Transcript Document

NET tumors definition:
Tumors originating from cells that:
• Produce neurotransmittor, neuromodulator or
neuropeptide hormones.
• Cells contain dense core granules that release
hormones by exocytosis by an appropriate
stimulus
• Lack of axons and synapses.
NET tumor- dense core
granules
Electron
micrograph of
midgut carcinoid:
not numerous
secretory granules
NET tumors- distribution
Common-
GI tract
lungs
pancreas
Less Commonthyroid
adrenal
Rarethymus
ovaries
other organs
GEP-NETS- Pathology
WHO 2010 classification:
• Neuroendocrine tumor gr. 1
• Neuroendocrine tumor gr. 2
• Neuroendocrine carcinoma gr. 3
• Mixed endocrine and exocrine tumors (MANEC)
• Tumor-like lesions
ENETS grading according to Ki-67 index:
Grade 1<2%
Grade 22-20%
Grade 3>20%
NET grading- Correlation
with prognosis
Pape et al. Cancer 2008
NETs- tumor markers
General:
Chromogranin A
Specific:
Tumor type
Marker(s)
Pancreatic NETs
Insulin
Glucagon
Somatostatin
PTHrp
GRF
CRF…
Carcinoid
Serotonin
5-HIAA
Medullary thyroid Ca.
Calcitonin, CEA
Pheochromocytoma
Catecholamines
Metanephrines
NETs- imaging
Anatomical:
Computerized tomography (dynamic triphasic studies)
Ultrasonography
MRI
Endoscopic ultrasound
Functional:
111Indium
DPTA-octreotide (Octreoscan)
68Ga-DOTATOC/NOC-PET
123I-meta-iodo-benzylguanidine
(MIBG)
Positron emission tomography (PET)-18 FDG, DOPA, 5-HTP
Pancreatic NETs- tumor syndromes
Tumor
% of
PNETs
Tumor
location
%
with
MEN1
%
malignant
Clinical syndrome
Insulinoma
3-5
Pancreas>99%
4-5
<10
Hypoglycemia
weight gain
Gastrinoma
20-25
Duodenum 25%
Pancreas 25%
20-25
>50
Abdominal pain
peptic ulceration
diarrhea, wt. loss
VIPoma
3-5
Pancreas 90%
6
>50
“WDHA”
Glucagonoma 1-2
Pancreas 100%
1-20
>70
Rash, cachexia,
diabetes
Nonfunctioning
Pancreas, GI
tract
18-44
>80
Abdominal pain,
wt. loss
70%
Pancreatic NETs- tumor
syndromes
Tumor
% of
PNET
s
Tumor
location
%
with
MEN
1
%
malignan
t
Clinical
syndrome
CRFoma
<1
Pancreas 414%
Rare
>99
Ectopic ACTH
Syn.
PTHrpoma
<1
Pancreas
Rare
>99
Hypercalcemia
GRFoma
<1
Pancreas
30%, lung
54%, jej. 7%
16
50
Acromegaly
NET tumors- GI tract
Class
Type
Carcinoid-
foregut
midgut
hindgut
Site
lungs, stomach,
small bowel,
ascending colon
colorectal
Management of patients with NETs
Diagnosis of NET
Hormonal control correction of deficiencies
Rule out hereditary syndromes
Staging (CT, Octreoscan, MIBG, PET)
Localized
Treatment of local
complications (bone mets)
Resection
Primary +
metastatic resection
Primary resection +
liver Tx?
Metastatic
“Cytoreduction”
Biotherapy
Somatostatin
analogogues
Interferon a
Chemoembolization
RFA
Systemic
chemotherapy
Radioligand
therapy
SMS analog
MIBG
Somatostatin
• Originally discovered as an inhibitor of growth
hormone release
• Released from neural, endocrine, and
enteroendocrine cells
• Has a very short half-life in tissue and in blood
• Exerts its effects through interaction with
somatostatin receptor (sst) subtypes 1-5
• A key regulatory peptide, with a largely
inhibitory physiological effect
Somatostatin Binding to Cell Surface
Ca++
close
K+
Phospholipase C
1
Somatostain 14
Somatostatin 28
Octreotide
2
3
Tyrosine phosphatase
4
5
a b
ATP
Gi
Five Receptor Subtypes
AC
CAMP
Somatostatin Inhibitory Actions
Brain
GH
TSH
ACTH
Pituitary
Electrical activity
ACh release
Pancreas
GI Tract
Insulin
Glucagon
Enzymes
Bicarbonate
Gastrin
Secretin
Motilin
Pepsin
Gastric acid
Motility
Blood flow
Glucose and protein absorption
Kidney
Renin
Somatostatin
• Natural Somatostatin:
Short duration of action (< 3 min)
• Synthetic peptides (Octreotide, Lanreotide):
longer acting (3-12h)
– Standard doses of short acting octreotide: 50-500ųg
three times daily, S.C
• Depot forms:
Sandostatin LAR: 10-30 mg, 1/month, IM
Somatuline Autogel: 60-120mg, 1/month, SC
Somatostatin Schematic Structure
Native vs. Synthetic
ala
gly
lys
asn
phe
phe
trp
S
S
Human
Somatostatin
D
phe
SMS 201-995
(Sandostatin®)
(Octreotide)
cys
lys
cys
ser
cys
phe
cys
phe
thr
D
trp
S
S
thr
ol
thr
lys
thr
Amino acids
essential for
receptor binding
Octreotide- anti-proliferative effect in
midgut carcinoid
Rinke et al. J Clin Oncol 2009
Neuroendocrine carcinoma- CT and
Octreoscan co-registration
Peptide Receptor
Radionuclide Therapy (PRRT)
Radionuclide
DOTA
Somatostatin
Suitable radionuclides :
• 90Y-DOTATOC- high energy b-emitter
(2.27 MeV)
• 177Lu-DOTATOC- a medium energy b-emitter
(0.5 MeV) and gamma radiation-emitter
Range of the ß particles :
• 90Y-DOTATOC - 150 cell diameter (>10mm)
More effective for larger tumors, poorly
vascularized
• 177Lu-DOTATOC- 20 cell diameters
More effective for smaller tumors
Tumor Response after PRRT
•
•
•
•
Complete or partial remission- 30%
Minor remission- 21%
Tumor stabilization (in progressive disease)-26%
Time to progression (median): 3y with PRRT
less than 1y with chemotherapy
• Objective tumor response after PRRT is more likely in
patients with fast growing tumors
Carcinoid- clinical manifestations
65 Year old man
• Diarrhea, flushing-6 month, intestinal obstruction
• Midgut carcinoid
• 5-HIAA 88 mg/d (<14)
• Sandostatin LAR 30mg x 1/month
• Diarrhea-resolved, Flushing improvement
Metastatic Midgut Carcinoid
• 49 year old woman
• Midgut carcinoid (flushing, abdominal pain,
watery diarrhea, 12 kg. weight loss 5-HIAA-.)
• Mets in bones and liver
• Treatment: Sandostatin-LAR 30mgx1/m• Partial resolution of symptoms
• Treatment: 90Y-DOTATOC
• Clinical and radiological improvement (liver mets
Midgut carcinoid- Octreoscan
Post.
Ant.
4 hours
Post.
Ant.
48 hours
Midgut carcinoid CT scan
After
90Y-DOTATOC
Rx
Before
Pancreatic NETs- tumor syndromes
Tumor
% of
PNETs
Tumor
location
%
with
MEN1
%
malignant
Clinical syndrome
Insulinoma
70-75
Pancreas>99%
4-5
<10
Hypoglycemia
weight gain
Gastrinoma
20-25
Duodenum 25%
Pancreas 25%
20-25
>50
Abdominal pain
peptic ulceration
diarrhea, wt. loss
VIPoma
3-5
Pancreas 90%
6
>50
“WDHA”
Glucagonom
a
1-2
Pancreas 100%
1-20
>70
Rash, cachexia,
diabetes
Nonfunctioning
4-50
Pancreas, GI
tract
18-44
>80
Abdominal pain,
wt. loss
Pancreatic gastrinoma
46 Year old man
• Abdominal pain, dyspepsia, diarrhea, weight loss
• Abdominal CT- Pancreatic mass, liver mets
• Treatment:
–
–
–
–
Omeprazole (PPI)
Sandostatin-LAR- 30 mgx1/m
Streptozotocin + 5-FU (11 years)
PRRT treatment (90Y-DOTATOC)
• Clinical, biochemical and radiological
improvement
Gastrinoma- CT
Gastrinoma- After 90Y-DOTATOC therapy
Pancreatic NETs- tumor syndromes
Tumor
% of
PNETs
Tumor
location
%
with
MEN1
%
malignant
Clinical syndrome
Insulinoma
70-75
Pancreas>99%
4-5
<10
Hypoglycemia
weight gain
Gastrinoma
20-25
Duodenum 25%
Pancreas 25%
20-25
>50
Abdominal pain
peptic ulceration
diarrhea, wt. loss
VIPoma
3-5
Pancreas 90%
6
>50
“WDHA”
Glucagonom
a
1-2
Pancreas 100%
1-20
>70
Rash, cachexia,
diabetes
Nonfunctioning
4-50
Pancreas, GI
tract
18-44
>80
Abdominal pain,
wt. loss
VIP-oma - Case Presentation
57 Year old female
• 16 kg weight loss over 2 years
• Severe dehydration, hypokalemia and
incapacitating secretory diarrhea
• VIP levels markedly elevated
57 y.o. Female with Metastatic VIPoma
Pre-treatment CT
Octreotide dose
(mcg/d)
Clinical Follow-up of VIPoma Patient