kerrington smith, m.d. ctos nov 14, 2008

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