Genetic classification of STS

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

Genetic classification of STS

• Sarcomas with recurrent translocations

• Sarcomas with oncogenic mutations

• Sarcomas with simple genetic profile

• Sarcomas with complex genetic profile

Sarcomas with complex genetic profile

• Leiomyosarcomas

• Adult rhabdomyosarcomas

• Pleomorphic liposarcomas

• Myxofibrosarcomas

• Poorly-differentiated sarcomas / MFH

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

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%)

French Sarcoma Group DatabaseSarcomas 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

Sarcomas with complex genetic profileRe-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

• 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 profileRe-classification - Results

Sarcomas with complex genetic profileRe-classification - Results

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%)

Sarcomas with complex genetic profilePatients

• 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%)

Sarcomas with complex genetic profilePredictive 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

Metastasis-free survival

MyxoFS (n=128)

MFH (n=294)

LeiomyoS (n=355)

P = 6.4 x 10-6

Myogenic sarcomas (n=383)

P = 4.3 x 10-7

Time in months

pro

bab

ility

Metastasis-free survivalMyogenic differentiation

Non-myogenic sarcomas (n=472)

Metastasis-free survivalDegree of differentiation

Well D LeiomyoS (n=172)

Poorly D LeiomyoS (n=182)

MFH (n=294)

P = 0.002

Sarcomas with complex genetic profilePredictive 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

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

Sarcomas with complex genetic profileConclusions

• 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