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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