NEUROENDOCRINE TUMOURS PART - 1 Shankar Zanwar
NEUROENDOCRINE TUMOURSPART - 1Shankar Zanwar
CarcinOIDs – for less aggressive tumours than adenocarcinomas – Oberndorfer(1888)
Neuroendocrine tumours in gastrointestinal tracts – Pancreatic neuroendocrine tumours GI carcinoids
Pancreatic neuroendocrine tumours Functional – with clinical syndrome Non – functional – without it
Epidemiology Annual incidence – GI NETS -7-13/106
pNETs account for 1-10% of all pancreatic tumours
Peak age of incidence 6th and 7th decade
Overall prevalence 1/105, of functional pNETs
Non functional pNETs – 60-80% of all pNETsYao JC, Ann Sur Onc 2007
Origin of NETs NETs originate from diffuse neuroendocrine cells
- scattered throughout the GIT, respiratory tract, thyroid
Share chemical properties of Amine Precursor Uptake and Decarboxylation – APUDoma(earlier)
Proposed to have common embryologic origin in neural crest and endocrine cells
Grande, Cancer Rev 2012
Histology All NETs in common have
Solid, trabecular, gyriform or glandular pattern.
Homogenous sheets of small round nucleus
Uniform nuclei, salt and pepper chromatin
Finely granular cytoplasm
Mitotic figures are characteristically rare <2/HPF
Malignancy of the tumour is defined only by invasion or mets
Both GI and pancreatic NETs secrete can produce a number of hormones – can be identified by IHC
Like insulin, glucagon, VIP, serotonin, chromogranins, and HCG(α and ß sub units)
But they seldom secrete them producing any syndrome.
All tumours of all site can secrete all hormones in the NETs spectrum, thus localization based on hormone using IHC for primary is difficult.
IHC can be of help in identifying the O-methyl guanine methyl transferases(MGMT) – DNA repair enzyme – predicts response of temozolomide
Half of the P-NETs are deficient in MGMT while none of the GI-NETs response rate of temozolomide 34% in P-NETs while 2% in GI-NETs
Kulke Clin Cancer Res 2009
Classification Based on functionality – i.e. syndrome produced –
Insulinoma Gastrinoma VIPoma Glucagonoma Somatosatinoma Growth hormone relasing factor (GRFoma) ACTHoma Rare tumours secreting – renin, erythropoietin,
leutinizing hormone and cholecystokinin.
Newer WHO classification
Ki – 67 protein product of gene – Ki 67, on chr. 10 A/w cell replication and ribosomal RNA transcription Marker of cell replication Ki derived from the city of discovery – Kiel, Germany.
Grade Ki 67 index
Mitotic count( per HPF)
Differentiation
Low grade (ENET G1) <3% < 2 Well
Intermediate grade (ENET G2)
3-20% 2-20 Well
High grade (ENET G3) >20% >20 Poor
Molecular pathogenesis Major players – Retinoblastoma and p53 gene
inactivation
Most common altered gene in non familial pNETs – MEN – 1 – 44% Other pathways – DAXX – death domain
associated protein ATRX – α thalassemia/mental retardation/ X linked mTOR pathway – mediated through tyrosine
kinase – 15%
Syndromes a/w NETS MEN – 1 – Wermer’s synd, Chr. 11, autosomal dominant,
MEN II no NETs, characterised by Hypercalcemia Hyper parathyroidism Pheocromocytoma Without medullary carcinoma of thyroid
Gene – Menin – transcriptional regulation of cell division
Microscopic pNETS – 80-100%, clinical – 20-80%, GI carcinoids – gastric – 15-35%
Commonest pNET – PPoma – 80-100%
von Hipple - Lindau synd Chr. 3 , autosomal dominant VHL gene, target hypoxia inducible factor. Pancreatic involvement –
Primary cysts – 60% pNETs – 10-70%
pNETs – most often asymptomatic Mean age 29-38 Liver mets seen in 9-37% of pNETs pateints.
Neurofibromatosis – 1 Chr. 17, autosomal dominant 0-10% GI carcinoid Most common – periampullary duodenal somatosatinoma NF-1 – 48% of all duodenal SSoma, 25% of all ampullary
GI-NETs
Tuberous sclerosis Autosomal dominant - hamartin gene pNETs seen in 4% of TSC – 56 % non functional and 44%
functional Arva NC – Am J of Surg Patho -2012
Insulinoma Always located in pancreas, non pancreatic rare
Distributed evenly throughout pancreas
Usually <1cm – 39%, >5cm – 8%, multiple – 3-13%(MEN related)
Malignancy – 5-16%; Often the larger ones (avg- 6cm)
Well encapsulated, firmer than rest of the pancreas and highly vascular
Age – non specific, usually 20 to 75y, M:F - 2:3
Fasting hypoglycemia Neuroglycopenic syndrome
Diplopia, blurred vision commonest, others – seizures, syncope, paresthesia weakness, least common ataxia
Adrenergic syndrome Sweating, tremors Hunger, nausea Palpitations
Patient learn to avoid fasting eat frequently obesity
Diagnosis Whipple’s triad
Traditionally – 72 hour fasting planned, and fasting insulin levels and c-peptide measured, can stopped if any hypoglycemic event occurs earlier
Nearly 75-80% will develop symptoms before 24 hours.
Plasma insulin: glucose ratio of ≥0.3 is considered diagnostic
Most sensitive and spf. method – FBS and proinsulinVezzosi – Eur Jour Endocriniology - 2007
Tumour localization and metastatic disease
Treatment Diet – rapidly absorbed carbohydrates should
be avoided, slowly absorbed ones preferred – Starches, breads, potatoes and rice
Medical therapy Diazoxide
nondiuretic thiazide – inhibits insulin release, enhances glucogenolysis
Initiated at 3-8mg/kg/d max upto 15mg/kg/d S/e – Na retention, edema, GI upset & hirsutism Response rate – 60%
Octreotide – symptom control 40-60% Mechanism – high affinity somatostatin receptors in
tumor From 50 μg to 1500 μg per day Lanreotide newer long acting analog – 2-4 weekly dosing S/e – bloating, abdominal cramps, malabsorption and
cholelithiasis
Everolimus – For metastatic insulinoma non responding to other therapies.
Bernard, Eur J of Endocrino 2013
Surgical therapy When no liver mets on imaging ( >90%) – surgical exploration
enucleation/resection
Cure rate 70-97%
Tumour localization EUS, hepatic venous sampling after Cal stimulation and intraop US can be used.
Failure to localize during surgery empirical distal pancreatectomy only 50% success, not indicated any more.
Lymphnode dissection is not neededFendrich, Nat Rev Clincal Onco 2009
Gastrinoma Zollinger Ellison syndrome – ectopic gastrin
secretion excessive gastric acid secretion PUD, GERD and diarrhea.
Hypergastrinemia is also seen in tumours of Ovary Lung Pheochromocytoma Acoustic neuroma Colorectal carcinomas
Hypergastrinemia ↑ maximal acid secretion and basal acid output
↑ gastrin parietal cell and gastric fold hyperplasia and hyperplasia of enterochromaffin cells increased risk of type II gastric carcinoids ~ 23% of ZES
↑ acid secretion causes diarrhea Low pH – direct small intestinal damage Inactivation of lipases Low pH precipitates bile acids
Gastrinomas - non beta islet cell tumors
Locations of gastrinoma >50 % in duodenum and in duodenum
D1 – 56%, D2- 32%, D3-6% and D4 – 4% Pancreas – Head:body:tail – 1:1:2 Gastrinoma /Passaro’s triangle – 60-90%
gastrinoma location Non duodenal/pancreatic location – 2-24% -
ovary, liver, jejunum, omentum and pylorus
Spread – lymphnode and hepatic mets common seen in 60-90% of tumours Pancreatic lesion & lesions > 3cm ↑
hepatic mets risk
Two growth patterns Aggressive – 25% - 10y survival 30% Non aggressive 75% - 10 y survival 96%
Clinical features Duodenal and pancreatic gastrinoma presentation same
M>F 3:2, avg age – 41-53y,
Symptoms Pain 75% Diarrhea – 73% PUD – 71% Nausea, vomiting, heartburn Bleeds 25%, perforations 8-10%, esophageal stricture – 8-10%
Berna, medicine NIH databank 2006
MEN – associated in 25%, possibility if Younger age 34y vs 43 for sporadic Hyperparathyroidism - h/o nephrolithiasis/ renal colic – 47% Personal or family history of endocrinopathies
Clues to ZES Ulcers refractory to Rx or associated with complications Diarrhea with ulcers Non – H. pylori non NSAIDs ulcers Hypertrophied folds on endoscopy Family or personal history of endocrinopathy
Most pts. have typical DU at diagnosis, older studies multiple ulcers in atypical location.
Previous studies ~100% developed complication, now with PPI <30% present with complications
Diagnosis Diagnosis is usually delayed by 4-6 years, main
cause PPI, false +ve diagnosis may also be caused by PPi due to hypergastrinemia
Diagnosis of ZES needs demonstration of ↑ acid secretion in presence of ↑ gastrin
Thus fasting gastrin level and basal acid output needed for diagnosis
Fasting gastrin level ↑ in 97-99% of ZES, thus ZES unlikely with normal gastrin level. False –ve if Hyperparathyroidectomy done for MEN-1
PPIs can elevate fasting gastrin levels repeat gastrin level after 1 week of PPI stoppage
But rebound acidity and increased risk of complications
abrupt stoppage of PPI not recommended now, use either tapering dosage or or pursue diagnosis by other modalities - imaging
Hypergastrinemia with high pH(low acidity) Acholrhydria – chronic atrophic gastritis, level >70X ULN PPI gastrin levels >4X in 25% pts
Hypergastrinemia with low pH(high acidity) Gastric outlet obstruction Chronic kidney disease Short bowel syndrome Antral G cell hyperplasia
These pts. secreting testing and BAO measured Since gastrinoma related secretin stimulation high amount of gastrin
release (↑ secretin receptors in tumor) – gastrinemia >120pg/ml on 2U/kg IV secretin injection
BAO ↑ in ZES (~90%) > 15mE/hr in normal and >5mEq/hr post surgery pts.
Treatment Two issues – Hyperacidity and gastrinoma perse For gastric hypersecretion
Medical PPI – starting dose equivalent to 60mg omeprazole/d Sufficient dose is one that ↓ acid secretion <10mEq/hr before
next dose Upto 60mg BD may be required in severe GERD Since requirement of PPI may change over period – check acid
secretory control after 6 months – OGD/ BAO
Surgical Earlier - total gastrectomy, Vagotomy, Now main surgery in ZES is parathyroidectomy - ↓ gastrin
level, ↓ BAO and ↑ sensitivity to PPI
Treatment of gastrinoma perse Surgical exploration indicated if no
Diffuse mets to liver MEN-1
Sporadic gastrinoma – surg – 51% can be resected, 34% can have 10y survival. Gastrinoma resection and routine duodenectomy reduces risk of recurrence
Role of curative surgery in ZES related gastrinoma – controversial
In operated pts. disease free cure rate <5% in ZES, unfavourable because – multiple tumors in duodenum and lymphnodal spread
Long term survival of MEN1/ZES < 2cm ~100% for 15 years
Surgery indicated in MEN1/ZES if Lesion >2cm, consensus of studies only gastrinoma resection and no
pancreatoduodenctomy since adverse outcomes
Glucagonoma Syndrome caused by excess glucagon secretion
Weight loss Anemia Glucose intolerance Necrolytic migratory erythema(NME)
Most of the tumors are large 5-10cm(unlike insulinoma)
Usually malignant
Most common mets – liver and LN
Most are in pancreas(90%) and most are solitary
Hyperglycemia – d/t gluconeogenesis and glycolysis, glucosuria - renal tubular damage
Weight loss (56- 96%)– hypercatabolism, aversion to food d/t GLP-1
NME Hypoamminoacidemia Essential fatty acid deficiency ↑glucagon Zinc deficiency
Anemia - ?nutritional cause not known – normocytic normochromic
Thromboemboslism(12-35%) and psychiatric problems
Clinical features Age 50-70
NME (54-90%) – precedes diagnosis of glucagonoma years before Starts as erythematous rash raised bulla crustcentral
healingpigmentation(over 1-2weeks) Intertrigenous areas, buttocks, thighs and perineum
Glossitis(34-68%) and angular stomatitis
Dystrophic brittle nails
Diarrhea(14-15%)
Diagnosis Usually suspected d/t rash - NME
13-17% are part of MEN-1, and 20% may be a/w ZES
Fasting plasma glucagon level >200pg/ml usually 500-600 Mild elevation may be seen in
DKA Pancreatitis Cirrhosis Sepsis Acromegaly Hepercorticism Celiac, startvation
Treatment Medical
Nutritional rehabilitation –hyperalimentation or TPN
Treatment of diabetes
NME treatment nutritional replacement may treat NME Long acting somatostatin – octereotide may help in 30% DM no help 100-400 μg/d
Surgical Since usually malignant surgical treatment
considered in all resectable cases
50-90% have mets at diagnosis
Many develop recurrences
VIPoma Vasoactive intestinal polypeptide excess secretion, that
causes syndrome of Watery diarrhea Hypokalemia Acholrhydria
Also known as pancreatic diarrhea
Most are pancreatic, 42-75% occurring in the tail region
Extrapancreatic –liver, retroperitoneum and esophagus
Unlike other mets in HPE if VIP is detected it is very likely of VIPoma
Flushing(14-33%) – vasodilatory effects of VIP
Hypokalemia – fecal K loss
Hypercalcemia and achlorhydria mechanisms not know
Clinical features Mean age 42-51y,
Diarrhea – 89-100% May be episodic Like tea water ~1 liter /d, usually >3 liter Persist during fasting Most patients > times a day No steatorrhea
Weight loss, abdominal cramps
Volume depletion 44-100%
Tetany due to hypomagnessemia
Diagnosis Secretory diarrhea persisting on fasting gives clue
Exclude – celiac disease, laxative abuse, HIV
VIP levels – Normal 0-180pg/ml, Sn – 88%, Sp -100%
Other conditions that ↑ VIP IBD fasting CKD Radiation enteritis Small bowel resection Nesidioblastosis
In diagnostic dilemma – intestinal perfusion studies – where net secretion of electrolytes instead of absorption is seen
Treatment Medical
Fluid and electrolyte replacement May require >5L/d of fluid K+ replacement - ~350mEq/d
Diarrhea – Octreotide helps in 78-100% 22% require increase in dosage at 6 months
Surgical Imaging to assess the localization and resectability Surgical resection helps in 1/3rd and 30% are cures.
Somatostatinoma Usually originate in SI and pancreas
Syndrome of somatostatinoma Diabetes Gallbladder disease Diarrhea Weight loss Hypochlorhydria
Rarest of all pNETs
Just presence of somatostatin in tumor- does’nt suffice somatostatinoma
Majority occur in pancreas 47-75%
Extrapancreatic are usually in duodenum(90%) and in the ampullary region(90%)
Often solitary, size 1.5-10cm
Mets seen in 43-90% at the time of surgery, >2cm size 78% sensitive for prediction of mets
Mets more common pancreatic than duodenal
Specific histologic feature of duodenal somatostainoma – psammoma bodies – round calcium collection
DM is due to inhibitory action of somatostatin(SS) on insulin
GB disease – d/t inhibition of GB emptying by SS Cholelithiasis and sludge
Hypochlorhydria – gastric acid secretion inhibition
Weight loss – secondary to steatorrhea
Clinical features Age 40-65 Abdominal pain Weight loss Diarrhea – 3-10/d, steatorrhea(20-76g/d), foul smelling Nausea and vomiting Jaundice due to periampullary tumour/ stones
A/w NF-1 – 7% MEN -1 - < 1% VHL
Diagnosis Incidental
HPE may suggest presence of SS
Psammoma bodies may aid in diagnosis
Modestly elevated level of SS may not clinch the diagnosis, since ↑ only in pNETs and not so with intestinal SSoma
Treatment Medical –
Correction of malnutrition – hyperalimentation or TPN Treatment of diabetes A very small number of patients may respond to somatostatin
analogs
Surgical Surgically resectable 50-90% Late diagnosis resection is not curative Duodenal SSoma
<1cm endoscopic treatment 1-2cm transduodenal resection >2cm – whipples
5 year survival – 100% without mets and with mets 33-60%
Nonfunctioning pNETs
Indian scenario
Amrapurkar, tropical gastroenterology, 2010
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