1. Prognostic value of myogenic differentiation in adult soft tissue sarcomas (STS) A study of 855 cases from the French Sarcoma Group N Stock, MC Chateau, F Collin, L Guillou, A Leroux, B Marques, JJ Michels, D Ranchere, YM Robin, P Terrier, M Trassard, I Valo and JM Coindre Department of Pathology, Institut Bergonié, Bordeaux, France and Pathology subgroup, French Sarcoma Group, France

2. Genetic classification of STS Sarcomas with recurrent translocations Sarcomas with oncogenic mutations Sarcomas with simple genetic profile Sarcomas with complex genetic profile

3. Leiomyosarcomas Adult rhabdomyosarcomas Pleomorphic liposarcomas Myxofibrosarcomas Poorly-differentiated sarcomas / MFH

4. Sarcomas with complex genetic profile Spindle cell / pleomorphic sarcomas Difficult to classify Prognosis and myogenic differentiation –Fletcher et al. J Clin Oncol 2001;19:3045-50 –Deyrup et al. Cancer 2003;98:805-13

5. French Sarcoma Group Database 2538 adult STS with primary event (January 2006) STS with translocations: 785 (27.2%) ALT/WDLPS and dedifferentiated LPS: 355 (12.3%) MPNST, angioS, chondroS, osteoS,..: 401 (13.9%) LMS, adult RMS, pleomorphic LPS, MFS and poorly- diff sarcomas/MFH: 1348 ( 46.7%)

6. French Sarcoma Group Database Sarcomas with complex genetic profile LMS, adult RMS, pleomorphic LPS, MFS and poorly-diff sarcomas/MFH: 1348 1002 with paraffin block directly available (biopsy and/or surgery in FSG centers) 276 cases with frozen tissue for CGH-array and cDNA

7. Sarcomas with complex genetic profile Re-classification - Methods Pathology review (1002) IHC on whole tissue sections (520): SMA, desmin, caldesmon, myogenin… IHC on TMA (482): muscular markers, keratin, S100, CD34, MDM2, CDK4,…. Fletcher et al, J Clin Oncol 2001;19:3045-50

8. 1002 cases: –928 complex genetic profile sarcomas –74 reclassified: 27 DDLPS, 47 others 73 with metastasis at time of diagnosis and thus excluded for metastasis free survival study. Sarcomas with complex genetic profile Re-classification - Results

9. Initial diagnosis (855) LMS: 279 (32.6%) Adult RMS: 23 Pleomorphic LPS: 50 MyxoFS: 32 (3.7%) MFH: 471 (55%) Final diagnosis (855) LMS: 355 (41.5%) Adult RMS: 28 Pleomorphic LPS: 50 MyxoFS: 128 (15%) MFH: 294 (34.4%)

10. Sarcomas with complex genetic profile Patients Median age: 62 (15 - 98) Sex: 447 M / 408 F Locations: extremities 601 (70.3%), trunk wall 159 (18.6%), internal trunk 69 (8.1%), head and neck 26 (3%) Deep tumors: 716 (83.7%) Median size: 8 cm (1 - 30) Median FU: 102 months Distant metastasis: 296 (34.6%)

11. Sarcomas with complex genetic profile Predictive factors for metastasis Univariate analysis Grade: 3.1x10 -8 Myogenic differentiation: 4.7x10 -7 Internal trunk location: 1.4x10 -4 Tumor depth: 2.7x10 -9 Tumor size: 4.4x10 -7

12. Metastasis-free survival MyxoFS (n=128) MFH (n=294) LeiomyoS (n=355) P = 6.4 x 10 -6

13. Myogenic sarcomas (n=383) P = 4.3 x 10 -7 Time in months probability Metastasis-free survival Myogenic differentiation Non-myogenic sarcomas (n=472)

14. Metastasis-free survival Degree of differentiation Well D LeiomyoS (n=172) Poorly D LeiomyoS (n=182) MFH (n=294) P = 0.002

15. Sarcomas with complex genetic profile Predictive factors for metastasis Multivariate analysis 1- Histological grade: x 4.65 2- Tumor depth: x 2.91 3- Myogenic differentiation: x 1.56 4- Internal trunk location: x1.52

16. Complex genetic profile sarcomas excluding internal trunk n=626 Predictive factors for metastasis Univariate analysis Grade: 3.2x10 -5 Myogenic differentiation: 1.6x10 -5 Tumor size: 0.03 Multivariate analysis Histological grade: x 3.3 Myogenic differentiation: x 1.44

17. Sarcomas with complex genetic profile Conclusions Myogenic differentiation is an adverse prognostic factor About 30% of sarcomas with complex genetic profiles are poorly differentiated and difficult to classify Studies of genetic alterations should provide help for a more reproducible classification

18. Bibliography Pisters P, Leung D, Woodruff J and al. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. JCO, 1996, 14(5); 1679-89. Fletcher CDM, Gustafson P, Rydholm and al. Clinicopathologic re evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. JCO, 2001, 19(12); 3045-50. Deyrup A, Haydon R, Huo D and al. Myoid differentiation and prognosis in adult pleomorphic sarcomas of the extremity. Cancer, 2003, 98, 805-13. Massi D, Beltrami G, Capanna R and al. Histopathological reclassification of extremity pleomorphic soft tissue sarcoma has clinical relevance. EJSO; 2004, 30, 1131-36. Thank you!