Pr©sentation PowerPoint - SFHTA
Transcript of Pr©sentation PowerPoint - SFHTA
Hypertension Unit, HEGP
Diagnostic et prise en charge des
phéochromocytomes (PH) et
paragangliomes (PG)
PF Plouin, L Amar et AP Gimenez-Roqueplo
COMETE, ENS@T et HEGP/Université Paris-Descartes
Hypertension Unit, HEGP
Chromaffin tumors: PH and PG
PH proper
Functioning PG Head and neck
PG
Hypertension Unit, HEGP
Paraaortic bodies
MESH: small masses of chromaffin cells found near the sympathetic ganglia
along the abdominal aorta, also called the organs of Zuckerkandl
Hypertension Unit, HEGP
yes
Op
era
te
MN postop.
Lifetime
clinical and
MN follow-up
Imaging tests
yes
High metanephrine (MN) levels
no
Paroxysmal or resistant hypertension,
incidentaloma, family history
Anatomical (CT/MRI) + functional (123I-MIBG or 18F-FDG) imaging
Genetic counseling and testing
Hypertension Unit, HEGP
When to screen for a PH/PG
Paroxysmal hypertension and/or hypertension
with adrenergic symptoms
Drug-resistant hypertension
Hypertension + diabetes and BMI <25 kg/m2 in
patients <50 years*
Positive family history or syndromic presentation
Incidentaloma
* La Batide Alanore et al, J Hypertens 2003;21:1703 [OR 19]
Hypertension Unit, HEGP
Presentation by quartile of date of operation
Incidentalomas, %
13
8
15
25
Q1 Q2 Q3 Q4
Plasma adrenaline, pg/ml 274
110
55 73
Q1 Q2 Q3 Q4
Duration of HTN, y 4 4
3
1
Q1 Q2 Q3 Q4
Tumor diameter, mm 60
50 50 42
Q1 Q2 Q3 Q4
Amar L et al, J Clin Endocrinol Metab 2005;90:2110
p for trend <0.01
Hypertension Unit, HEGP
Metanephrine determinations
Adrenaline NorA
Metanephrine NorMN
MN sulfate NorMN sulfate
COMT
SULT1A3
To
tal
Free
MN NMN
Hypertension Unit, HEGP
Plasma free MN or urinary MN excretion?
MNs are continuously
produced by the tumor
Total MNs include conjugated
MNs produced by a gut sulfo-
transferase
Free MNs mostly have an
extra-renal clearance
Eisenhofer G et al, JCEM 1998;83:2175
Eisenhofer G, Clin Chem 2001;47:988
Lenders J et al, JAMA 2002;287:1427
Hypertension Unit, HEGP
Anatomical imaging: CT, MR
Hypertension Unit, HEGP HEGP
Functional imaging
Specific: 123I-MIBG, FDA-PET Nonspecific: 18F-FDG-PET
DOPA-PET, Octreoscan
Hypertension Unit, HEGP
Image fusion
Hypertension Unit, HEGP
73 77
CT/MR
78
94
FDG
45
62
MIBG
Bone Soft T.
Sensitivities (%) of imaging tests
96
74 77 83
75
50
non-
metastatic
CT/MR 18F-FDG 123I-MIBG
Timmers HJ et al, J Natl Cancer Inst 2012;104:700
Metastases
Hypertension Unit, HEGP
Inherited PH/PG (%) in 4 European series
Spain, n=192
Germany, n=271
France, n=301
Italy, n=490
Cascon A et al, J Clin Endocrinol Metab 2009;94:1701
in: Gimenez-Roqueplo AP et al, Clin Endocrinol 2006;65:699
Amar L et al, J Clin Oncol 2005;23:8812
Mannelli M et al, J Clin Endocrinol Metab 2009;94:1541
8.6 7.3 5.8
0.3
31.9
9.9
VHL RET SDHB SDHD SDHC All
1254 patients with PH/PG
(excluding cases with NF1)
Hypertension Unit, HEGP
Tumor features in SDH mutation carriers
Gimenez-Roqueplo AP et al,
Cancer Res 2003;63:5615
SDHB mutations and
odds ratio for:
Extraadrenal tumor 18.9
Metastatic or
recurrent tumor 19.8
Neumann H et al, JAMA 2004;292:943
Amar L et al, J Clin Oncol 2005;23:8812
72
47 22
81
64
13
34 0 4
71
0 15
SDHB SDHD no
mutation
Extraadrenal, %
Metastatic, %
** **
** ** **
mutation mutation
Hypertension Unit, HEGP
Suggested screening
Plouin & Gimenez, Nat Clin Pract Endocrinol Metab 2006;2:60
Gimenez & al for ENS@T, Clin Endocrinol 2006;65:699
Apparently sporadic tumor
PG
VHL
SDHB, SDHD
Familial or
syndromic
presentation
Targeted
screening
Solitary
adrenal
tumor
Bilateral Malignant
VHL
first
SDHB
first
NF1:
clinical
diagnosis
Provide patient/family information/psychological counseling
SDHB immunostaining facilitates genetic screening
Recent reports of mutations in TMEM127, SDHAF2 and SDHA
Transcription-based classification
Gimenez-Roqueplo AP, Dahia P, Robledo M. Horm Metab Res 2012;44:1
Cluster 1A Cluster 1B
Cluster 2
SDHB, C and
D-related tumors SDHA and SDHAF2
VHL-related
tumors except 2C
RET/NF1 TMEM127 and MAX
Kinase receptor
signaling pathways
Pseudohypoxic pathways
Cluster 1A
Cluster 1 tumors synthetize noradrenaline, uptake FDG,
and could respond to antiangionenic Rx
Hypertension Unit, HEGP
Unopposed b-blockade can induce acute crises in Pheo Sibal L et al, Clin Endocrinol 2006;65:186
Preoperative control of BP
Use Do not use
a-blockade then b-blockade b-blockade alone
Plasma volume expansion Diuretics
Calcium-channel blockers Drugs that affect
(renin-angiotensin antagonists) catecholamine turnover
Hypertension Unit, HEGP
Drugs that can induce PH crisis
D2 receptor antagonists
metoclopramide, chlorpromazine, droperidol
Monoamine oxidase inhibitors
Non cardio-selective b-blockers
Noradrenaline and serotonin reuptake inhibitors
Peptides: ACTH, glucagon
Steroids in high doses
Hypertension Unit, HEGP
Total number 1486
with malignant primary tumor 83 5.6%
No. with follow-up (2-15 years) 991
with malignant recurrence 112 11.3%
with new tumor 44 4.4%
with any tumoral event 156 15.7%
Malignant at any time 195 >13.1%
Amar L et al, Horm Metab Res 2012;44:385
Postoperative follow-up: rationale
Hypertension Unit, HEGP
Follow-up of a patient with SDHB mutation
-1,0
-0,5
0,0
0,5
1,0
1,5
2,0
2,5
0 10 20 30 50 60 70 80
ln(M
NT
/cr)
PG +
metastases
RA Pheo
+ PG
7.5 GBq
Lu*octreotate
Hypertension Unit, HEGP
Survival in malignant PH/PG
54 malignant tumors including 23 with SDHB mutations
Median survival in
SDHB+ vs SDHB-
42 vs 244 months
p=0.012
0 1 2 3 4 5 6 7
0
25
50
75
100
Pro
babili
ty o
f su
rviv
al, %
Amar L et al, J Clin Endocrinol Metab 2007;92:3822
Hypertension Unit, HEGP
MN
SDHB,
Imaging
Tumor resection
or debulking
Proposed management following 1st metastasis
Tumor
Progress.
no
yes
monitoring
Clinical, MN,
imaging tests
MIBG
uptake
yes
131I-MIBG
no Chemotherapy
systemic
Rx effective yes no Antiangio. Rx
Hypertension Unit, HEGP
Antiangiogenic Rx in metastatic PhH/PG FIRSTMAPPP, a randomized phase II multicenter trial
Unresectable metastatic PH/PG Progression >20% over 18 months
Evaluable by RECIST criteria
Randomization Stratified on SDHB
status and line of Rx
PF
S a
t 6 m
on
ths Sunitinib
Placebo
ENS@T-Cancer is funded by the European Commission within the 7th Framework Programme
Hypertension Unit, HEGP
Summary
The most specific and sensitive diagnostic test for PH and
functional PG is the determination of metanephrines
Tumors are located by CT/MR and MIBG or FDG
Targeted genetic testing should be offered to patients with
evidence of syndromic or familial disease, and testing for
VHL and SDHx mutations should considered in patients
with apparently sporadic tumors
SDHB mutations are associated with a risk of malignancy
Patients, especially those with familial, extra-adrenal or
large (>6 cm) tumors, should be followed-up indefinitely
Hypertension Unit, HEGP
Hypertension Unit, HEGP
MN/Cr rises exponentially in malignant T
Linear
r=0.762
0
2
4
6
8
10
10 20 30 40 50 60 70 80 90
MN/cr
-1
0
1
2
10 20 30 40 50 60 70 80 90
ln(MN/cr)
Logarithmic
r=0.933
Amar L et al, Ann NY Acad Sci 2006;1073:383
Hypertension Unit, HEGP
Effect of tumor embolization
Embolisations of
liver metastases
-2
-1
0
1
2
3
4
5
20 40 80 100 120 140
ln(M
NT
/cr)
1 2 3
mo
Hypertension Unit, HEGP
Slope 0.069
doubling time 14
MN/Cr doubling time and survival ln
(MN
T/c
r)
0 1 2 3 4
Slope 0.048, doubling time 21
0
1
2
3
4
1 2 3 4
10 30 50 70 90 110 130
Slope 0.026, doubling time 38 mo
months
Slope vs survival
r=0.65 p=0.04
0
.04
.08
.12
.16
50 100 150 200 250
Hypertension Unit, HEGP
Reintervention reduced the MN/Cr ratio
and apparently delayed tumor growth by 18 months
(n=20, 95% CI: 16.0-18.0 mo, p<0.001)
Effect of tumor debulking on survival
-1.5
-1.0
-0.5
0.5
1
1.5
-20 -10 10 20 30
months Ln
(MN
/cr)
0
0
First reintervention
Hypertension Unit, HEGP
CT/MRI vs 123I-MIBG and 18F-FDG
For nonmetastatic tumors CT/MR have a sensitivity of 96% and a specificity of 90% 123I-MIBG and 18F-FDG have lower sensitivities (75% and
77%) and similar specificities (92 and 90%)
FDG uptake is higher in SDH/VHL-related that in MEN2-
related tumors
For metastases Sensitivity is 83% for 18F-FDG, 74% for CT/MR, 50% for 123I-MIBG (FDG vs MIBG and CT/MR vs MIBG, p <0.001)
Timmers HJ et al, J Natl Cancer Inst 2012;104:700
216 patients including 155 with PH/PG
Hypertension Unit, HEGP
Destabilization of the complex II in SDH tumors
Van Nederveen F et al, Lancet Oncol 2009;10:764
SDHB SDHC SDHD
VHL RET NF1
Van Nederveen F et al, Lancet Oncol 2009;10:764
Hypertension Unit, HEGP
Clinical Signs
Symptoms Frequency
– HTN 50-60 %
– Paroxysmal HTN 30 %
– Orthostatic Hypotension 10-50 %
– Hyperglycemia 40 %
– Headaches 60-90 %
– Sweating 55-75 %
– Palpitations 50-70 %
– Palor 40-45 %
– Perte de poids 20-40 %
Lenders, Lancet 2005
Hypertension Unit, HEGP
Sensitivities (%) of imaging tests
96
74 77 83
69
75
50
33
non-
metastatic
metastases HNT
CT/MR 18F-FDG 123I-MIBG
73 77
CT/MR
78
94
FDG
45
62
MIBG
Bone Soft T.
Timmers HJ et al, J Natl Cancer Inst 2012;104:700