Gastro Intestinal

Neuro Endocrine
Tumor
INTRODUCTION
• Arise from endocremaffin cells of GIT, Respiratory tract and
langerhans cell of pancreas.
• Grouped based on their origin
GI NET
P NET
• P NET more common than GI NET
• Two types
Functional
Non Functional
• P NET is 2nd most common neoplasia of pancreas.
• m/c being ductal carcinoma(adenocarcinoma)
• Gastrinoma and insulinoma are the m/c functional P NET
Inherited Syndromes and GEP NET
Syndrome Genetics Features Type of NET
(prevalence/lakh)

Men type 1 Menin gene mutation on Hyperparathroidsm(m/c) Non functional 80-100%

Wermer syndrome chr 11 in 3rd decade
(1 to 10) Among functional
Knudson 2 hit hypothesis P NET in 4th to 5th decade gastrinomas are more
common
Pituitary adenoma in 20%
Screening of family is
important in MEN 1
associated P NET.
VHL VHL gene 232 AA and Main pancreatic lesion is Non functional 98%
(2-3) target HIF alpha cyst followed by P NET
Functional 2%

Neurofibromatosis 1 Neurofibromin 1 chr 17 0-10% develop GI NET in Somatostatinoma and

(von-Recklinghausen 2845 AA periampullary area of D2 rarely symptomatic
disease)
Psammoma bodies

Tuberous sclerosis TSC 1 and TSC 2 Non functional >

(bournville disease) functional P NET
P NET
NON Functional neuroendocrine
tumor
• More common
• Not associated with symptoms of hypersecretion
• Remain clinically silent
• Incidental finding or if metastatised or multiple tumor causing
anatomic symptoms.
• General treatment recommendation is surgical removal.
• If metastatised resection is not recommended.
• <1cm follow up
• >3 cm resection
FUNCTIONAL NEUROENDOCRINE
TUMOR
• Tumor associated with symptoms of hormone secretion
• This include
Gastrinoma
Insulinoma
Glucagonoma
VIPoma
Somatostatinoma
Insulinoma
• m/c functional P NET.
• Hormone secreted- Insulin
• Located in pancreas as single,small and mostly benign (if multiple
then suspect MEN 1)
• <10% malignant
Clinical Features
• Hypoglycemia- confusion, headache, disorientation, visual difficulties,
irrational behaviour, coma
• Symptoms on fasting and also during exercise.
• d/t increased secretion of insulin.
• Whipple’s triad
Fasting hypoglycemia (<50mg/dl)
Symptoms of hypoglycemia
Relief of symptoms with iv glucose.
Diagnosis
• CT and EUS to localize insulinoma.
• EUS is preferred imaging to localize small tumor.
• Somatostatin scintigraphy less consistent than other P NET.
• Serum level of insulin, c-peptide and pro insulin are increased.
• Helps differentiating insulinoma from exogenous hypoglycemic agents
induced hypoglycemia.
Treatment
• Diet – slowly absorbable CHO preferred
- iv glucose for symptomatic hypoglycemia
• Diazoxide-
 Glycogenolysis and decrease in secretion of beta cells
A/E edema, nausea, hirsutism
60% response
Dose- 3mg/kg/day per oral divided 8-12 hrly initially, typical dose
range from 3-8 mg/kg/day.
• Octreotide-
Lower response compared to other P NET (low somatostatin receptors)
If response (no hypoglycemia) to short acting agents than use long
acting agents like LAR octreotide, lanreotide
A/E- bloating, cramps,malabsorption, cholelithiasis,
hypoglycemia( decrease GH, glucagon)
• Everolimus-
Induce insulin resistance and have antitumor effect
refractory cases and metastatic insulinoma
• Surgery-
• 70-90% resectable
Gastrinoma
• Zollinger ellison syndrome
• >50% in duodenum
• 60-90% in possaro’s triangle
• Possaro’s triangle- bounded by duodenum,
• pancreas and confluence of the cystic and
• common bile duct
• 60-90% malignant
• 2 types based on their nature-
Sporadic
MEN associated (25%) family history and
 hyperparathyroidism should be evaluated
• 2 types based on their aggressiveness-
Aggressive (75%)
 Factors determining aggression- pancreatic, >3 cm, liver/bone mets,
MEN 1, ectopic cushing d/t ACTH
Non Aggressive(25%)
Clinical features
• Abdominal pain- m/c symptoms and <30% develop complication
(bleeding, perforation,obstruction,esophageal stricture)
• Diarrhea- direct damage to small intestine and pancreatic lipase
inactivation and precipitate bile acid diarrhea (2nd m/c)
• GERD
• MEN 1 suspected if-
Nephrolithiasis and renal colic
Younger age
 personal or family H/O endocrinopathies
Diagnosis
• CT scan
• MRI
• EUS
• Somatostatin scintigraphy
• These are small and are difficult to localize.
• Fasting S. grastin levels image
Treatment
• Medical management-
PPI is first line- 60mg/day omeprazole
Target- BAO <10meq/hr in no surgery and <5 meq/hr in those
previous surgery
Double dose PPI-
 MEN 1/ZES
 S. GERD
 Previous Billroth 2
• Surgery
To overcome PPI resistance
In MEN1 /ZES – parathyroidectomy in presence of hyperparathyroidism
as PPI resistance is more
Surgery of lesion
 Not advised if <2 cm
 Unfavourable in Men 1 ( multiple gastrinoma and liver mets)
 pancreaticodudenectomy (>2cm)
Glucagonoma
• 90% in pancreas, solitary and large
• Most are malignant with LN and liver mets.
• Necrolytic Migratory Erythema is characteristic:
erythematous patch in periorificial, intertriginous area like groin,
buttock, thigh.
Raised with central blisteringrupture and heal  hyperpigmentation
Clinical features
• Hyperglycemia
• No ketosis
• Weight loss
• Anemia (glucagon decrease erythropoiesis)
• Thromboembolism
• Glossitis and angular stomatitis

• Diagnosis- fasting glucagon >1000 pg/ml

- imaging
Treatment
• Medical management
 TPN with normalize essential fatty acid and amino acid
 Octreotide response in 30%
• Surgery-
 Mostly metastatic
 Localised – distal pancreatectomy and splenectomy.
VIPOMA
• Pancreatic cholera/Verner Morrison syndrome/WDHA (watery
diarrhea, hypokalemia,achlorhydia)
• 80-90% arise from pancreas
• Most are malignant
 CLINICAL FEATURES
• 42-51 yrs
• Watery diarrhea(>1L/day) and persist in fasting (secretory)
• Hypokalemia (loose stool, increase in secondary aldosterone due to
volume depletion and release renin by VIP)
• Achlorhydia
• Tetany (due to hypomagnesemia)
• Hypercalcemia
• Hyperglycemia
• Flushing(vasodilation)

• DIAGNOSIS- VIP>190 pg/ml with diarrhea

• Raised VIP without diarrhea
Radiation
IBD
CKD
Fasting
Bowel resection
Treatment
• Medical
Iv fluid
Correct electrolyte imbalance
Octreotide
• Surgery-
If no metastasis
Somatostatinoma
• Present with DM, GB disease, diarrhea, steatorrhea
• Primarily in pancreas and duodenum
• Diagnosis is based on raised somatostatin
• Surgery in localised tumor
• Somatostatin use is queastionable
Gastro intestinal NET
(extrapancreatic)
• 75% all carcinoid (carcinoid is rare in P NET and 25% in respiratory
tract)
• m/c in small intestine (ileum>duodenum>jejunum)
Typical carcinoid
• Mid gut carcinoid (D3, D4, jejunum, ileum,caecum and ascending
colon)
• Contain enzyme dopa decarboxylase which convert 5HTP to
5HT(serotonin) further metabolized to 5 HIAA and excreted in urine.
• Increased serotonin in blood causing typical carcinoid syndrome.
Atypical Carcinoid
• Foregut and Hindgut ( gastric+ D1 + D2 + rest of colon)
• Lack dopa decarboxylase
• Normal serotonin in blood causing atypical carcinoid syndrome
• But increased serotonin secretion in urine
Clinical features of Carcinoid
syndrome
• Flushing- d/t histamine, other mediators include substance P, neurokinins and
GI peptides
• Diarrhea- Serotonin is the m/c culprit and can occur with flushing (85%) or
occur alone (15%)
• Heart disease- mainly affect tricuspid valve and then pulmonary followed by
mitral (TR 90-100% >TS>PR>PS)
27 to 43% had heart disease at time of diagnosis, with use of SSA
incidence is decreasing.(circulating 5HT)
Lesions- plaque like, fibrous endocardial thickening
• Asthma
• Pellagra like features- d/t Tryptophan consumption
• Wide spread fibrosis- Retroperitoneal, Peyronie disease, intra abdominal
fibrosis, pleural and pulmonary fibrosis and mesenteric occlusion
• Carcinoid Crisis-
 d/t tumor manipulation-> serotonin surge causing crisis
 Hypotension > hypertension
 Confusion, stupor
 Flushing
 Diarhhea
 Bronchospasm
 Arrhythmia
 Hyperthermia
• Prevention-
 100-200 mcg octreotide, 2-3 times a day during surgery in minor surgery
 100 mcg 3 times/day for 2 weeks prior to surgery in major surgery to
avoid carcinoid crisis.
Diagnosis
• 24 hr urine 5 HIAA (better for typical or mid gut carcinoid)
• For mid gut 5 HT in urine can also be assessed
• Chromogranin A even in atypical carcinoid and has sensitivity of 80%
and can be false positive in
Renal and Hepatic failure
PPI and chronic gastritis
• ENDOSCOPY-
Hypoechoic mass in gastroduodenal or rectum and biopsy can be
taken
• CT enteroclysis- radiation strands of fibrosis and spiculations of
intestine are characteristic
• CT/MRI- lymph node and liver mets
• MR enteroclysis: give an idea about different layers of GIT
• Somatostatin receptor imaging:
Indium 111 labelled octreotide or PET with 68Ga labelled somatostatin
analogue
FDG-PET CT for high and low grade tumor.
CT/MRI + 68Ga SSA PET> 111 In pentetreotide scintigraphy
can be used to treat by delivering radiolabelled SSA
Gastric NET
Type 1 (M/C) Type 2 Type 3
demography 65-80 yrs 5-6 yrs 14-25 yrs
F>M F=M M>F

Associated condition Gastric atrophy MEN 1/ ZES Sporadic

Gastric pH High pH (leads to Low pH Normal pH
pernicious anemia)

Number of tumor multiple multiple single

Mets 0-2% <10% 50-100%
Treatment Benign can be monitored <1 cm- EndoR Surgery with Lymph node
with serial endoscopy 1-2 cm- EndoR or Surgery removal
<1 cm-EndoR, >2 cm- > 2cm- Surgery LN involvement- 75-100%
surgery

5 yr Survival 100% 60-90% 50%

Small Intestinal NET
• m/c small intestinal neoplasm
• SI NET (jejunal + ileal) and D NET(duodenal NET mostly D1 and D2)
(Ileum being most common site)
• Arise in muscularis therefore hard to detect at early stage
• Associated with Desmoplasia and mesenteric fibrosis resulting in
bowel obstruction and sometimes bowel ischemia
• Spoke and wheel appearance in CT- LN mets , calcified , associated
with fibrosis
Clinical Features
• Duodenal NET-
Usually asymptomatic
Incidentally detected in UGI endoscopy
10% present as ZES
Those in periampullary area as obstructive jaundice
• SI NET-
2-20 yrs
SI obstruction
Intestinal ischemia
Intussusception
GI hemorrhage
Hepatomegaly
Carcinoid syndrome
 SI NET D NET

Location 40-70% within 2 feet(61 cm) from ileo- >90% in D1 and D2

caecal valve 18-20% in periampullary region

Size 1/3 – 1 cm 75% - <2 cm

1/3 – 1-2 cm
1/3 - >2 cm
Number 25% multiple Solitary and if multiple suspect MEN 1/ZES

Type Usually carcinoid m/c is gastrinoma but somatostatinoma and

gangliocytic paraganglioma predominate in
periampullary region
Clinical feature Tumor related or Carcinoid Syndrome Usually diagnosed during UGI scopy and can
present as ZES in 10%

Carcinoid More common 4% cases (D3, D4)

5 year survival 70% 80-95%

Poor Prognostic marker
• Male
• Older age
• Metastasis and advanced stage
• Large primary tumor
• Depth of invasion
• Mitotic activity and differentiation
Appendiceal NET
• Most occur in tip of appendix usually incidentally detected
• Not associated with carcinoid syndrome
• Excellent prognosis
• Treatment-
<1 cm: simple appendicectomy
1-2 cm: simple appendicectomy (if at base or >3mm
mesoappendiceal invasion  right hemicolectomy)
>2 cm: Right hemicolectomy
Rectal NET
• Carcinoid is uncommon
• Screening colonoscopy- increased incidence of diagnosing R NET
• Treatment –
< 2cm if no LN or muscularis propria involvement : Endoscopic
resection
> 2 cm or of LN or muscularis propria involvement : surgery
Colonic NET
• m/c site is caecum and highly metastatic and ceacal NET has high
chance for carcinoid syndrome (mid gut carcinoid)
• Treatment-
Surgery
Treatment
• Symptomatic-
Somatostatin analogue- controls diarrhea and slow tumor growth
1. Octreotide – s/c 150 mcg 8 hrly
2. Octreotride LAR- s/c or i/m 30 mg once a month
Tryptophan Hydroxylase inhibitor- refractory diarrhea
1. Telotristat Ethyl- 250mg or 500 mg 8 hrly
• Tumor progressor inhibitor
1. Peptide receptor radioligand Therapy
 Used for tumors progressing on SSA therapy
 Radiolabelled SSA
 Renal and Heamatotoxic, duodenal ulceration and cholecystitis
2. Mtor inhibitors
 Everolimus- 160 mg/day
 A/E- rash, nausea, less commonly pneumonitis
3. Tyrosine kinase inhibitors
 Sunitinib
 Pazopanib
 Acts on a range of GF resceptors including VEGFR2
4. Alkylating agents (if no other option feasible)
 Temozolamide + Capecitabine
Liver metastases
• Surgery/ablation- well differentiated, limited to liver
• Ablation- less morbid and limited exposure
• Hepatic artery embolization- Large, multiple and involve both lobes
• Liver Transplant- majority of cases show tumor recurrence
5 year median survival= 50%
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