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Transcription

Timing in NF2 tumor treatment:
which, when, why ?
Michel KALAMARIDES,
S. GOUTAGNY, D. BOUCCARA
A. GRAYELI, O. STERKERS
Neurosurgery & ENT Departments
Hopital Beaujon, Paris, France
NF2 reference center
Neurofibromatosis
type 2
Bilateral vestibular schwannoma (90%)
Birth incidence 1/33 000
Diagnosis : NF2 mutation or
diagnostic criteria (Manchester)
Meningioma (50%)
multiples
spinal tumors: 80%
ependymoma
(20%)
Other schwannomas
Cataract
(60-80%)
Plaque lesion
(skin 70%)
Evans 2000
Evans 2005
Neurofibromatose de type 2
NF2-/-
NF2+/-
NF2-/-
Tumeur sporadique
Méningiome
NF2-/-
NF2+/+
Schwannome
NF2-/-
NF2+/+
Mosaicism
2nd hit
Tumor
Leucocytes > no mutation
Mosaïcisme
Mosaicism est fréquent dans la NF2
Les échantillons tumoraux doivent être congelés au
moment de la chirurgie
Pour les founders, l’analyse de la mutation doit
commencer avec l’AND tumoral
Mosaicism peut influencer significativement l’évolution
clinique et donc le pronostic
Le conseil génétique doit tenir compte du mosaicism
avec risque réduit de trasnmission
Le produit du gène NF2: schwannomin/merlin
Sequence divergent
in isoform 1&2
100%
NH3+
FERM-domain
304
COO- 595aa
a-helical domain
prolin rich seq.
Ezrin
NH3+
61%
COO- 586 aa
Radixin
NH3+
63%
COO- 583 aa
Moesin
NH3+
63%
COO- 577 aa
N-terminal domain:
Interaction avec membrane
C-terminal domain :
Interaction avec cytosquelette
… comme les protéines ERM, la schwannomin se situe
à l’interface membrane / cytosquelette et ainsi occupe
une situaton inhabituelle pour un suppresseur de tumeur …
SCH
actin
merlin: rôle majeur dans l’inhibition de contact à confluence
QuickTime™ et un
décompresseur TIFF (LZW)
sont requis pour visionner cette image.
QuickTime™ et un
QuickTime™ et un
Modèles animaux de la NF2
adénoCre
meningioma
model
Kalamarides et al., 2002
Nf2flox/flox
X
P0-Cre
schwannoma
model
Giovannini et al., 2000
Common Assumptions
• Severity of NF2 ranges from mild to
severe
• NF2 natural history remains uncertain.
Some negative factors have been
identified: young age at diagnosis, several
non VS-tumors (meningiomas)
• Goals of NF2 patient management is to
preserve quality of life: intact neurological
function including hearing, balance and
facial functions, swallowing, and vision.
• => Need to carefully evaluate
benefits/risks of therapeutic interventions
GOLD STANDARD FOR NF2 PATIENT FOLLOW-UP
Annual clinical examination (including audiometry testing) & cranial +/- spinal MRI
Tumor spectrum
63%
94%
31%
80%
Tailored therapeutic decisions
–
–
–
–
–
–
–
–
Neuro-otologist
Neurosurgeon
Radiologist
Audiologist
Speech therapist
Ophthalmologist
Neurologist
Geneticist
– Psychologist
Treatment options for NF2 VS
1. Wait & Scan policy: should we treat only actively growing VS ?
2001
2008
Natural history of vestibular schwannoma in NF2
40 patients with non-treated bilateral VS (80 VS) with a follow-up of at
least 12 months (2 MRIs)
Surgeon’s decision :
small VS <1cm
medium-sized VS (1-3cm) with good hearing,
age, family history …
Patient’s decision : surgery or radiosurgery refusal, transitory loss of
follow-up
Mean follow-up: 89.9 months (7.5 years)
Natural history of vestibular schwannoma in NF2
Results
40 patients, 80 VS
• average growth (maximal extracanalar diameter): 1.91 mm/year
• pattern of growth:
• no growth : 23 (28.8%)
• ≤1.5mm/y : 29 (36.2%)
• >1.5<4mm/y : 15 (18.8%)
• ≥4mm/y : 13 (16.2%)
• Tumor control: at the latest evaluation, 21/80 (26,2%) of VS have been
resected (bilaterally in 6 patients)
• 3% of spontaneous facial palsy
Questions

5 years of actuarial tumor control : 85% (dimension progression < 25%)
(Mathieu , 2007) or surgery free: 85% (Regis ).
How tumor control is defined?
What is the benefit of radiosurgery?

Shunting procedures, ABI or CI insertion after radiosurgical procedures.
How are these considered in the evaluation of radiosurgery results?

Risk of malignancy:
some NF2 patients reported with MPNST or glioma and some other
unpublished (rapid enlargment of tumor leading to death without histological
analysis)
Treatment options for NF2 VS
2. Surgery: obvious indications :
3 years later
Patient
B2035
Patient
B1914
VS surgical management at the Beaujon Hospital in Paris
Removal of large VS (> 3cm in CPA)
Wait & Scan policy for small VS (<1cm)
asymptomatic
good hearing (except in few selected cases for hearing preservation surgery)
no growth on serial MRI
Timing of removal for 1-3cm VS
Size and growth pattern (based on MRI at 6mo. and yearly thereafter)
Hearing function on affected side
Size of controlateral VS and hearing function
Intracranial and intraspinal Tumor burden (including meningioma)
VS surgical management at the Beaujon Hospital in Paris:
Tumor removal
132 NF2 patients (82% with bilateral VS and 12 % with unilateral VS)
Median age @ diag= 31, median follow-up= 9.5 years
21% of patients operated on bilaterally, 44 % unilaterally
No recurrence
35% no VS surgery
Therapeutic options for NF2 VS
DCN
3. Auditory rehabilitation
- Cochlear implant
AVCN
- Auditory Brainstem Implant (ABI)
PVCN
•
Objective ABI performance results:
–
–
–
–
•
Recognition of environmental sounds
Recognition of stress patterns and words
Lipreading enhancement
Open-set sentence understanding for a few
Bilateral ABI
Subjective ABI performance results
(Patient questionnaire):
– ABI offers significant improvements in many
listening situations
– Recipients are satisfied with ABI and the
benefits they receive
VS surgical management at the Beaujon Hospital in Paris:
Auditory rehabilitation
Auditory Brainstem Implant in 23% of patients (n=30)
35% Excellent results: VS < 3 cm in CPA
(word and sentence comprehension > 50% with ABI alone)
27% Good results
(word and sentence comprehesion with lipreading > 50%)
38% poor results or non users
6 “sleepers”
1 with controlateral efficient CI
Cochlear Implant in 4% of patients (n=5)
100% Good results
AB Grayeli. Otol Neurotol 2008
Patient B3047
M 21yo
Bilateral VS
5 IC meningiomas
Diagnosis in 1994
22 Dec. 2006
3 Sept. 2007
22 March 2008
Patient B1769
F 27yo
Right VS &
Cervical intraspinal Sch.
dec 2004
sept 2007
nov 2006
june 2007
sept 2007
june 2007
Patient B2301
M 24yo
Bilateral VS
5 IC meningiomas
Blind after CS meningioma
Radiotherapy
Total deafness
Patient B1212
M 31yo
Total deafness
1999
2007
QUIZZ
1999
2007
2008
)
Summary of meningiomas in our NF2 patient series
• affect 63.4% of NF2 patients
• 2/3 patients have less than 3 tumors
• 6% de novo meningiomas (<20yo)
• in a 9 years follow-up period, 26.5% of NF2 patients with
meningioma(s) were operated on and 43/243 (17.7%) of meningiomas
removed
• 30% of resected meningiomas show histological aggressive features
(10-15% in sporadic): pathological and molecular analysis ongoing
Patient B1087
tetraparesis
C4
NF2 spinal tumors
management
80% of NF2 patients have spinal tumors
(schwannoma, meningioma, ependymoma)
Surgical removal of spinal tumors when
they became symptomatic: spinal cord
compression syndrome.
15% of NF2 patients operated on for
extramedullary tumor n=19
Patient B4398
M 23yo
Right facial schwannoma 2000
Thoracic intraspinal schwannoma 2001
Left spheno-orbitary meningioma 2001
ICHT , shunt 2007
Left facial schwannoma + ABI 2007
4 days later, sudden tetraplegia
Patient B1769
Dec 04
June 08
Progressive paraparesis
changes in ependymoma signal
cyst
Laminectomy cyst evacuation
large tumor debulking without
aggravation
NF2 spinal tumors
management
20% of NF2 patients have intramedullary tumors = ependymoma
Patient B1769
4% of NF2 patients operated on for
ependymoma n=5
Dec 04
June 08
Patient B2007
2001
1997
2004
2006
Non vestibular schwannoma management
Trigeminal and cranial lower nerves
2% of NF2 patients operated on (31%
have trigeminal S and 15 % caudal S) n=3
Conclusions : NF2 tumor treatment
Efficacy evaluation of therapeutic options (including clinical trials to come) requires
precise knowledge of NF2 tumor natural history
Yearly and life-time clinical and radiological follow-up is required to monitor tumor
growth, the majority of tumors being present at the time of diagnosis
Need to identify NF2 patients or individual tumors in NF2 patients with potential of
growth
Wait & scan policy is a valid option in selected cases
Auditory rehabilitation : CI & ABI.