EKPA-LAIKO ENETS Center of Excellence · 2019. 4. 24. · EKPA-LAIKO ENETS Center of Excellence Endocrinology Unit National University of Athens Greece. DISCLOSURE OF INTEREST Honorarium

FUNCTIONING PANCREATIC NEOPLASMS

Gregory Kaltsas MD FRCPEKPA-LAIKO ENETS Center of Excellence

Endocrinology Unit

National University of Athens

Greece

DISCLOSURE OF INTEREST

Honorarium : IPSEN

Departmental Research Grants: IPSEN, NOVARTIS, PFIZER, SHIRE, SANOFI

CLINICAL PRESENTATION OF COMMON FUNCTIONING PANNENS :

PRODUCING DISTINCT CLINICAL SYNDROME

SSAs first line treatment: Gastrinomas, VIPomas,

Glucagonomas, Insulinomas, ACTH secreting NETs

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

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)

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

Endo Society, 2012

GLP-1 RADIONUCLEAR IMAGING

AVCS: USE OF CALCIUM OR SECRETIN TO LOCALISE

INSULINOMAS AND GASTRINOMAS

World J Surg 2006 30 1-111

DIAGNOSTIC WORK-UP FOR HYPOGLYCEMIA

SECONDARY TO AN INSULINOMA

ENETS Neuroendocrinology, 2016; 103:153-171

INSULINOMA MEDICAL TREATMENT : INSULIN SECRETING

PATHWAYS

SSA’s

Closes ATP-sensitive K

channels

Opens ATP-sensitive K

channels

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

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

INSULIN RESPONSE TO 177LU-DOTATATE IN

MALIGNANT INSULINOMA

Ong et al. EJE 2010

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

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

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

GLUCAGONOMA

� Glucagonoma (3%)

� Characteristic clinical

presentation

� Many NF panNEN stain

glucagon

� Somatostatin analogs

� Correct hypoaminoacidemia &

mineral deficiency

� Antibiotics

� LMWH: risk thrombosis

RESPONSE OF GLUCAGONOMA RASH TO OCTREOTIDE

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)

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

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

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

JCEM 2006, 91(12):4733-6JCEM 2006, 91(12):4733-6