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Management of pancreatic endocrine tumors
Guillaume Cadiot Reims
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Different types of endocrine tumors of the
duodeno-pancreatic area
Type Incidence
(per million) Insulinoma
1-2 Zollinger-Ellison 0,5-1,5 VIPom
a 0,05-0,2 Glucagonoma
0,01-0,1 Somatostatinoma Very
rare Non functioning ?
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Endocrine tumors of the duodeno-pancreatic area
Liver mets MEN1 () () Insulinomas 10 5-8 ZES
25 25 VIPomas 25 10 Glucagonomas gt 50 lt
5 Somatostatinomas 50 lt 5 Non functioning ? ?
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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Signs at diagnosis

• Functioning tumors
• functioning signs
• liver metastases
• Non functioning tumors
• signs due to the size or location of the tumor,
  liver metastases
• fortuitous

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Signs of the endocrine tumors of the
duodeno-pancreatic area
Type Functioning
symptoms Insulinoma
Hypoglycemia Zollinger-Ellison Ul
cers, diarrhoea VIPoma Diarrhoea
Glucagonoma Cutaneous,
diabetes Somatostatinoma Diarrhoea,
diabetes Non functioning None
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Zollinger-Ellison syndrome
Duodenal ulcer
Esophagitis
Diarrhoea

• Complicated
• Resistant
• Beyond 1st duod
• Recurrence after HP eradication
• HP/NSAIDs neg

• Frequent
• Severe

• Frequent
• Reduced by PPI
• Isolated (3)

• Vomitting
• Weight loss
• Kydney stone

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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Diagnosis of functioning PET

• Peptide measurement
• Not enough in ZES

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Main causes of hypergastrinemia
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Hypergastrinemia and pernicious anemia
N
Sjöblom et al. Gut 1993
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Basal gastrinemia DU vs ZES
Bichat series
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H. pylori-related DU with hypergastrinemia and
high BAO
David Metz et al. Dig Dis Sci 1995
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Secretin test (3 U/kg/h infusion)
94 of ZES patients gt 1 specific criteria at
99-100
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Biochemical investigations. Pancreatic
tumor French recommendations

• REFERENCE
• If functioning tumor dosage of the specific
  peptide
• dynamic test (secretin test, prolonged fast)
• Glycemia, calcemia, phosphoremia
• PTH
• Chromogranin A
• ALTERNATIVE
•  All peptides 

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Chromogranin A Sensibility in pancreatic
endocrine tumor

72
8
0
52
45
6
0
35
C
g
A
4
0
N
S
E
2
0
0
Functioning
Non functioning
Baudin et al. Ann Oncol 2001
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Chromogranin A

• Sensibility small tumor low ??
• Specificity pancreatic tumor
• CgA 70
• NSE 100
• Correlation between evolution of CgA levels and
  that of tumor mass

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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Prevalence of MEN 1
MEN 1 () ZES 25 Insulinoma 5-8 VIPoma 10 Gluca
gonoma lt 5 Somatostatinoma lt 5 Non functioning
tumors ?
M Mignon et al
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MEN 1 assessment French recommendations

• Reference
• Only if stomach (and ZES), duodenum, pancreas
• Search for symptoms in patients and relatives
• Basal ionized calcium levels and PTH levels
• Large suspicion of MEN 1 or high risk
  conditions dosage of all peptides, MEN 1 gene
  mutations, imagery (pituitary, adrenals, chest)

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ZES MEN 1 other endocrinopathy frequency
other series
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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Extension assessment

• Searching primary tumor(s)
• Searching liver metastases
• Synchronous 24
• Metachronous 6 (mean F-U 9 years)

data for ZES
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Primary tumors Sporadic ZES (75)

• Unique except associated lymph nodes
• 65 duodenum and/or lymph nodes
• 25 pancreas lymph nodes
• 10 not found

• Duodenal gastrinoma lt 1 cm 77
• Pancreatic gastrinoma gt 3 cm 73

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Primary tumors ZES and MEN 1 (25)

• Multiple
• Duodenum gt 80 (gastrinomas)
• Pancreas gt 80 (gastrinomas 20 ?)
• Small 90 pancreatic tumors lt 3 cm

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French recommendations

• Initial morphological explorations
• Abdominal ultrasound
• Abdominal and pelvic CT-scan
• Somatostatin receptor scintigraphy
• Endoscopic ultrasonography (stomach, duodenal,
  pancreatic tumors)

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Localization of duodeno-pancreatic tumors
Duodenum - EUS 50 Pancreas - EUS
75-100 - CT-scan, MRI 60-85
(mean tumor size 2 cm) Octreoscan - gt
15-20 mm 90-100 - lt 15 mm 40
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Endoscopic ultrasonography of the pancreas in MEN
1
Isoechogenic small pancreatic tumor
Lymph node
Hyperechogenic small pancreatic tumor
Hypoechogenic small pancreatic tumor
Thomas-Marques et al. Am J Gastroenterol 2005 (in
press)
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Insulinoma
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Gastrinomes duodénaux
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Sporadic Zollinger-Ellison syndrome
Posterior view
Lymph node
Lymph node
Duodenal gastrinoma
Lymph node
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RT Jensen, NIH
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Detection of duodenal gastrinoma and lymph
nodes Cadiot et al. Gastroenterology
1996111845-54

• All Duodenum Lymph nodes
• gastrinomas (n8) duodenum
• (n19) (n11)
• EUS 11 (58) 5 (63) 6 (55)
• SRS 11 (58) 3 (38) 8 (73)
• EUS SRS 17 (90) 7 (88) 10 (91)

Lymph nodes duodenum (n5) US and CT-scan
always negative
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Detection of liver metastases (gastrinoma) Gibril
et al. Ann Intern Med 199612526-34
46
42
71
62
83
92
96
12
4
0
25
50
75
100
Percentage of positive patients
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Liver metastases
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Magnetic resonance imaging Endocrine liver
metastases
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Bone metastases
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Plan
1- Think to the diagnosis 2- Control functioning
syndrome 3- Confirm the diagnosis 4- Search for
MEN 1 5- Extension assessment 6- Specific therapy
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Sporadic pancreatic endocrine tumor
Surgery, even when tumor is invasive, except
contra-indications due to poor condition
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Surgery in MEN 1 ?
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Development of liver metastases according to
primary tumor size
No pancreatic tumor
Pancreatic tumor lt 3 cm
Pancreatic tumor gt 3 cm
77 patients with ZES and MEN 1
Cadiot et al. Gastroenterology 1999
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Risk of metastases according to non-functioning
PET size
Triponez, GTE, Ann Surg 2005
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Life expectancy
P 0.33
No pancreatic tumorNFPET 2 cm
Cumulative survival
Age
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Indications for surgery in MEN 1 ?

• All functioning tumors except ZES
• For ZES and non-functioning tumors
• Tumor size gt 2 cm or increasing size assessed by
  EUS
• Probably take into account liver metastases in
  first degree relatives

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Which operation ?
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Insulinoma

• Hypoglycemia
• Sporadic tumor (not MEN 1-related) (95)
• Single, small
• Pancreatic (99)
• Benign (90)

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VIPoma

• Diarrhoea often profuse (gt 5 litres 37 )
• Déshydratation, troubles ioniques
• Diarrhée intermittente (50)
• Flushs (23 )
• Elévation de la VIPémie
• Tumeur pancréatique (84 ), gt 3 cm (78 ),
  maligne (50 ), sporadique (gt 85)

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Glucagonome

• Erythème nécrolytique migrateur (90 )
• Amaigrissement massif (96 )
• Diabète (87 )
• Manifestations thrombo-emboliques
• Anémie normochrome normocytaire (40)
• Hyperglucagonémie franche
• Tumeur unique, grosse, maligne, sporadique
• Tum. asymptomatiques hyperglucagonémie ?

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Glucagonome Erythème nécrolytique migrateur
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Somatostatinome Vinik et al Sem Oncol
198714263-81
Pancréas Duodénum (n27) (n21) Diabète 21/27 3
/14 Lithiase vésiculaire 17/18 6/14 Diarrhée 11/12
3/8 Stéatorrhée 10/12 1/8 Amaigrissement 9/10 4/9
Ictère - 3/9 Siège Tête, corps Ampullaire
5 Métastases Foie 19/23 3/16
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Autres tumeurs fonctionnelles exceptionnelles !

• GRF
• ACTH
• Sérotonine
• Thyrocalcitonine (fonctionnelles ?)
• PTHrp