ekpa-laiko enets center of excellence · 2019. 4. 24. · ekpa-laiko enets center of excellence...
TRANSCRIPT
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FUNCTIONING PANCREATIC NEOPLASMS
Gregory Kaltsas MD FRCPEKPA-LAIKO ENETS Center of Excellence
Endocrinology Unit
National University of Athens
Greece
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DISCLOSURE OF INTEREST
Honorarium : IPSEN
Departmental Research Grants: IPSEN, NOVARTIS, PFIZER, SHIRE, SANOFI
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CLINICAL PRESENTATION OF COMMON FUNCTIONING PANNENS :
PRODUCING DISTINCT CLINICAL SYNDROME
SSAs first line treatment: Gastrinomas, VIPomas,
Glucagonomas, Insulinomas, ACTH secreting NETs
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INSULINOMA : WHIPPLE’S TRIAD
SYMPTOMS and SIGNS TUMOR DISTRIBUTION
Neuroglycopenia
- Mild personality changes
- Confusion
- Seizures
- Coma
Catecholamine excess
- Diaphoresis
- Pallor
- Tachycardia
Other symptoms
- Hunger
- Fatigue
- Nausea, Vomiting
- Peripheral neuropathy
Whipple’s Triad
Symptoms of low glucose
Low plasma glucose
Resolution with glucose
normalization
Whipple’s Triad
Symptoms of low glucose
Low plasma glucose
Resolution with glucose
normalization
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INSULINOMA
• Rare tumor (4 per million per year), mostly ‘benign’
• Whipple’s triad
• Biochemical Diagnosis
• Provocation testing � Concurrent measurement: Glucose, Insulin, C-peptide
� Plasma/urine sulphonylurea screen
• Localization (almost always in the pancreas)
• Non-invasive vs. invasive
• Structural vs. functional• Cross-sectional imaging techniques (CT/MRI)
• Endoscopic ultrasound
• Calcium stimulation study
• GLP1-radionuclide imaging (vs. SRS)
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FUNCTIONING PANCREATIC NENS
HYPOGLYCEMIA : DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Review history, examination and lab data for specific disorders
Exclude critical illness, surgery, hormone deficiencies (GH, Cortisol), non-islet cell tumors
(Big IGFII), factitious
Consider use of provocation testing
� Prolonged supervised fast
� Mixed meal test, OGTT (subset of patients post-prandial hypoglycaemia)
Controversy regarding hypoglycaemia threshold
Glucose 5.0 pmol/L
Consider post-glucagon glucose > 25mg/dl & β hydroxybutyrate < 2.7 mmol/L
JCEM 2009, 94:709-728
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Endo Society, 2012
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GLP-1 RADIONUCLEAR IMAGING
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AVCS: USE OF CALCIUM OR SECRETIN TO LOCALISE
INSULINOMAS AND GASTRINOMAS
World J Surg 2006 30 1-111
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DIAGNOSTIC WORK-UP FOR HYPOGLYCEMIA
SECONDARY TO AN INSULINOMA
ENETS Neuroendocrinology, 2016; 103:153-171
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INSULINOMA MEDICAL TREATMENT : INSULIN SECRETING
PATHWAYS
SSA’s
Closes ATP-sensitive K
channels
Opens ATP-sensitive K
channels
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MEDICAL TREATMENT OF INSULINOMAS
� Frequent meals high in carbohydrate
� Somatostatin analogs (test dose octreotide
or SRS as low sstr expression)
� Diazoxide (50-300mg, max up to 600 mg)
� Edema, hirsutism, RF
GH & glucocorticoids◦ Multiple side effects
� Glucagon
� Verapamil, phenytoin, β blockers◦ Not proven efficacy
� Everolimus (malignant insulinomas)
� Pasireotide
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EFFICACY OF 90YDOTATOC IN MALIGNANT INSULINOMA
315 mCi/4cycles
480 Gy to tumour
Volume: 22 cc
Uptake: 1.23 ID%
Baseline
CT-scan
OctreoScan111™
Volume: 3 cc
Uptake: 0.23 ID%
1 year
Bushnell et al. JCO 2010
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INSULIN RESPONSE TO 177LU-DOTATATE IN
MALIGNANT INSULINOMA
Ong et al. EJE 2010
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GASTRINOMAS : SPORADIC OR MEN 1 RELATED
ECL cells
G cell
ANTRUM BODY
FUNDUS
Gastrin
D cell
Somatostatin
Histamine
H+
H+H+
PGE2 & I2 Nervous system
Gastric gland
Parietal cells
Gastrinomas: Regulation of gastric acid
secretion
Majority of gastrinomas are found in the duodenum
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FSG > 10 X & PH < 2 facilitate diagnosis
60% gastrinomas do not fulfil these criteria and need
40% secretin test
Secretin test under supervision with PPI
discontinuation
GASTRINOMA DIAGNOSTIC ISSUES
ENETS Neuroendocrinology, 2016; 103:153-171
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GASTRINOMAS : ZOLLINGER – ELLISON SYNDROME
MEDICAL THERAPY
� PPIs (40-80 mg omeprazole)
� ± H2 blockers
� SS analogs
� CCK-B antagonists
25-30% MEN1� Hypercalcemia
� Pituitary tumors
� Adrenocortical tumors
� ‘Foregut ‘NETs
Titration to reduce acid hyper-secretion
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GLUCAGONOMA
� Glucagonoma (3%)
� Characteristic clinical
presentation
� Many NF panNEN stain
glucagon
� Somatostatin analogs
� Correct hypoaminoacidemia &
mineral deficiency
� Antibiotics
� LMWH: risk thrombosis
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RESPONSE OF GLUCAGONOMA RASH TO OCTREOTIDE
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VIPOMA
� VIPoma
� Vigorous rehydration
� Somatostatin analogs
� Diarrhea with low osmotic gap <
50mOsm/Kg (>700ml/D)
� Hyperglycemia, hypercalcemia
� Repletion of fluid electrolytes
(>350mEq/d K)
� Ringer Lactate (↑ HCO3)
� SSA (doses of up 500mcg/h)
� Glucocorticoids (60 mg/d)
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PANNETS: ALTERATION OF FUNCTIONAL STATUS
� 3-6% panNENs multiple hormones obscuring clinical phenotype
� Alterations functional status
� Non-functioning Functioning
� Functioning Change secretory component
� Meta-chronous hormonal secretion
� 15/435 panNENs (3.4%)
� Insulin, VIP
� Ki-67 LI
� Reduced median survival
De Mesier et al 2015
Crona et al 2016
De Mesier et al 2015
Crona et al 2016
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FUNCTIONING PANNETS : PRODUCING CLINICAL
SYNDROME�Pancreatic NETs (F-panNENs)
� Gastrinomas and insulinomas
� Rare F-pNETs (>100 cases)� VIPoma, Glucacagonoma, GRFoma, ACTHomas, panNETs causing CS
� PTHrPomas, Somatostatinomas
� Very rare F-pNETs (1-5 cases)� Renin, LH, EPO, IGF-II, CCK (CCKoma)
� p-NETs secreting Ct, Neurotensin, PP, Ghrelin
CCKoma: Watery diarrhea, weight loss, gallbladder disease,
peptic ulcer and normal gastrin level, NEJM 2013, 368:1165
PGomas, SSomas, EPO
JCO 2013, 31:1690-1698
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DURATION OF FASTING
Hirshberg B et al JCEM 2000
127 patients with proven insulinoma
NIH cohort 1970-2000
62% female, 37% male
84% benign, 16% malignant, 12% MEN1
NIH Protocol
Fast until glucose 40 mg/dL (2.2 mmol/L)
with neuroglycopaenia
66.9% hypoglycaemic within 24 hours
94.5% concluded within 48 hours
7 patients continued fast beyond 48 hrs
Retrospective data review :
Biochemical criteria fulfilled in all in
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JCEM 2006, 91(12):4733-6JCEM 2006, 91(12):4733-6