Expression of EGFR, ERRB2, and Expression of EGFR, ERRB2, and KIT in Adult Soft Tissue Sarcomas:KIT in Adult Soft Tissue Sarcomas:

A Clinicopathological Study of 281 CasesA Clinicopathological Study of 281 Cases

Takuro Wada, O Sato, A Kawai, T HasegawaSapporo Medial University, Sapporo JapanNational Cancer Center, Tokyo Japan

Purpose

To analyze expression patterns of EGFR, ERBB2, and KIT on 281 patients with common adult STS by standard immunohistochemical technique on formalin-fixed, paraffin-embedded sections

To Verify whether a significant association with prognosis is present

Patients

281 adult patients with common soft tissue sarcomas in the extremities and trunk diagnosed and treated at the NCC, Tokyo, Japan

Histologic subtypeFibrosarcoma (FS) 　　 11Leiomyosarcoma (LMS) 　　　　　 11 Myxoid liposarcoma 　（ LSM) 　　　　　 　 52Well differentiated liposarcoma （ LSW) 　　 　 50MPNST 　　　　　　　　　　　　　　　　　 18Myxofibrosarcoma (MFS) 　　　　　 53Pleomorphic MFH (PMFH) 　　　　 44Synovial sarcoma (SS) 　　　　　　　 42

Characteristic of 281 patients

Gender: 152 females and 129 males Age: 10 to 85 years (median 50 yrs) Treatment:

Resection All patientsRadiotherapy 25Chemotherapy 37Chemo + Radi 23

Pathology reviewing, grade and Staging Tumor typing

WHO Classification of Soft Tissue Tumors Histologic grade

Differentiation, necrosis, MIB-1 index TNM staging classification

Primary Antibodies

Antibody Source Dilution Positive control

EGFR, mouse monoclonal

DakoCytomation,

Clone 2-18C9

Prediluted Breast ca

ERBB2, rabbit polyclonal

DakoCytomation 1:500 Breast ca

KIT, rabbit polyclonal

DakoCytomation 1:50 Mast cell

０

１＋or 　≤ 10% = Negative

２＋

３＋and >10% = Positive

Strength Distribution

Evaluation of staining

Results

Immunohistochemical Pattern

Histologic type No. EGFR

Fibrosarcoma 11 4 (36%)

Leiomyosarcoma 11 8 (73%)

Myxoid liposarcoma 52 3 (6%)

Well-D liposarcoma 50 19 (38%)

Myxofibrosarcoma 53 16 (89%)

MPNST 18 47 (89%)

PMFH 44 39 (89%)

Synovial sarcoma 42 32 (76%)

Total 281 168 (60%)

Immunohistochemical Pattern

Histologic type No. EGFR ERBB2 KIT

Fibrosarcoma 11 4 (36%) 0 0

Leiomyosarcoma 11 8 (73%) 0 0

Myxoid liposarcoma 52 3 (6%) 0 0

Well-D liposarcoma 50 19 (38%) 0 0

Myxofibrosarcoma 53 16 (89%) 0 0

MPNST 18 47 (89%) 0 0

PMFH 44 39 (89%) 0 0

Synovial sarcoma 42 32 (76%) 3 2

Total 281 168 (60%) 3 2

Diffuse EGFR (2+) in leiomyosarcoma

Diffuse EGFR (3+) in MPNST

Diffuse EGFR (3+) in spindle cells of biphasic synovial sarcoma

Focal ERBB2 (2+) in epithelioid cells of biphasic synovial sarcoma

Focal KIT (2+) in spindle cells of monophasic synovial sarcoma

Overall survival curves for EGFR

N=281 P=0.03

month

706050403020100

Ove

rall

surv

ival

1.0

.8

.6

.4

.2

0.0

EGFR (+)

EGFR (-)79％

64％

Variables associated with patient survival: Univariate analysis Stage Histological grade Depth Size Positive EGFR staining

Variables associated with patient survival: Multivariate analysis Stage Histological grade Depth Size Positive EGFR staining

706050403020100

1.0

.8

.6

.4

.2

0.0706050403020100

1.0

.8

.6

.4

.2

0.0

Kaplan-Meier survival curves stratified by EGFR status and by tumor size

Size 5-10cm (n=135) Size>10cm (n=77)

EGFR-EGFR-

EGFR+

EGFR+

p=0.03 p=0.06

706050403020100

1.0

.8

.6

.4

.2

0.0706050403020100

1.0

.8

.6

.4

.2

0.0

Kaplan-Meier survival curves stratified by EGFR status and by histological grade

Grade 2 (n=74) Grade 3 (n=111)

EGFR-

EGFR-

EGFR+

EGFR+

p=0.08 p=0.7

Discussion

Expression of EGFR in STSs

Authors Cases Positive Subtype

Gusterson et al. (1985) 35 18 (51%) MFH, SS, Epi

Perosio et al. (1989) 40 20 (50%)

Duda et al. (1993) 43 21(49%)

Barbashina (2002) 19 13 (68%) SS

Nielsen (2002) 42 18 (52%) SS

This study 281 170 (60%)

MFH, SS, MPNST

Expression of ERBB2 and KIT

Merimsky et al. (2002)No overexpression of ERBB2 in 230 STSs

Hornick et al. (2002)Very limited expression of KIT in 365 STSs

This studyLimited expression of ERBB2 and KIT

Overall survival curves for EGFR

N=281 P=0.03

month

706050403020100

Ove

rall

surv

ival

1.0

.8

.6

.4

.2

0.0

EGFR (+)

EGFR (-)79％

64％

IMC-C225ABX-EGFTyrosine kinase inhibitor

Irresa

Target-specific agents and approaches for anticancer therapy

Conclusion

We analyzed the expression of EGFR, ERBB2, and KIT in 281 patients with STS

Positive staining of EGFR: 168/281 (60%) Positive staining of ERBB2, KIT was limited EGFR overexpression was a negative

prognostic factor associated with histological grade