cyclooxygenase-2 (cox-2) overexpression is associated with a poor prognosis in chondrosarcomas

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


The he histologic grading system is

separated into three grades Based on

1. cellularity

2. nuclear atypia

3. pleomorphism


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


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


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


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)


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)


A monoclonal anti-COX-2 antibody

(clone CX-294; 1:100; DakoCytomation) Definition of overexpression:

More than 10% of the tumor cells stained


Immunohistochemical analysis of COX-2


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


＜ 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


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%


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


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


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



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.



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.


ConclusionConclusion

COX-2 overexpression in chondrosarcomas is a useful predictor of patient outcome that is strongly associated with histologic grade.


AcknowledgementAcknowledgementss

Orthopaedic oncologyYuki MorimotoYoshiyuki SueharaEisuke KobayashiKen Takeda


Pediatric oncologyAko Hosono

PathologyKunihiko Seki

Secretarial assistanceYuriko Kawaguchi

cyclooxygenase-2 (cox-2) overexpression is associated with a poor prognosis in chondrosarcomas

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