1. Kerrington Smith, M.D. CTOS Nov 14, 2008
Malignant peripheral nerve sheath tumors (MPNST): clinical, pathologic and molecular predictors of survival
Sarcoma
Research Center
UT MDACC
Kerrington Smith, M.D.
CTOS
Nov 14, 2008

2. Clinical challenges in MPNST
Diagnostic challenges
Which deep neurofibromas will
undergo malignant transformation?

3. Clinical challenges in MPNST
Prognostic challenges
After resection which patients will recur?
What is the pattern of recurrence?
NF1-MPNST vs. sporadic MPNST?

4. Clinical challenges in MPNST
Therapeutic challenges
Effective systemic therapy?

5. CASE

37. Which factors alter clinical outcome?
Patient factors….NF-1 status?
Tumor factors?
Treatment related factors?

38. MPNST epidemiology Neurofibromatosis Type 1 (NF-1) 40-50% 50-60%
History of radiation
exposure
10%
Autosomal dominant
1 in 3500 live births
Nf1 gene on Ch 17
40-50%
50-60%
Sporadic
MPNST
Evans DG J Med Genet 2002:39;311-4 38

39. How are MPNSTs staged? AJCC staging MPNST Histopathologic grade
Primary tumor
Size
Depth
Regional lymph nodes
Distant metastases
Most high grade
Most >10 cm
All deep
Rare
Coindre JM et al. Cancer 2001:91;

40. There is a need to subclassify
stage III MPNST

41. Molecular prognostic factors unknown
No consensus in re prognostic factors
World Series of MPNST
Patient Presentation
Reference Year No Status Site Size Grade NF1
Ducatman et al. (Mayo) NR NS NS NS +
Hruban et al. (MSKCC) NR NS + + NS
Wanebo et al. (NCI) NR + + NS NS
Doorn et al. (Dutch) NR NR NR NR NS
Wong et al. (Mayo Clinic) NR NS NS + +
Cashen et al. (MGH) NR + NR + NS
Anghileri et al. (Italy) NS NS
In the Anghileri study only 46 patients had NF-1
Molecular prognostic factors unknown

42. Purpose
To identify and validate tumor, pathologic and molecular factors prognostic of MPNST clinical behavior 42

43. MDACC clinical database
Methods
MDACC clinical database
Univariate and multivariate statistical analyses
MPNST tissue microarray 43

44. Study population Study dates: 1985 to 2006
Median length of follow up: 91 mo (2 to 236)
Total patients
N=140
With NF-1 Syndrome
N= 72
Without NF-1 Syndrome
N= 68

45. Which clinical factors are associated with worse MPNST survival outcomes??
Presentation status
Primary
Recurrent
Metastasis 87 26 27
62.1
18.6
19.3
Age – year
<35
>35 69 71 49 51
Gender
Male
Female 89
63.6
36.4
NF-1 status
With NF-1
Without NF-1 72 68
51.4
48.6
Radiation exposure
Yes No 12
128 15
91.4
Tumor location
Head and neck
Trunk
Extremity 20 77 43
14.3
55.0
30.7
Tumor size
<5 cm
5-10 cm
>10 cm
Unknown 29 34 52 25
20.7
24.2
37.1
17.8

46. Metastasis trumps NF1 biology
Presentation status
Primary
Recurrent
Metastasis 87 26 27
62.1
18.6
19.3
Age – year
<35
>35 69 71 49 51
Gender
Male
Female 89
63.6
36.4
NF-1 status
With NF-1
Without NF-1 72 68
51.4
48.6
Radiation exposure
Yes No 12
128 15
91.4
Tumor location
Head and neck
Trunk
Extremity 20 77 43
14.3
55.0
30.7
Tumor size
<5 cm
5-10 cm
>10 cm
Unknown 29 34 52 25
20.7
24.2
37.1
17.8

47. What drives metastasis in patients with localized MPNST??

48. Factors associated with development
of distant metastases

49. Development of distant metastases in MPNST
Tumor size
S100 staining
NF-1 status
% Metastasis Free
Time (months)
Time (months)
Time (months)
???
???

50. What drives survival in localized MPNST?

51. 113 patients with localized MPNST

52. Factors linked to survival in Patients with localized MPNST
Tumor size
Surgery
Survival probability
Time (months)
Time (months)

53. What drives survival after complete surgical resection?

54. 85 completely resected patients

55. Factors linked to survival after complete resection
Tumor size
S100 staining
Survival probability
Time (months)
Time (months)

56. Can molecular factors predict survival outcomes in MPNST??

57. Construction of MPNST Tissue Microarray
Surgical specimens 127
Deep neurofibromas 31
MPNST 96 NF
Sporadic 41

58. Putative molecular targets
dysregulation
EGFR
signalling
RAS
signaling
Proliferation
Angiogenesis

59. Deep neurofibromas vs MPNST: Differential marker expression

60. Deep neurofibromas vs MPNST: Differential marker expression

61. Deep neurofibromas vs MPNST: Differential marker expression

62. A possible early target in NF-1?
Deep
Neurofibroma
N=24
MPNST
N=69
EGFR (0.78) (1.04)
Prophylactic resection of EGFR(+) deep neurofibromas?

63. MPNST-specific survival:
associated TMA markers

64. MPNST-specific survival:
associated TMA markers

65. Conclusions MPNST patients presenting with metastasis
have significantly worse outcomes

66. Conclusions Tumor size, NF-1 status and loss of S100
are linked to development of metastasis

67. Conclusions 3. Complete surgical resection is the dominant
factor affecting survival of patients with
localized MPNST

68. Conclusions After a complete resection: Large tumor size
Loss of S100 staining
Worse MPNST-specific survival

69. Conclusions A worse MPNST-specific survival
5. EGFR and nuclear P53 expression
A worse MPNST-specific survival

70. The UT MDACC Sarcoma Research Center
Acknowledgments
Dina Lev
Raphael Pollock
Alexander Lazar
Chang-Ye Zou
Guy Lahat
The UT MDACC Sarcoma Research Center

71. Thank you for your attention
Sunset over Houston, Texas

73. 85 patients with completely resected MPNST