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Dr. JIGYASA SHAHANI
Moderator: Dr. FAREED AHMED
-Term given to an embryologically related group
of tumours of endocrine organs.
They are believed to arise from neuroendocrine cells,
which are derived from neural crest,and, whose
normal function is to serve at neuroendocrine
-APUD= amine precursor uptake and
-Tumours of this system = APUDomas; secrete
hormone of the tissue of origin
-The term was coined in about 1974;
has since been revised and called NEUROENDOCRINE
Cells with these properties have been
grouped together as the APUD system.
They contain characteristic granules on
They secrete polypeptides or amines or both
The cells included here are:
The chromaffin cell system- These are found in the
adrenal medulla and in association with the
The non-chromaffin cells of the paraganglia (Carotid
body, glomus jugulare).
The argentaffin (Kultschitzky) cells.( found in the
intestine). Similar cells occur in the salivary glands,
pancreas, and bronchial mucosa. The argyrophil cells.
These are widely distributed in the intestine.
Neural crest cells are a transient , multi-
potent,migratory cell population unique to
vertebrates that give rise to a diverse cell
lineage including melanocytes,craniofacial
cartilage and bones,smooth muscle ,
peripheral and enteric neurons and glia.
After gastrulation,neural crest
cells are specified at the
border of the neural plate and
the non neural ectoderm.
During neurulation,the border
of the neural plate,also known
as the neural folds,converge at
the dorsal midline to form the
Subsequently,neural crest cells
from the roof plate of the
neural tube undergo an
epithelial to mesenchymal
the neuroepithelium and
migrating through the
periphery where they
differentiate into varied cell
Neuroendocrine tumors are:
-Usually small, <1cm
-Slow growing over months to years
-Usually metastasize before becoming
symptomatic, often when tumour > 2cm
-Expression is episodic, may be silent for years
- often misdiagnosed
-Complex diagnosis requiring advanced
-In the past all NET’s were termed carcinoid;
-Has since been classified into:
-According to WHO 5 major categories:
i. well differentiated endocrine tu’s
ii. Well differentiated endocrine ca’s
iii. Poorly differentiated endocrine ca’s
iv. Mixed endocrine and exocrine ca’s
v. Neuro-endocrine – like lesions
Incidence of GEP-NETs
Other neuroendocrinal cells are present in the
stomach and small intestine
These are responsible for secretion of
VIP,cholecystokinin, gastrin,5HT, etc
Pancreatic islet cells, Thyroid C cells,Parathyroid
cells,Some cells of the anterior pituitary, and The
Usually present with symptoms or
manifestations caused by mechanical effects
of their presence, growth, and metastasis; or
caused by the effect of their particular
- Slow growing; delay diagnosis – 4-6years
- Pattern of growth varies; with the exception
of 90% of insulinomas, almost all have long
term malignant potential.
-hormone: insulin, proinsulin
-Clinical features: hypoglycaemia, wt gain, CVS
Symptoms (17%), neuroglycopaenic symptoms
-site: >95% pancreas; mostly small
- >10% malignant
- about 50% undetected before Sx
-diagnosis: 72hr fast – hypoglycaemia,
Elevated C-peptide and proinsulin
-localization: CT, MRI, selective arteriography,
selective portovenous sampling
-Most insulinomas are benign and can be
-Metastatic islet cell tumour:
i. diazoxide; or
ii. Streptozotocin + 5-FU
-Cure rate of 33% in patients with sporadic
-If patient has no hepatic metastasis and
limited surgical risk then a distal
pancreatectomy, LN Dissection and duodenal
-Octreotide Rx for progressive metastatic
Gastrinoma – 53% response rate.
- tumours are found in the tail + body of
-If tumour can still be localized – resection
-Preoperative planning: TPN containing amino-
acids, (steroids, Zn supplementation, Abics:
Useful for the rash)
-Long term chemotherapy: streptozotocin +/-
- Response rate of 30%
-Due to the high malignant potential, if
tumour can be localized, should be resected.
-Metastasis need to be excluded if Whipples
procedure is considered.
-At surgery a cholecystectomy should also be
-Optimal form of chemotherapy yet to be
-If tumour found excision should be
-Even with metastasis debulking is indicated
-Long term octreotide useful for control of
diarrhoea as well as benefit with tumour
arrest or regression.
- Chemotherapy is rarely of benefit
They originate in the enterochromaffin cells of the
intestine and have the ability to produce various
peptides and hormones.
Previously categorised by their embryological
origin – foregut, midgut & hindgut.
Revised classification has taken into account
tumour location, histological grade and
Neuro-endocrine tumours of the gastrointestinal
tract (carcinoids) are rare tumours
Origin of carcinoid tumors
-Typical small neoplasm occurring in
-Growth of the tumor is slow; vast majority
are < 1cm ( 5% > 2cm)
-It grows outward leaving the mucosa intact
-As it reaches the serosa it can cause a
desmoplastic reaction and lead to kinking of
Carcinoid syndrome is almost uniquely associated
with midgut carcinoids (neuro-endocrine tumours
of the gastrointestinal tract)
Carcinoid syndrome was first described by Thorson
and co-workers in 1954
Systemic symptoms are caused by an excess of
biogenic amines, peptides and other factors
(serotonin, tachy- and bradykinins and histamine)
in the circulation only after liver metastases.
Diarrhoea ( 80% of patients), mainly caused by
serotonin excess, also
histamine, kallikrein, prostaglandin, substance P and
Flushing ( 94% ), linked to several humoral factors –
tachykinins, serotonin & histamine. Provoked by
e.g. nuts & cheese, certain drugs & alcohol
Carcinoid heart disease ( 40% ), characterised by
so-called ‘plaques’ at the right side of the heart with
involvement of the tricuspid and pulmonary valves
Pellagra ( 5% ) characterised by
dermatitis, diarrhoea & dementia
– result of niacin deficiency
Intermittent bronchial obstruction (10%) often
Carcinoid crisis – rare, potentially fatal – provoked
by anaesthesia /surgery if not treated sufficiently
with somatostatin analogues
Carcinoid tumours less than 1cm in diameter &
confined to the mucosa and submucosa generally
remain subclinical for years.
Larger than 1 cm – generally malignant & have
metastasized to regional lymph nodes and later to
the liver and other locations.
Patients have generally been complaining for years
of intermittent abdominal discomfort, erroneously
diagnosed as a functional disorder such as irritable
Intermittent intestinal obstruction due to kinking of
the small bowel can occur at a later stage as a
result of the desmoplastic reaction in the
Incidence of midgut (neuro-)endocrine tumours is
0.2-2/100 000 population/year
Equal distribution between males & females
Incidence is higher in black than white people
Most prevalent location is the terminal ileum close
to the ileocaecal valve
Is often multiple
In up to 15% of patients other malignancies such as
gastrointestinal adenocarcinoma and breast cancer
have been demonstrated
Biochemical diagnosis includes measurements of serum
chromogranin A and urinary excretion of 5-HIAA.
Estimation of plasma serotonin is facultative
- transabdominal ultrasound is the initial imaging
procedure in most patients with metastasized
◦ Contrast-enhanced three-phase CT or MRI followed
by needle biopsy for pathology can be performed.
◦ In-pentetreotide scintigraphy is positive in 80-90% of
◦ Echocardiography is mandatory in patients with
carcinoid heart disease
-Based on site, size and presence/absence of
-<1cm: no nodal involvement – segmental
->1cm: + nodes – wide excision of bowel
-For tumours with widespread metastasis, Sx
is still of benefit.
-Is directed to patients with malignant carcinoid
syndome and those with widespread metastasis.
-Somatostatin analogues ( sandostatin): relief of
symptoms (diarrhoea + flushing); also tumor
-Serotonin receptor antagonists: used with
limited success. (methysergide no longer used)
-Cytotoxic chemotherapy: agents used
Streptozotocin + 5-FU/cyclophoshamide (33%)
Targeted chemotherapy agents have been approved
in Pancreatic Neuroendocrine Tumors by the FDA
based on improved progression free survival
EVEROLIMUS is labelled for patients with
unresectable,locally advanced or metastatic disease.
The safety and effectiveness of everolimus in
carcinoid tumors have not been established.
SUNITINIB is labelled for treatment of
progressive,well differentiated PNETs in patients with
unresectable,locally advanced or metastatic disease
Platinum & Etoposide combination is sometimes
given in pulmonary carcinoids.
This is a type of radioisotope therapy where the
tumor is treated intravenously with a peptide or
hormone conjugated to a radionuclide or
radioligand. This is also called as peptide
receptor radionuclide therapy or hormone
delivered radiotherapy and can attack all lesions
in the body .
Typically radiolabelling octreotate to lutetium
177, yttrium 90 or indium 111 is done.
This is a highly targetted and effective therapy
with minimal side effects in tumors with high
levels of cell surface somatostatin receptors.
Radiation is taken up at the sites of tumor or
excreted in urine.
Metastasis to liver can be treated by hepatic
artery treatments based on the observation
that tumor cells get nearly all their nutrients
from the hepatic artery. Hepatic artery
embolization or chemoembolization occludes
the blood flow to the tumor achieving
significant shrinkage in over 80% of cases.
Selective internal radiation therapy deliver
radioactive microsphere by injection into the
Radiofrequency ablation is used when a
patient has relatively few metastases.
Cryoablation has been less successful for
GEP-NETs than RFA.
EPOTHILONE B:- A novel cytotoxic agent
It is a potent anti angiogenesis agent.
It acts by blocking the polymerization of
tubulin in blood vessels
Action is similar to that of taxane
More suitable for slow growing tumors.
-Best prognosis of all small bowel tu’s
-Resection of localized tu – 100% survival rate
-65% for patients with regional disease;
- 25-35% for patients with distant
multiple endocrine neoplasia type 1 (MEN1)
multiple endocrine neoplasia type 2 (MEN2)
von Hippel-Lindau (VHL) disease
neurofibromatosis type 1
Immediate onset of a debilitating and life-threatening
condition associated with carcinoid syndrome
May occur spontaneously or may be precipitated by
anesthesia, chemotherapy, infection, stress, catecholamine
s, tumor manipulation or embolization procedures
Symptoms include prolonged severe
flushing, diarrhea, hypotension,tachycardia, severe
dyspnea, peripheral cyanosis and sometimes
Appropriate precautions include immediate therapy
and close monitoring before, during and after surgical
Prophylactic administration of octreotide
must be given by continuous intravenous
infusion at a dose of 50 μg/h for 12 hours
prior to and at least 48 hours after the
procedure to prevent a cardiovascular
For anaesthetic purposes,patients with
carcinoid tumors should be regarded as
suffering from a multi-system disease and so
require thorough pre-planning f/b post
operative management in a high dependency
Main aims are to maintain normal
haemodynamics and prevention of
occurrence of carcinoid crisis.
History and Examination:
signs/symptoms suggestive of ongoing
uncontrolled hormonal activity-
Cardiovascular history-reduced exercise
Even if patients lack symptoms,there is potential
for unpredictable,uncontrolled hormone release
precipitated by anaesthetic/surgical stimulus.
CXR-carcinoid lesions or miliary shadowing of
ECHO- Rt.side carcinoid
S.Electrolytes-effects of chronic diarrhoea
LFT- deranged when liver is infiltrated.
CBC- diffuse marrow spread
Cross match sample
24 hr urine- 5HIAA
Titration of adrenergic,histaminic and
serotonergic receptor blocking drugs to
Monitoring intravascular volume status
Octreotide infusion 50 microgram/hr for at
least 12 h immediately before surgery and 48
h after surgery should reduce tumor
Thoracic epidural insertion before induction of
GA is a reasonable technique to help achieve
good pain relief and reduce post operative
It provides excellent analgesia thereby reducing
the risk of carcinoid crisis. However,potential
hypotension may require vasoconstrictors that
may lead to exaggerated response.
The balance of risks would seem to favour the
use of epidurals with drug volumes and
concentrations cautiously titrated to blood
The primary aim is to provide stable,controlled
conditions and avoiding stimulatory factors.
Reliable large bore access in case of rapid volume
Availability of fluid warmers
Use of rapid infusion system are sensible
Stable induction,adequate depth of anaesthesia
before intubation and maintenance of
anaesthesia& analgesia peri-operatively are key
to preventing instability.
Histamine releasers are AVOIDED- eg.
Suxamethonium has been implicated in release
of peptides from liver as a result of
depolarization induced fasciculations. To be
Ramifentanyl 0.05-0.2 microgram/kg/min may
have a role in optimizing intubating
conditions,provision of titrable analgesia &
intraop BP control.
catheter, oesophageal doppler.
There is a risk of hypo or hypertension
The response to inotropes or vasopressors is
unpredictable. Norepinephrine and
epinephrine can be hazardous in carcinoid
Practically,small doses of phenylephrine has
Aprotinin – a kallikrien antagonist has a
significant place in symptomatic control
If prolonged vasocontriction is
required,vasopressin can be used.
Vasoactive hormone release intraop is best
treated with iv boluses of 20-50microgram of
octreotide titrated to hemodynamic response
Blood loss monitoring is very important.
For prolonged hypertension,labetolol
infusion have been used.
As with the intra-operative management, post-operative
care focuses on the provision of stable cardio-respiratory
conditions and adequate analgesia.
High-dependency care is recommended. Ongoing
hormonal control of the tumour is important as post-
operative crisis are possible and surgery may have been
aimed at reducing the bulk of carcinoid tumour
present, rather than eliminating it.
Intravenous and then subcutaneous octreotide follow-up
will help control any further hormone release and there
may well be residual, hormonally active tumour remaining.
Forty-eight hours of invasive monitoring, analgesia and
fluid management may be required to ensure safe recovery
from the surgery.
There has been a review of the biology of
enteroendocrine tumours over the past 1-2
decades, and significant advances have been
There is a need for enhanced awareness of the
heterogenous features of these tumours as well as
multiplicity of modalities available for their
Increasing acceptance of the more aggressive
and customized treatment with recognition that
favorable responses in these pts result from
sequential use of multiple modalities.