Pancreatic Neuro-endocrine Tumours

– NETs arise from cells which produce and secrete hormones– Most NETs are slow growing and malignant, with metastatic potential– Common sites of origin are:

• GI tract• Lungs• Pancreas

2

Introduction to NETs

3

WHO Classification for NET

Ong SL, et al. Pancreatology. 2009;9:583-600.

NeuroendocrineTumours

Site of Origin• GI tract• Pancreas• Lungs• Thyroid• Pituitary• Others

Malignant Potential• Benign• Benign or low

malignant potential (uncertain)

• Low malignant potential

• Highly malignant

Functional Activity• Functioning• Non-Functioning

The Pancreas Is the Most Common Primary Location of NET Breakdown in Middle East & Asia Pacific Region

Stomach 6%Liver 4%

Bile duct and gallbladder 3%Omentum/abdominal lining 1%Rectum 1%Ovary 1%Lung 1%

Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.

Pancreatic neuroendocrine tumors (pNET)

• Pancreatic endocrine tumors, islet cell carcinoma, or pancreatic carcinoid

• Low - to intermediate-grade neoplasms and have a more indolent course compared to pancreatic adenocarcinoma

• Functional if they are associated with a hormonal syndrome– Disease bulk– Stage – Secretory status– Whether the peptide secreted is intact and causes distinct clinical

symptoms– Functional status of these tumors may change over time or with

treatment

• Majority of pNETs are malignant, with the exception of insulinomas, which are benign in 95% of patients

EPIDEMIOLOGY• Relatively rare neoplasms• 2%-10% of all pancreatic tumors• Incidence and prevalence are somewhat elusive• Age-adjusted incidence of pNETs has risen significantly over the

last three decades– Better diagnosis and – Classification– Environmental factors including the use of certain medications

• Incidence of pNETs in the United States was estimated to be 5.6 per million in 2010

• Prevalen ce of small asymptomatic islet cell tumors may be 100-fold more common

• Slightly more common among men (53%) than women (47%)

• Median age at diagnosis was 60 years• At diagnosis,

– 14% had localized disease, – 22% had regional disease, and – 64% had distant disease.

• The survival of patients with pNETs has improved over time• 1988 through 2004, the 5-year survival rates among patients

with localized, regional, an distant pNETs were 79%, 62%, and 27%, respectively

Pathology

• Tumors arise from islets or ducts ???– Transgenic mice expressing potent oncogenes in

endocrine cells and multiple endocrine neoplasia (MEN)1 knockout mice point to an islet origin of tumors

– Molecular evidence from islet microdissection in patients with MEN1 indicate a duct cell origin

– Endocrine tumor cells largely display the same phenotype as their normal endocrine counterpart

• Multiple Endocrine Neoplasia Type 1– Tumor size may not be a completely reliable predictor of

malignant behavior, as metastatic disease may be present in patients with MEN1 even when the primary tumors are small

– Thompson was the first to advocate a specific surgical procedure in patients with MEN1 with nonfunctioning pNETs >1 cm in diameter to include distal subtotal pancreatectomy, enucleation of any identified lesions in the pancreatic head or uncinate process, and regional lymphadenectomy

• Tuberous Sclerosis– The genes responsible for tuberous sclerosis, TSC-1 and

TSC-2, are located on chromosomes 9q34 and 16p13.3, respectively, and code for the proteins hamartin and tuberin

– TSC1/2 complex is an inhibitor of mTOR• Neurofibromatosis

– Von Recklinghausen disease, is an autosomal dominant disease

– Protein neurofibromin 1 and is located on chromosome 17– NF1 is associated with the development of NETs in the

region of the duodenum and ampulla of Vater– Endocrine tumors that arise from Von Recklinghausen

disease (NF1) are somatostatinomas

• Von Hippel-Lindau Syndrome– Autosomal dominant– Retinal, cerebellar, and spinal hemangioblastoma,

as well as renal cell carcinoma, pheochromocytoma, and pNETs

– vHL gene is located on chromosome 3p26-p25– pNETs occur in approximately 15% of patients with

VHL

2010 World Health Organization (WHO) classification

• Well-differentiated tumors– Trabecular, glandular, acinar, or mixed structures; the stroma is generally

fine and rich in welldeveloped blood vessels, sometimes with hyalinised deposits of amyloid; tumor cells are monomorphic with abundant, variably eosinophilic cytoplasm, low cytological atypia and low mitotic index.

– Necrosis is usually absent or may be seen as spotty, limited areas in histologically more aggressive neoplasms

– Neuroendocrine tumor• Poorly differentiated neuroendocrine carcinomas

– Prevalent solid structure with abundant necrosis, often central, round tumor cell of small to medium size with severe cellular atypia and high mitotic index

– Neuroendocrine carcinoma

• Diagnosis of pNET is necessary (1) to meet the previously defined histologic and

cytologic criteria,(2) to assess the status of endocrine differentiation,

and (3) to evaluate prognostic markers (proliferative

index).

• Fine Needle Aspiration Versus Core Needle Biopsy– FNAC

• Simplicity, low invasiveness, and cost• Disadvantages -operator-dependent efficacy and limited

option for further study (small sample size) to include prognostic variables.

– Core needle biopsy (ideally 2 mm in diameter) • Larger sized tumor sample - cyto-/histologic diagnosis

complete with all known prognostic parameters. • Potential for further studies to include all IHC studies and

assessment of proliferative index. • Disadvantages are the invasiveness of the procedure(s) and

the relatively higher costs– core needle when considering biopsy of liver

metastases and FNA for biopsy of the pancreas.

• Immunohistochemistry Markers– (1) positively identify the degree of endocrine

differentiation in tumor cells, and (2) determining the proliferation activity status.

– General markers• Neuron-specific enolase (NSE)• Chromogranin A [CgA]• Synaptophysin

– Hormones and/or amines are produced by specific cell types - specific markers

– Proliferation status is achieved by Ki67 IHC using the MIB1 antibody or it can be expressed as mitoses per 10 high power microscopic fields (or 2 mm2)

• Low (G1) and intermediate (G2) grade neoplasms are termed pNETs

• Aggressive high-grade (G3) neoplasm are termed pancreatic neuroendocrine carcinoma

• Optimal Ki-67 cut-off between G1 and G2 remains debated in the literature.

• Some authors have proposed 5% (instead of 2%) as a more discriminatory cut-point for important outcomes including overall survival (OS)

• distinction between G1 and G2, while prognostic, does not have major therapeutic implications

• Platinum-based chemotherapy is generally recommended for G3 tumors

• Response rate to platinum-based chemotherapy was low for the subgroup of G3 patients with Ki-67 between 20% and 55%.

• Tumors with a Ki-67 >55% appear more responsive to platinum-based chemotherapy

Molecular Genetics of Pancreatic Neuroendocrine Tumors

• Exome sequencing studies identified three main groups (pathways) of mutations in sporadic - MEN1, DAXX or ATRX, and mammalian target of rapamycin (mTOR)

• Nonfunctional Tumors• 60%-80% of pancreatic NETs as non-functional• Symptoms

– Usually asymptomatic – The tumor bulk results in pain

• Invasion of the autonomic mesenteric plexus• Liver metastases that invade the liver capsule • Extend to the parietal peritoneum

– Jaundice due process-obstruction of the intrapancreatic portion of the common bile ductto - right of the superior mesenteric vessels -head or uncinate

– Gastric outlet obstruction– Gastrointestinal hemorrhage secondary to tumor erosion into

the duodenum or secondary to splenic vein occlusion causing gastroesophageal varices (sinistral portal hypertension)

• pNETs arising to the left of the SMA and superior mesenteric vein may cause vague, poorly localized upper abdominal pain or dyspepsia, but such tumors are usually asymptomatic until they reach a considerable size

• Computed tomography (CT)– Characteristically appear hyperdense, as they are

hypervascular– During the arterial phase is critically important to detect

these lesions and their hypervascular liver metastases– Occasionally appear hypodense compared with adjacent

pancreatic parenchyma, and they may contain cystic components or microcalcifications

– Intrapancreatic accessory splenic tissue can present as an asymptomatic, hypervascular mass involving the distal pancreatic tail, thus mimicking a pNET

• Magnetic resonance imaging (MRI)– Patients with a history of allergy to iodine contrast material– Renal insufficiency– More sensitive than CT for the detection of small liver

metastases• Endoscopic ultrasound (EUS)

– Most sensitive modality for identifying small pNETs– Used for preoperative tumor localization in patients with

MEN1, in which multifocal disease is common– FNA biopsy of the tumor

• Serum Tumor Markers– Evaluated for the diagnosis and follow-up

management of pNETs– General markers– CgA - 49-kDa acidic polypeptide

• Present in the secretory granules of neuroendocrine cells• Elevated in the majority of patients with either

functioning or nonfunctioning pNETs• Prognostic – decreased during therapy has increased

progress free survival

• NSE, is a dimmer of the glycolytic enzyme enolase– Less specific as a diagnostic marker, it may be helpful in the

follow-up of patients with unresectable disease• PP- at least three times the age-matched normal basal

level obtained in a fasting state• Chromogranins such as chromogranin B and C,

pancreastatin, substance P, neurotensin, neurokinin A, gastrin, glucagon, vasoactive intestinal peptide, insulin, proinsulin, and cpeptide.

• In general, blood markers should be drawn in the fasting state

Somatostatin receptor scinitigraphy

• Octreotide conjugated with diethylene-triamine-pentaacetic acid (DTPA) and labeled with 111In is a radiolabeled somatostatin analog with great affinity for sstr2 and widely used in clinical practic

• 68Ga PET/CT is becoming the new gold standard for somatostatin receptor imaging of PNET. The sensitivity of this technique varies between 91 and 95% with a specificity of 82-97%

• Functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC

• Nuclear scans

Surgical Treatment

• Goals of surgery are to maximize local disease control and to increase the quality and length of patient survival

• Resect localized, nonmetastatic disease confined to the pancreas if a gross complete resection can be performed

• If radiographically occult liver metastases are found at the time of the operation, they are removed if possible

• If the liver metastases are of small volume but diffuse, the primary tumor is usually removed due to the potential for major morbidity from the primary, which is a possibility because of the relatively long-anticipated survival of the patient

• Nonfunctioning pNETs < (approximately) 2 cm in diameter are of limited metastatic potential

• Observation may be the best approach– Patients of advanced age– Clinically significant comorbiditie– Incidental finding on CT/MRI obtained for an unrelated

reason– Repeat imaging in 6 to 12 months– Observation is chosen - functional study such as

somatostatin receptor scintingraphy

• Metastatic disease or a large, borderline resectable primary tumor, we would first initiate systemic therapy as a bridge to eventual operation.

• Significant downstaging of the overall tumor burden can improve the safety of surgery in some patients

• Rationale for aggressive management of the primary tumor despite the presence of extrapancreatic disease may become more compelling.

• However, treatment sequencing will likely emphasize a surgery-last strategy (after induction systemic therapy) to identify those patients most likely to benefit from large, multiorgan resections

• Resectable primary tumor and resectable liver metastases. – Remove the pancreatic tumor first– Resecting the liver under the same anesthesia induction or two-

stage procedure if all needed surgery cannot safely be performed at one operation

• Because of the longer survival times of patients with pNETs (even advanced disease), we favor operative bypass of the bile duct and duodenum in most cases.

Advanced Pancreatic Neuroendocrine Tumors

• Goals of oncologic management include palliation or prevention of symptoms and cytoreduction of bulky tumors in an effort to prolong survival

• Cytotoxic chemotherapy, • Everolimus,• Sunitinib, • Somatostatin analogues,• Peptide-receptor radiotherapy, as well as • Ablative approaches such as hepatic artery embolization

and radiofrequency ablation (RFA)

• Somatostatin Analogues– Octreotide and lanreotide both bind with high

affinity to SSTR 2 and with slightly lower affinity to SSTR 5.

– Pasireotide is a novel cyclohexapeptide in development that binds to SSRT 1, 2, 3, and 5

– Approved for the control of symptoms related to hormonal hypersecretion in NETs

– Associated with significant benefit in PFS

– Somatostatin (SST) receptors are highly expressed on the surface of GI NETs

• More than 80% of all NETs express SST receptors

– Overexpression provides basis for regulation by SST

– SST receptor activation inhibits secretory and proliferative activity

35

PathophysiologySignificance of Somatostatin Signaling

Octreotide May Have a Direct Antitumour Effect via sst2 and sst5

sst5

↑ Apoptosis ↓ Cell growth

PI3K

PDK1

Akt

GSK3β

p53

↑Zac1

mTOR

p70S6K

sst2

JNK

G protein

SHP1

NF-KB

sst2

G protein

G protein

SHP1

SHP2Src

PTPŋ

MAPK

p27

cGMP↓

PKG↓

• sst2 and sst5 both downregulate MAPK

• sst2 binding effects the P13K/Akt/mTOR pathway and SHP1 signalling

• Antiproliferative effect also mediated via protein tyrosine phosphatase (PTPase) modulation

Florio T et al. Front Biosci 2008;13:822–840Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181Theodoropoulou M et al. Cancer Res 2006;66:1576–1582

• Phase III randomized, double-blind, placebo-controlled study

• Primary endpoint: Time to tumour progression (blinded central review)• Secondary endpoints: objective response rate, survival, quality of life, safety

PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg

Patients with midgut NETs • Treatment naïve• Histologically confirmed • Locally inoperable

or metastatic• Well differentiated• Measurable (CT/MRI)• Functioning or non-

functioning

Octreotide LAR 30 mg im

every 28 days

Placebo im every 28 daysRA

NDO

MIZ

ATIO

N (1

:1)

Treatment until CT/MRI

documented tumour

progression or death

Month 3 6 9 12 15 18

Rinke A et al. J Clin Oncol 2009;27:4656–4663

Patient DemographicsOctreotide LAR

30 mg (n=42)Placebo(n=43)

Total(n=85)

Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82)

Sex male (%) female (%)

47.652.4

53.546.5

50.649.4

Time since diagnosis, months (range) 7.5 (0.8–271.2) 3.3 (0.8–109.4) 4.3 (0.8–271.2)

Karnofsky score ≤80 (%) >80 (%)

16.783.3

11.688.4

14.185.9

Carcinoid syndrome* (%) 40.5 37.2 38.8

Resection of primary (%) 69.1 62.8 65.9

Hepatic tumour load0%0–10%10–25%25–50%50%

16.759.57.111.94.8

11.662.84.79.311.6

14.161.25.9

10.68.2

Octreoscan positive (%) 76.2 72.1 74.1

Ki-67 up to 2% (%) 97.6 93.0 95.3

CgA elevated (%) 61.9 69.8 65.9

* not requiring octreotide for symptom control

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.

PROMID

Octreotide LAR 30 mg Extends TTP in Patients with Functioning and Non-functioning Tumours

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 900

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Based on the per protocol analysis

P=0.0008; HR=0.25 [95% CI: 0.10–0.59]

Prop

ortio

n w

ithou

t pro

gres

sion

P=0.0007; HR=0.23 [95% CI: 0.09–0.57]

Prop

ortio

n w

ithou

t pro

gres

sion

Patients with non-functioning tumours Patients with functioning tumours

Time (months)Time (months)

Octreotide LAR 30 mg: 17 pts / 11 events Median TTP 14.26 months

Placebo: 16 patients / 14 events Median TTP 5.45 months

Octreotide LAR 30 mg: 25 pts / 9 events Median TTP 28.8 months

Placebo: 27 patients / 24 events Median TTP 5.91 months

Arnold R. Abst #4508 presented at ASCO 2009, Orlando FLRinke A et al. J Clin Oncol 2009;27:4656–4663

• Everolimus– Loss of TSC2 and NF1 are both associated with

mTOR activation– mTOR pathway mutations were also found in

sporadic pNETs– RADIANT-1

• 160 patients were treated in two strata, with everolimus (n = 115) or everolimus plus octreotide (n = 45) based on whether patients were on octreotide at study entry

• Advanced pNETs with progression following chemotherapy

• Median PFS for patients receiving everolimus or everolimus plus octreotide were 9.7 months and 16.7 months, respectively

– RADIANT- 3• 410 patients with progressive pNETs were randomly

assigned to receive everolimus or placebo• Everolimus prolonged median PFS from 4.6 months to

11 months leading to a 65% risk reduction for progression compared to placebo (HR = 0.35; 95% CI, 0.27 to 0.45; p <0.0001).

• Treatment also reduced the level of tumor-secreted hormones

• Sunitinib – Activity against VEGF receptors, c-Kit, and platelet-

derived growth factor receptor– 3 study compared sunitinib to placebo in pNETs– Results of an early unplanned analysis showed

improved PFS (5.5 months versus 11.4 months).– Due to the small number of events and unplanned

nature of the analyses, the results failed to cross the O’Brian Fleming efficacy threshold for statistical significance

Cytotoxic Chemotherapy

• Role of cytotoxic chemotherapy continues to be debated

• Streptozocin-Based Chemotherapy– Streptozocin was originally isolated from

streptomyces achromogenes in the 1950s– Antitumor activity in pNETs was first reported in

1973; in a study that included 52 patients, a response rate of 50% was reported

– Eastern Cooperative Oncology Group subsequently compared this combination to streptozocin plus doxorubicin72 and reported a significantly higher response rate (69% versus 45%), time to progression (median, 20 months versus 7 months), and OS (median, 2.2 years versus 1.4 years) for streptozocin plus doxorubicin than for streptozocin plus 5-FU.

– Based on these data, combination chemotherapy with streptozocin-based regimens is considered the standard treatment option by many

– Two small retrospective series have recently cast doubt on the value of streptozocin-based chemotherapy.

– Each of these studies examined only 16 patients. – Both reported a disappointing radiologic response

rate of only 6%

• Dacarbazine- and Temozolomide-Based Chemotherapy– Dacarbazine was initially studied in a phase 2 study that

included 42 patients with pNETs. A response rate of 33% was observed

– Temozolomide-based therapy is generally well tolerated, absolute lymphopenia may occur and has been associated with opportunistic infections.

– These studies suggest that temozolomide may have activity in pNETs.

– A randomized study comparing temozolomide versus temozolomide plus capecitabine is ongoing

• Peptide Receptor Radiotherapy– 111In-, 90Y-, or 177Lu-labeled somatostatin analogues

have reported promising results in the control of hormone-associated symptoms

– Largest reported series, a response rate of 30% was found among a subset of 310 patients.

– However, if intent-to-treat analysis were performed, the objective response would be approximately 18%

– Toxicities with peptide receptor radiotherapy included nausea, vomiting, abdominal pain, cytopenia, and hair loss.

– More serious side effects, including renal failure, leukemia, and myelodysplastic syndrome, have also been reported

– Large-scale random assignment trials are needed to define its role in the management of pNETs.s

Liver-Directed Regional Therapy

• Liver is the most common and sometimes the only site of metastasis

• Treatment approaches are generally palliative• In the absence of a hormonal syndrome, typical

indications for liver-directed therapy– Right upper quadrant pain, – Early satiety due to gastric compression by an

enlarged left hepatic lobe, and the need to – Control slowly progressive but bulky disease

• Hepatic Artery Embolization and Chemoembolization• Liver has dual blood supply, the normal liver derives

most of its blood supply from the portal circulation• pNET metastases, however, receive most of their

blood supply from the hepatic artery• Interruption of the blood supply from the hepatic

artery preferentially causes ischemic necrosis of the metastases while sparing most of the normal liver

• The choice of embolic material varies by center and may include lipiodol or ethiodized oil, small plastic particles, or gelatin foam particles

• Chemoembolization, cytotoxic agents are administered intra-arterially before the vessels are embolized, as this approach has the potential to enable delivery of a higher chemotherapy dose to liver metastases

• Retrospective study from MD Anderson, where the outcome of patients with pNET were separately examined, the objective tumor response rate was 35%

• Bland embolization group was compared with the chemoembolization group, a trend was observed for improved response rate with the addition of chemotherapy (50% versus 25%; p = 0.06)

• Investigators compared doxorubicin with streptozocin during embolization and reported a higher response rate with streptozocin-based chemoembolization after multivariate analyses

• Constellation of transient symptoms and laboratory abnormalities, sometimes referred to as “postembolization syndrome,” occurs in most patients

• Abdominal pain, nausea, fever, fatigue, and elevated liver enzymes

• Crises related to massive release of hormone(s) may occur in the presence of functional tumors; prophylactic administration of somatostatin analogues should always be considered

• To minimize the risk of hepatic insufficiency, embolization should be carried out in one liver lobe at a time

• In patients with bulky disease or poor liver function, more limited embolization of liver segments should be considered

• Radioactive microsphere embolization is emerging as a well-tolerated outpatient procedure providing symptom relief and varying response rates

• Prospective studies are lacking in patients with NETs and specifically those with pNETs

Hepatic Metastasectomy and Transplantation

• Aggressive surgical resection has a role in the management of metastatic islet cell carcinoma

• Series of 170 patients with NET at Mayo Clinic– Total of 52 pNETs were included in this study– OS rate for all 170 patients was reported to be

61% and 35% at 5 and 10 years, respectively– Liver resection is not curative in most patients; the

disease recurrence rate was 85% at 5 years

• Patients with more extensive but still resectable disease, we advocate resection for those tumors with favorable biologic characteristics

• Liver resection should be avoided in patients with a high-grade histologic subtype

• Hepatic transplantation for the management of pNETs should be considered investigational

• Radiofrequency Ablation• RFA can be carried out during laparoscopy,

laparotomy, or via a percutaneous approach

• Choosing therapy at each stage should take into account the aggressiveness of the tumor, the burden (volume) of disease, and any symptoms due to tumor burden or hormonal secretion

Functional Tumors• Gastrinoma, or Zollinger-Ellison syndrome (ZES)

– Rare disease caused by a NET (gastrinoma) in the pancreas or duodenum

– Hypersecretion of gastrin results in uncontrolled stimulation of parietal cells and production of gastric acid causing refractory peptic ulcer disease

– If the serum gastrin level is still elevated 1 week after the patient has stopped acid-suppressive therapy, it is then important to measure gastric pH

– Patients with ZES should have a gastric pH of <2– Serum gastrin ≥1,000 pg/ml or 10-fold above the normal range,

and a gastric pH ≤2 secures the diagnosis of ZES

ZES contd.

ZES contd.

• Clinical Features

– Abdominal Pain 70%

– Diarrhea 70%

– Heartburn 50%

– Nausea 25%

– Vomiting 20%

– Weight Loss 15%

– Patients with gastrin levels between 100 pg/ml and 1,000 pg/ml and a gastric pH ≤2, a secretin or calcium stimulation test should be considered

• Positive secretin test is associated with a postinjection serum gastrin level increase of >200 pg/ml

• Positive calcium stimulation test with a postinjection serum gastrin level increase of >395 pg/ml

– Duodenal location being the most common– In pancreas -pancreatic head or uncinate process– Serum gastrin levels correlate with the extent of

disease

– Tumor localization studies should be performed as part of the preoperative evaluation

– Upper endoscopy with EUS of the pancreatic head and duodenum, multidetector CT, and somatostatin receptor scintingraphy

– When all localization studies are negative, the gastrinoma is most likely in the duodenum, which must be opened surgically (duodenotomy) to successfully locate and remove the tumor

– For pancreatic gastrinomas, the operation is based on the anatomy of the tumor and may consist of enucleation or pancreaticoduodenectomy

– Regional lymphadenectomy is critically important.

• Management of Advanced Gastrinoma– The introduction of PPIs brought significant advances in the

management of ZES, allowing for once or twice daily dosing– Dose of PPIs required to manage ZES is significantly higher

than typically used in idiopathic peptic ulcer disease– Advanced gastrinoma is the development of type II gastric

carcinoids in the setting of MEN1-associated ZES– Gastric carcinoids are often small, multifocal, and of low

malignant potential– When few in number, they can often be excised

endoscopically

Insulinoma• Most common functioning pNETs - 60% of functional tumours• Seldom malignant• 10% of insulinomas are multiple, 10% malignant, and 10% are

associated with the Multiple Endocrine Neoplasm (MEN) type 1 syndrome

• Insulinoma may occur either as a unifocal sporadic event or as part of MEN1

• Uncontrolled secretion of insulin results in hyperglycemia, manifested by neuroglycopenic symptoms such as blurred vision, confusion, and abnormal behavior, which may progress to loss of consciousness and seizure

• occur anywhere throughout the pancreas

• Body releases catecholamines, which elicit perspiration, anxiety, palpitations, and hunger

• Weight gain• Supervised fasting of the patient, including laboratory evaluation and

clinical observation• Serum levels of plasma glucose, C-peptide, proinsulin, insulin, and

sulfonylurea are measured at intervals of 6 to 8 hours and • When symptoms develop

– Insulin level >3 μIU/ml (usually >6 μIU/ml) when their blood glucose is <40 to 45 mg/dL.

– The insulin-to-glucose ratio is ≥0.3 reflecting the inappropriate secretion of insulin at the time of hypoglycemia

– Increase C peptide levels

• Localization studies performed as part of the preoperative evaluation include– Contrast-enhanced, multidetector CT– Upper endoscopy with EUS of the pancreas

• Tumor localization is not successful– Regionalization of an insulinoma is performed with selective

arterial calcium stimulation and hepatic vein sampling• Elevation of hepatic vein insulin following calcium infusion

of the gastroduodenal artery and/or SMA - head or uncinate process

• The splenic artery - body or tail of the pancreas

• Standard treatment is enucleation• Segmental resection of the pancreas, distal

pancreatectomy, or pancreatico duodenectomy may be necessary

• Large defects in the pancreas resulting from enucleation are usually treated with a Roux-en-Y pancreaticojejunostomy to prevent a pancreatic leak at the enucleation site

• Management of Advanced Insulinoma– Glycemic control is a key aspect of managing malignant

insulinomas– Mild symptoms sometimes can be controlled by diet– Medical therapy may include diazoxide, an antihypertensive agent

known to increase blood sugar– Glucagon may also have a role in the management of insulinomas– Short-acting somatostatin analogues be initiated under direct

medical supervision– The efficacy of everolimus for the treatment of insulinoma has

been confirmed in several case series– Streptozocin-based chemotherapy

VIPoma• Cause of the classic Verner-Morrison syndrome• Vasoactive intestinal peptide, which can cause watery

diarrhea, hypokalemia, and achlorhydria• Patients can have more than 20 bowel movements a day,

with a daily stool volume exceeding 3 L• In adults arise from the pancreas. • In children extrapancreatic location• Control of diarrhea is an important part of management• Somatostatin analogues108; octreotide can promptly

control diarrhea in 80% to 90% of patients• Interferon is rarely used in the frontline setting, but it may

have a role in cases refractory to somatostatin analogues• Cytoreduction should be initiated whenever possible.

• 0.05-0.2 new cases per million adults

• Third most common neuroendocrine tumor of the

pancreas

• Solitary, found in body or tail.

• 2/3 malignant

• Male-to-female ratio in children - 1:1,

in adults. - 1:3

• Constant features – Watery Diarrhea – Hypovolemia – Hypokalemia– Acidosis

• Variable features– Achlorhydria or hypochlorhydria– Hypercalcemia– Hyperglycemia– Flushing with rash.

• Diagnostic triad – Secretory diarrhea– High levels of circulating VIP > 150pg/ml– A pancreatic tumor

• Localization– SRS - 91% of primary tumors and 75% of metastases.

Nikou GC, et al. Hepatogastroenterology  2005

– Endoscopic ultrasound.– CT – MRI – Arteriography– IOUS

• Management Correction of metabolic abnormalityOctreotideDistal pancreatectomy/Debulking

VIPoma contd.

• Glucagonoma– Diabetes and a characteristic rash known as

necrolytic migratory erythema– Weight loss, diarrhea, glossitis, and angular

stomatitis have also been reported– Somatostatin analogues may have a role in the

management of the hormonal syndrome in patients with unresectable tumors

– Oral hypoglycemic agents and insulin can be used to control the diabetes

Somatostatinoma

• Arise from the pancreas or the duodenum• Insidious and nonspecific nature of the

symptoms - diagnosed at an advanced stage• Diabetes, diarrhea, and jaundice due to biliary

obstruction• Associated with von Recklinghausen disease

(neurofibromatosis)• Management for somatostatinomas parallel

those of nonfunctional pNETs

Adrenocorticotropic-Secreting Tumors

• Cushing syndrome due to ectopic production of adrenocorticotropic hormone.

• Metyrapone, ketoconazole, and mitotane tend to be more effective

High-Grade Neuroendocrine Carcinoma

• Early systemic dissemination and rapid growth• Clinical behavior with small-cell carcinomas of

the lung• Induction chemotherapy even for localized

potentially resectable cases due to the aggressive nature of this disease and the high rate of relapse

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