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Malignant peripheral nerve sheath tumors
(MPNST):clinical, pathologic
and molecular predictors of survival
Kerrington Smith, M.D.
CTOS
Nov 14, 2008
Sarcoma Research Center
UT MDACC
Clinical challenges in MPNST
Diagnostic challenges
Which deep neurofibromas will undergo malignant transformation?
Clinical challenges in MPNST
Prognostic challenges
After resection which patients will recur?
What is the pattern of recurrence?
NF1-MPNST vs. sporadic MPNST?
Clinical challenges in MPNST
Therapeutic challenges
Effective systemic therapy?
CASE
Which factors alter clinical outcome?
Tumor factors?
Patient factors….NF-1 status?
Treatment related factors?
MPNST epidemiology
50-60%
History of radiationexposure
10%
NeurofibromatosisType 1 (NF-1)
40-50%
SporadicMPNST
• Autosomal dominant
• 1 in 3500 live births
• Nf1 gene on Ch 17
Evans DG J Med Genet 2002:39;311-4
How are MPNSTs staged?
AJCC staging
Histopathologic grade
Primary tumorSizeDepth
Regional lymph nodes
Distant metastases
MPNST
Most >10 cm
Most high grade
All deep
Coindre JM et al. Cancer 2001:91;1914-26
Rare
There is a need to subclassify
stage III MPNST
Patient PresentationReference Year No. Status Site Size Grade NF1
Ducatman et al. (Mayo) 1986 120 NR NS NS NS +
Hruban et al. (MSKCC) 1990 43 NR NS + + NS
Wanebo et al. (NCI) 1992 28 NR + + NS NS
Doorn et al. (Dutch) 1995 22 NR NR NR NR NS
Wong et al. (Mayo Clinic) 1998 134 NR NS NS + +
Cashen et al. (MGH) 2004 80 NR + NR + NS
Anghileri et al. (Italy) 2006 205 + + + NS NS
No consensus in re prognostic factors
Molecular prognostic factors unknown
World Series of MPNST
Purpose
To identify and validate tumor, pathologic
and molecular factors prognostic of MPNST
clinical behavior
Methods
• MDACC clinical database
• Univariate and multivariate statistical analyses
• MPNST tissue microarray
Study population
Study dates: 1985 to 2006
Median length of follow up: 91 mo (2 to 236)
Total patientsN=140
With NF-1 SyndromeN= 72
Without NF-1 SyndromeN= 68
Presentation statusPrimaryRecurrentMetastasis
872627
62.118.619.3
Age – year<35>35
6971
4951
GenderMaleFemale
8951
63.636.4
NF-1 statusWith NF-1Without NF-1
7268
51.448.6
Radiation exposureYesNo
12128
1591.4
Tumor locationHead and neckTrunkExtremity
207743
14.355.030.7
Tumor size<5 cm5-10 cm>10 cmUnknown
29345225
20.724.237.117.8
n %
Which clinical factors are associated with worse MPNST survival outcomes??
Presentation statusPrimaryRecurrentMetastasis
872627
62.118.619.3
Age – year<35>35
6971
4951
GenderMaleFemale
8951
63.636.4
NF-1 statusWith NF-1Without NF-1
7268
51.448.6
Radiation exposureYesNo
12128
1591.4
Tumor locationHead and neckTrunkExtremity
207743
14.355.030.7
Tumor size<5 cm5-10 cm>10 cmUnknown
29345225
20.724.237.117.8
Metastasis trumps NF1 biology
n %
What drives metastasis in patients
with localized MPNST??
Factors associated with developmentof distant metastases
Time (months)
% M
etas
tasi
s F
ree
Time (months) Time (months)
Development of distant metastases in MPNST
NF-1 statusTumor size S100 staining
??? ???
What drives survival in
localized MPNST?
113 patients with localized MPNST
Su
rviv
al p
rob
abili
ty
Time (months) Time (months)
Factors linked to survival inPatients with localized MPNST
Tumor size Surgery
What drives survival after complete
surgical resection?
85 completely resected patients
Time (months)
Su
rviv
al p
rob
abili
ty
Time (months)
Factors linked to survival after complete resection
Tumor size S100 staining
Can molecular factors predict
survival outcomes in MPNST??
Construction of MPNST Tissue Microarray
• Surgical specimens 127
• Deep neurofibromas 31
• MPNST 96
NF1 55
Sporadic 41
Putative molecular targets
Proliferation AngiogenesisEGFR signalling
RAS signaling
P53dysregulation
Deep neurofibromas vs MPNST: Differential marker expression
DeepNeurofibroma
N=24MPNSTN=69
Deep neurofibromas vs MPNST: Differential marker expression
DeepNeurofibroma
N=24MPNSTN=69
Deep neurofibromas vs MPNST: Differential marker expression
DeepNeurofibroma
N=24MPNSTN=69
DeepNeurofibroma
N=24MPNSTN=69
EGFR 92 1.45 (0.78) 85 1.75 (1.04) 0.13
Prophylactic resection of EGFR(+) deep neurofibromas?
A possible early target in NF-1?
MPNST-specific survival: associated TMA markers
MPNST-specific survival: associated TMA markers
Conclusions
1. MPNST patients presenting with metastasis
have significantly worse outcomes
Conclusions
2. Tumor size, NF-1 status and loss of S100
are linked to development of metastasis
Conclusions
3. Complete surgical resection is the dominant factor affecting survival of patients with localized MPNST
Conclusions
4. After a complete resection:
Worse MPNST-specific survival
Large tumor size
Loss of S100 staining
Conclusions
5. EGFR and nuclear P53 expression
A worse MPNST-specific survival
Acknowledgments
Dina Lev
Raphael Pollock
Alexander Lazar
Chang-Ye Zou
Guy Lahat
The UT MDACC Sarcoma Research Center
Thank you for your attention
Sunset over Houston, Texas
85 patients with completely resected MPNST