Pancreatic endocrine tumors

Ayman Mismar

INTRODUCTION

• One million islets of Langerhans

• Several types of cells “Immunohistochemistery”– ß (beta) -> 70% insulin– А (alpha)-> 20% glucagons– D (delta)-> 5-10% somatostatin– P.P Cell -> 1-2% pancreatic polypeptide– Other rare cells:- D1 cells - VIP ( vasoactive intestinal polypeptide ) - Enterochromaffin cells - 5 HT-(serotonin)

Terminology and NETS Classification

NETS Grade Ki 67 Index

Mitoticcount

Differ-entiation

Low (G1) <3% <2/ HPF Well-differentiated NET

Inter-mediate (G2) 3-20% 2-20/ HPF Well-differentiated NET

High (G3) >20% >20/ HPF Poorly differentiated neuro-endocrine carcinoma

INSULINOMA

• Epidemiology

•Pathophysiology & Symptoms

•Dignosis & Locallization

•Management

Epidemiology

• First described by Harris in JAMA 1924

• Commonest hormone producing NET of GIT

• 99% of pancreatic origin

• 90% solitary, 90% < 2cm, 90% benign

• 8% ass. with MEN I (multiple, malignant in 25%)

• Median age at presentation is 47yrs

• F to M ratio 1.4:1

Pathophysiology

Hypoglycemia

↑glucagon(glycemic threshold 65-70mg/dl)

↑catecholamines

↑cortisol & GH

Neuroglucopenic symptoms(<50mg/dl)

Symptoms

– Adrenergic symptoms• Anxiety, nervousness

• Tremors

• Tachycardia, palpitations

• Hypertension

- Wt gain in 20-30%

Symptoms

• Neuroglucopenic symptoms

– Headache

– Visual disurbances

– Lethargy,lassitude,confusion

– Difficulty in speech, thinking

– Personality changes

– Convulsions, coma

Diagnosis

• Whipples triad

– Hypoglycemic symptoms brought about by fasting or exercise

– ↓BS during symptoms

– Relief on administration of glucose

• ↑ C peptide level

• ↑ plasma insulin

• Absence of sulfonylurea

Diagnostic testing

• 72 hrs fast(gold standard)– Plasma glucose ≤2.5 mmol/l

– Plasma insulin ≥6 μunits/ml (43 pmol/l)

– Plasma C-peptide ≥0.2 nmol/l

– Plasma proinsulin ≥0.5 nmol/l

– Plasma sulphonylurea Negative

– Plasma β-hydroxybutyrate <2.7 mmol/l

– Change in glucose with 1 mg glucagon ≥25 mg/dl at 30 min

– symptoms develop in 35 %of patients within 12 h, 75 % within 24 h, 92 % within 48 h and 99 % within 72 h

• C peptide suppression test

• Stimulation tests with glucagon, Ca, tolbutamide

Locallization

• CT, MRI

• Transabd USG, EUS

• Intraop US

• Somatostatin receptor scintigraphy

• Angiography

• Selective intra-arterial Ca. stimulation with splenic venous sampling

Management

• Surgical

– Resection is the treatment of choice

– Specialized units

– Enecluation in most cases

– Distal pacreatectomy/ whipples’s procedure in a few

– Blind resection shouldn’t be performed

INSULINOMA – RESULTS OF TREATMENT

(Charles University in Prague1980-2012)

125 insulinomas / microadenomatosis

115 operated 10 conservatively

in 104 removed (90 %) in 11 undiscovered

3 removed 8 conservative

(by reoperation)

Surgical success: 93 %

Agreement with preoperative examination : 64 of 81 (79 %)

Surgical and histological finding

a) localization (n=115)

Head: 30 %

Body: 28 %

Tail: 42 %

b) histology

Benign adenoma: 103

Malign carcinoma: 4

Uncertain biological activity: 5

Multiple microadenomatosis: 3

Management

• Medical

– When awaiting surgery

– Metastatic disease

– Failed surgery

• Dietary

• Diazoxide (with hydrochlorthiazide)

• CCBs, Verapamil, Nifedipine

• Somatostatin analogues, Octeotride

• CT- Streptozocin, 5FU, Doxarubicin

• Hepatic art. embolization

Management of

Unresectable/Metastatic Disease• Systemic therapy

– Somatostatin analogues

– Chemotherapy

– “Targeted” Agents

– Peptide receptor therapy

• Regional Therapies– Hepatic arterial embolization (± chemotherapy) or

radioembolization

– Ablative therapy (RFA, cryo, microwave)

– Radiation

• Surgical Intervention– Resection

– Hepatic arterial ligation

– Liver Transplant

Zollinger-Ellison Syndrome

• “Islet cell” tumor of the pancreas [or of the duodenum]

• Hypergastrinemia

• Gastric acid hypersecretion

• Consequences of acid hypersecretion :

– PUD, GERD [ with or without complications]

– Diarrhea, malabsorption

Epidemiology of Z-E syndrome

• Any age group ( mean age 50 years)

• Male : Female 3:2

• Annual incidence 0.5 - 1.0 per million

• MEN-1 in approximately 25% of cases

Classification of Z-E syndrome

• Sporadic 75-80%

• MEN-1(autosomal dominant) 20-25%

• Ectopic gastrin- producing tumors < 1%• ovary

• lung

• cardiac (ventricular septum)

The Gastrinoma Triangle

Symptoms in patients with the Zollinger-Ellison syndrome

• Pain and diarrhea 50-60%

• Pain without diarrhea 25%

• Diarrhea without pain 20%

• Heartburn ± dysphagia 30%

• MEN-1 features 20-25%

Locations of peptic ulcers in ZE syndrome

• Duodenal bulb

• Post-bulbar duodenum

• Jejunum

• Esophagus

• Stomach

• Marginal (stomal)

Clinical features suspicious for

Zollinger-Ellison syndrome (ZES)

•PUD in the absence of Helicobacter pylori or

• PUD in association with chronic diarrhea

• Post-bulbar duodenal ulcer

• Multiple duodenal and/or jejunal ulcers

•PUD refractory to standard medical therapy

•Giant PUD

Diagnosis of ZE Syndrome

• Begins with clinical suspicion

• Fasting serum gastrin measurement

– high sensitivity (> 95%)

– poor specificity, even at high levels

– modest positive predictive value

– excellent negative predictive value

Other causes of elevated

fasting serum gastrin

Achlorhydria / hypochlorhydria, usu. due to chronic gastritis

Medications: antacids, PPIs,

H2 blockers

Postoperative: vagotomy, retained antrum syndrome

Renal failure

Gastric outlet obstruction

Diabetes mellitus

Hypertriglyceridemia

Diagnosis of ZE Syndrome

• Fasting serum gastrin measurement– high sensitivity (> 95%)

– low specificity and modest positive predictive value can be enhanced with provocative testing with secretin (2 IU/kg or 0.4 ug/kg i.v.) or calcium infusion (4 mg/kg calcium gluconate per hour for 3 hours), where likelihood ratios increase 10-15 fold with a + test result and decrease 10-fold with a - test result

Management of ZE syndrome:

• Acid control

• Tumor search is designed to find tumor and to stage its/their extent

• Tumor search and possible resection for cure is only prudent for patients who are surgical candidates

Clinical symptoms and laboratory findings in patients with glucagonoma

Clinical Symptoms Frequency (%)• Dermatitis 64-90• Diabetes/glucose intolerance 38-90• Weight loss 56-96• Glossitis/stomatitis/cheilitis 29-40• Diarrhea 14-15• Abdominal pain 12

• Thromboembolic disease 12-35• Venous thrombosis 24

• Pulmonary emboli 11

• Psychiatric disturbance uncommonLaboratory Abnormality• Anemia 33-85• Hypoaminoacidemia 26-100• Hypocholesterolemia 80• Renal glycosuria unknown

VIPoma - Verner Morrison syndrome

• Watery diarrhea, hypokalemia and achlorhydria

• Very rare tumor

• Secretory diarrhea of ≥ 10 liters watery tea colored stool per day

• Serum VIP levels above 200 pg/ml

• Exclude other endocrine tumors, laxative and celiac sprue

• Octreotide allows for preoperative resuscitation and preparation

• 40% are malignant and 22% had hyperplasia

Clinical symptoms and laboratory findings in patients with the VIPoma syndrome (WDHA)

Symptoms/Signs Frequency (%)Watery (secretory) diarrhea 89-100

Dehydration 44-100

Weight loss 36-100

Abdominal cramps, colic 10-63

Flushing 14-33

Laboratory FindingsHypokalemia 67-100

Hypochlorhydria 34-72

Hypercalcemia 41-50

Hyperglycemia 18-100

Somatostatinoma

• Annual incidence: very rare

• Pancreatic> Duodenal>> other sites

• Incidence of Malignancy: > 70%

• Incidence in MEN-1: <1%

• Clinical Features – Diabetes mellitus

– Gallbladder disease

– Diarrhea/steatorrhea

– Weight loss

Clinical and laboratory findings in patients with somatostatinomas

Clinical Finding(s) Somatostatinoma Somatostatin syndr.

Pancreatic Intestinal Overall

• Diabetes mellitus 95 21 95

• Gallbladder disease 94 43 68

• Diarrhea 66-97 11-36 37

• Weight loss 32-90 20-44 68

Laboratory Finding(s)

• Steatorrhea 83 12 47

• Hypochlorhydria 86 17 26

GH-RFoma (GRFoma)

• Annual incidence: very rare

• Lung> Pancreas > Small Intestine> Other sites

• Incidence of malignancy: > 30%

• Incidence in MEN-1: < 1%

• Clinical Features:

– Acromegaly due to ectopic production of GH-RF

– GH and somatomedin-A levels elevated

Other Reported Functional NETs (?significance)

• ACTHoma– may occur with gastrinoma

• CCKoma

• Neurotensinoma

• Erythropoietinoma with polycythemia

• LHoma with masculinization (F) or loss of libido (M)

• Reninoma with hypertension

• PTHrPoma with hypercalcemia

DEFINITION

• A case or a family with hormone-secreting or hormone-

producing neoplasia in multiple tissue types

• It encompasses several types of etiology, varying from two

coincidental tumors to complex patterns of tumor types.

MULTIPLE ENDOCRINE NEOPLASIA

SYNDROMES

SIX MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

AND THEIR MAIN CHARACTERISTICS

MEN1-Related Endocrine Tumors And Their Prevalence

Parathyroid Adenomas (90%)

GEP Gastrinoma (40%)

Insulinoma (10%)

Others (VIPoma, PPoma, SSoma, Glucagonoma) (2%)

Non-functioning (20%)

Anterior Pituitary Functioning: PRLoma (20%)

GH-, GH/PRL-, TSH-, ACTH-secreting, or Non-functioning (17%)

Foregut Carcinoids Thymic (2%)

Bronchial (2%)

Gastric (ECLoma) (10%)

Adrenal Gland Non-functioning (20%)

MEN1-Related Non-Endocrine Tumors And Their Prevalence

Cutaneous Tumors Lipomas (30%)

Facial angiofibromas (85%)

Collagenomas (70%)

Central Nervous System Meningiomas (5%)

Ependymomas (1%)

Others Leyomiomas (10%)

InactivatingHRPT2/oncusuppressor1q25-q31HPT-JT/607393

InactivatingCaSR3q13.3-q21FHH-NSHPT/NHPT

145980-239200

Atypical inactivating CaSR3q13.3-q21ADMH/601199

Inactivating for MEN1,

HRPT2, and CaSR

genes

MEN1/oncosuppressor,

HRPT2/oncosuppressor,

CaSR

and still unknown genes

11q13, 1q25-q31,

3q13.3-q21/2p13.3-14,

and still unknown loci

FIHPT/145000

ActivatingRET/proto-oncogene10q11.1MEN2A/171400

InactivatingMEN1/oncosuppressor11q13MEN1/131100

Type of germline

mutationGene/activityChromosomal

localizationSyndrome/OMIM#°

Chromosomal localization and genetic defects underlying

each familial form of hereditary hyperparathyroidism

Gene Mutation

(%)

90

98

10-18

100

N.R.

60