high, up to around the SMA +/- its branches
- radical resection not possible if SMA surrounded by fibrotic reaction, do not want infarction and short gut post op
- unless close to end of ileum, in which case it should be possible to do a limited ileocolic resection
Evaluate rest of bowel carefully for additional lesions

Cholecystectomy?
Should be considered if unresectable because many patients on long-term long-term somatostatin analogs will develop problematic gallstones.

Appendiceal carcinoid

Appendiceal NETs review (BJS 2003):

1. lesions at the base of the appendix with tumour-positive margins
2. mesoappendiceal invasion
3. any high-grade malignant carcinoid (including those with a high mitotic index)
4. 2 cm in size (up to 30% chance of mets if >2cm; vs ~0% chance if <1cm)
5. atypical goblet cell adenocarcinoids (do not express somatostatin receptors)

Follow-up

Examine every 3m for 1y
- hx, exam +/- tumour markers +/- scans
Then every 6m from 2-5y
- yearly thereafter

Management of Metastatic Disease
50% of pts seen initially will have liver disease

There are liver mets:
Resect the primary tumour anyway, to prevent later local complications.

Liver resection?
Resection of liver mets is the gold standard treatment.
- must have resectable disease with acceptable remnant liver, inflow, outflow, biliary drainage; 2 stage procedures acceptable
- and acceptable comorbidities, including lack of R heart insufficiency (fibrosis)
- and no diffuse carcinomatosis
Other options for liver mets, if not all surgical resectable, include ablation, embolization, transplantation (may be in combination with surgery)
- RFA most common approach; can be delivered under radiological guidance
- but not for large tumours or those close to vital structures
- TACE is also affective, as liver met course is predominantly arterial.
--> effective control achieved in 50% through selective use of these strategies.
Resection of bowel, mesentery, nodes, hepatic mets and fibrosis may all improve quality of life.
- debulking ok, including with liver resection, but would need to eradicate / debulk most of it to achieve effective palliation; makes drugs more effective.
- aggressive resections may prolong survival.
Transplantation is reasonable in selected patients with fulminant liver disease
- but long-term survival is exceptional.

Long-Acting Somatostatin Analogs
Highly effective in symptom control; response rate ~60%
- stabilization of progression may also be seen in ~1/3
Depot administrations can be given every 4 weeks
Side effects can include abdo discomfort, gallstones, malabsorption and steatorrheoa.
Monitor response with urinary 5-HIAA, plasma serotonin, plasma substance P,

Other therapy
Interferons second line therapy
Chemo efficacy is very limited.

Peptide-labelled radionucleotide therapy
Promising, may soon become treatment of choice in advanced disease
Treatment response in up to a third, often for >2 years
Depends on how reactive tumour is with SRS

Survival
5-yr survival is ~60% but 'stage' dependent
- 90% for good down to 40% for bad.
- there is actually no formal staging system, tumours are lumped by extent of spread.
Negative predictors:
Age >55, male, tumour primary >1cm, distant mets, positive margins
Surviellance
Yes. 85% will ultimately develop liver mets.
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REFERENCES
Robbins
Cameron 10th