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12 th CTOS Annual Meeting in Venice, Italy 2-4, November, 2006. Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in chondrosarcomas. Makoto Endo, 1 Tadaki Matsumura, 2 Umio Yamaguchi, 1 Fumihiko Nakatani, 1 Akira Kawai, 1 Hirokazu Chuman, 1 - PowerPoint PPT Presentation
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Cyclooxygenase-2 (COX-2) overexpressionCyclooxygenase-2 (COX-2) overexpressionis associated with a poor prognosis is associated with a poor prognosis
in chondrosarcomasin chondrosarcomas
Makoto Endo,Makoto Endo,11 Tadaki Matsumura, Tadaki Matsumura,22 Umio Yamaguchi, Umio Yamaguchi,11
Fumihiko Nakatani,Fumihiko Nakatani,11 Akira Kawai, Akira Kawai,11 Hirokazu Chuman, Hirokazu Chuman,11
Yasuo Beppu,Yasuo Beppu,11 Tadashi Hasegawa Tadashi Hasegawa22
11 Division of Orthopaedic Oncology, National Cancer Center Hospital, Tokyo, Japan Division of Orthopaedic Oncology, National Cancer Center Hospital, Tokyo, Japan22 Department of Clinical Pathology, Sapporo Medical University School of Medicine, Department of Clinical Pathology, Sapporo Medical University School of Medicine,
Sapporo, JapanSapporo, Japan
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
BackgroundBackground
Chondrosarcoma
The second most common
malignant bone tumor A broad array of presentations The histologic grade is the standard
for predicting the outcome
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
The he histologic grading system is
separated into three grades Based on
1. cellularity
2. nuclear atypia
3. pleomorphism
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
Grading of chondrosarcomas
Fletcher CDM, et al (eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone, 2002.
In some borderline cases, exact histologic grading is
difficult using only routine histopathologic examinations
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
Grade 1 Grade 3 Grade 2
Cyclooxygenase-2(COX-2) An isoform of COX A key enzyme that catalyzes the synthesis of prostaglandins (PGs) from arachidonic acid COX-2-derived PGs play an important role in carcinogenesis
1. induce angiogenesis2. inhibit apoptosis and immune surveillance3. increase invasion and metastatic potential
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
To investigate the expression profile of investigate the expression profile of
COX-2 using immunohistochemical stainingCOX-2 using immunohistochemical staining
in formalin-fixed, in formalin-fixed, paraffin-embedded
chondrosarcoma specimenschondrosarcoma specimens
To confirm whether COX-2 expression isTo confirm whether COX-2 expression is
associated with prognosisassociated with prognosis
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
PurposePurpose
Materials &Materials & Methods Methods
74 patients Sex: men, 37; women, 37 Age: 14 - 81 y/o (median, 50 y/o) Size: 2.7 - 32 cm (median, 8.0 cm)
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
Location:Axial skeleton, 47(pelvis, 20; rib, 19; vertebra, 4; scapula, 3; skull base, 1)
Long bones, 27(femur, 10; humerus, 5; tibia, 5; fibula, 2; ulna, 1; others, 4)
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
A monoclonal anti-COX-2 antibody
(clone CX-294; 1:100; DakoCytomation) Definition of overexpression:
More than 10% of the tumor cells stained
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
Immunohistochemical analysis of COX-2
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
COX-2 staining in the chondrosarcomas wasCOX-2 staining in the chondrosarcomas was
consistently observed in atypical chondrocytesconsistently observed in atypical chondrocytes
with a strong and cytoplasmic patternwith a strong and cytoplasmic pattern
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
< 10% of cells stained
= Negative
≧10% of cells stained
= Positive
Results (74 cases)Results (74 cases)
Histologic grade Grade 1: 39 Grade 2: 32 Grade 3: 3
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
COX-2 overexpression Positive: 16 (22%) Negative: 58 (78%)
12th CTOS Annual Meeting in Venice, Italy
Associations between COX-2 overexpression and clinical variables
Variable No. of patientsNegative Positive % P value
Age (yrs) < 50 36 31 5 14% 0.11>= 50 38 27 11 29%
Gender Male 37 28 9 24% 0.57Female 37 30 7 19%
Site Long bones 27 19 8 30% 0.21Axial skeleton 47 39 8 17%
Size < 8 cm 36 30 6 17% 0.31>= 8 cm 38 28 10 26%
Surgical margin Wide 47 37 10 21% 0.92Not wide 27 21 6 22%
COX-2 overexpression
Grade 1 39 38 1 3% <0.0012 32 19 13 41%3 3 1 2 67%
2+3 35 20 15 43%
12th CTOS Annual Meeting in Venice, Italy
Variables associated with patient survival: Univariate analysis
Variable No. of patients 5-year survival rate 10-year survival rate log-rankP value
Age (yrs) < 50 36 91.1 73.6 0.84>= 50 38 85.9 72.6
Gender Male 37 92.5 75.3 0.35Female 37 84.2 71.7
Site Long bones 27 91.6 91.6 0.26Axial skeleton 47 86.5 68.0
Size < 8 cm 36 100 67.4 0.38>= 8 cm 38 77.2 77.2
Surgical margin Wide 47 92.8 92.8 0.24Not wide 27 83.4 58.1
Grade 1 39 100 86.6 0.0022-3 35 72.9 56.2
COX-2 overexpression Negative 58 93.2 83.5 < 0.001Positive 16 68.6 25.7
12th CTOS Annual Meeting in Venice, Italy
0
30
60
40
50
20
10
0 50
100
90
80
70
150 200100Months
Cum
ulat
ive
Dis
ease
-spe
cific
Sur
viva
l (%
)
COX-2 overexpression (+)
COX-2 overexpression (-)
Multivariate Cox proportional hazards regression analysis for overall survival
Variable Hazard ratio (95% CI) P value
Age (yrs) < 50 1>= 50 0.29 (0.065-1.3) 0.1
Gender Male 1Female 1.6 (0.45-5.9) 0.46
Site Long bones 1Axial skeleton 2.1 (0.37-11) 0.41
Size < 8 cm 1>= 8 cm 1.6 (0.49-5.1) 0.45
Surgical margin Wide 1Not wide 1.4 (0.3-6.1) 0.66
COX-2 overexpression Negative 1Positive 2.5 (0.59-11) 0.21
12th CTOS Annual Meeting in Venice, Italy
Grade 1 12-3 6.4 (1.2-33) 0.027
DiscussionDiscussion
The first immunohistochemical evidence
that COX-2 overexpression is significantly
associated with decreased survival
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
DiscussionDiscussion
In the multivariate analysis, the only
independent risk factor for a poor outcome
was a high histologic grade.
COX-2 overexpression was significantly
associated with the histologic grade.
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
DiscussionDiscussion
COX-2 overexpression can be definitivelyCOX-2 overexpression can be definitively
evaluated evaluated based on the proportion of stained
tumor cells, enabling the subjectivity of
interpretations to be minimized.
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
ConclusionConclusion
COX-2 overexpression in chondro- sarcomas is a useful predictor of patient outcome that is strongly associated with histologic grade.
12th CTOS Annual Meeting in Venice, Italy2-4, November, 2006
Recommended