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
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