WHAT IS MDM2? (MDMTWOMICS) MDM2 IN SARCOMAS? (MDMTWOMAS) MDM2MICS? NO CONFLICT OF INTERESTS 5/07/2018 MDM2 IN SOFT TISSUE AND BONE SARCOMAS
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1 IN SOFT TISSUE AND BONE SARCOMAS WHAT IS? (MDMTWOMICS) Raf Sciot, M.D., PhD. Department of Pathology, University Hospitals Katholieke Universiteit Leuven, LEUVEN, Belgium IN SARCOMAS? (MDMTWOMAS) MICS? NO CONFLICT OF INTERESTS Murine Double Minute clone 2: oncogene in double minutes of spontaneously transformed mouse fibroblasts 12q15 Controls/blocks p53 activity: p53: nucleus cytoplasm, ubiquitination inhibits p53 transactivation domain
2 MICS? amplification/overexpression for cancer cells is an elegant means to block p53 7% of human cancers show amplification Molecules that block the -p53 interaction can reestablish wild type p53 activity MAS? Atypical lipomatous tumor/well differentiated liposarcoma Dedifferentiated liposarcoma Intimal sacoma Low grade osteosarcoma (parosteal/intramedullary) ATYPICAL LIPOMATOUS TUMOR/WELL DIFFERENTIATED LIPOSARCOMA Synonyms 40-45% liposarcoma Middle-aged adults, extremities (deep) > retroperitoneum, paratesticulum, mediastinum Variation adipocyte size/hyperchromatic/atypical nuclei/lipoblasts(+/-) Lipoma- like/sclerosing/inflammatory Prognosis: extremities >>> retroperitoneum
3 ATYPICAL LIPOMATOUS TUMOR/WELL DIFFERENTIATED LIPOSARCOMA Giant markers/supernumerary ring chromosomes: 12q13-15 Amplification of, CDK4, HMGA2, GLI1 FISH to detect amplification is very useful Cave immunohistochemistry: focal to negative nuclear macrophages often false + /CDK4/p16 immuno: sensitivity * *Thway et al. Am J Surg Path 2012;36: lipoma-like sclerosing inflammatory spindle cell
4
5 CD68 Probes /12q15-BIO CDK4/12q14.1-DIG Well differentiated fatty tumor FISH test for recommended Recurrent lesion Deep extremity lesion >10 cm, pt > 50 years Equivocal atypia Retroperitoneum/abdomen/pelvis None of the above criteria but worrisome clinical/radiological features FISH test for not recommended Superficial location Hands/feet FISH probes: -SO (red) + CEP12-SG (green) as a reference probe (covering centromeric region of chromosome 12) Clay et al. Am J Surg Path 2015;39:
6 DEDIFFERENTIATED LIPOSARCOMA Transition of WDL/ALT towards a nonlipogenic sarcoma in 1 e tumor or recurrence The well differentiated component may be lacking 90% de novo, +/- 10% of WDL/ALT dedifferentiate Retroperitoneum (80%) > extremities most frequent retroperitoneal sarcoma extremity undifferentiated pleomorphic sarcoma with amplification = dediff. Liposarc*. *Le Guellec et al. Am J Surg Path 2014;38: DEDIFFERENTIATED LIPOSARCOMA Giant markers/supernumerary ring chromosomes: 12q13-15 (, CDK4, HMGA2 ) immuno usually strongly + 6p23, 1p32 (JUN!) co-amplification Well differentiated liposarcoma/atypical lipoma 12q amplification (, CDK4, ): low high level *Barretina et al. Nat Genetics 2010;42: Dedifferentiated liposarcoma 12q amplification (, CDK4, ): high level + JUN, YEATS4* DEDIFFERENTIATED LIPOSARCOMA Usually looks like a high grade spindle/pleomorphic sarcoma but also: myxoid, low grade looking, heterologous differentiation (chondro-, osteo-, myogenic ) Recurrence 40% Metastasis: 15-30% Correlation between grade and outcome?* * * *Dantey K et al. Human Pathol 2017;66: Male, 66 yrs, retroperitoneal tumor (35 cm)
7 Ring Ring chromosome FISH /12q15-BIO CDK4/12q14.1-DIG dod 3 yrs after resection: recurrences and inoperability Male, 83 yrs, retroperitoneal tumor (26 cm)
8 dod 5 yrs after resection (inoperable recurrence) Female, 58 yrs, retroperitoneal tumor
9 awd, inoperable recurrence after 3 yrs, chemotherapy Male, 52 yrs, tumor lower pole kidney: punction biopsy
10 FISH probes: -SO (red) + CEP12-SG (green) as a reference probe (covering centromeric region of chromosome 12)
11 INTIMAL SARCOMA Very rare, adults with broad age range Wall of large blood vessels, proximal pulmonary arteries most frequent Most frequent primary cardiac sarcoma* Very poor prognosis (embolic dissemination) Histology very heterogeneous: spindly/anaplastic/ myxoid/sclerotic/osteoid any weird looking intraluminal sarcoma: think intimal sarcoma! *Neuville et al. Am J Surg Path 2014;38: Male, 51 yrs, tumor pulmonary artery* *Cuppens et J Thorcic Oncol 2014;9: INTIMAL SARCOMA Amplification of 12q12-15: /CDK4 Amplification/activation of PDGFRα/KIT (4q12) and EGFR (7p11)
12
13 Boy, 4 yrs, tumor left ventricle 5/07/2018
14 PAROSTEAL OSTEOSARCOMA 4-5% of osteosarcoma, most frequent surface osteosarcoma Peak incidence in 3rd decade, slight female predominance 70%: posterior surface of distal femur, tibia, humerus also rarely involved Case 3 244k Agilent CGHarray analysis PDGFRA/KIT/VEGFR-2 /CDK4 EGFR EGFR PAROSTEAL OSTEOSARCOMA Log2(ratio) Log2(ratio) Log2(ratio) Case 2 Case 1 PDGFRA /CDK4 CDKN2A/CDKN2B /CDK4 Looks often benign. Fascicles of non-atypical spindle cells admixed with parallel bone trabeculae, +/- osteoblastic rimming. 50%: cartilage islands and CDK4 expression/amplification by immuno/fish Complete resection: 5 yr survival 91%. No chemotherapy, unless dedifferentiated (15-20%), then prognosis as in conventional type X Chromosomes Dewaele et al. Cancer Research 2010;70:
15 male, 14 yrs, increasing problems with knee flexion ned 14 yrs after resection
16 resection, after 3 yrs recurrence? Female, 19 yrs, slowly increasing pain in shoulder since 6 months, and palpable mass resection, after 3 yrs recurrence?
17 = recurrence of parosteal osteosarcoma! Male, 24 yrs, car accident 4 yrs ago, knee pain since then, recently increasing pain and swelling above the knee, biopsy and resection
18 dedifferentiation 5/07/2018
19
20 FISH: -SO + CEP12-SG (Kreatech) LOW GRADE CENTRAL OSTEOSARCOMA Permeation of pre-exsiting bone or soft tissue extension may be only clue for malignancy and CDK4 expression/amplification by immuno/fish Upon resection 5 yr survival = 90% Chemotherapy only in cases with progression to high grade osteosarcoma (10-36%) LOW GRADE CENTRAL OSTEOSARCOMA 1-2% of osteosarcoma 50% in 2nd-3rd decade Long bones lower extremity, mainly distal femur and proximal tibia Fascicular moderately cellular fibroblastic proliferation with minimal/no atypia Curved bone trabeculae (fibrous dysplasia-like) or long longitudinal seams of bone (parosteal osteosarcoma-like) Female, 57 yrs, painless swelling of knee
21 ned 12 yrs after resection FISH: -SO + CEP12-SG (Kreatech) 100x 60x
22 CONCLUSIONS M eaningful, molecular mechanism D M 2 iagnostic, FISH>Immuno aybe drugable make the life of a pathologist easier
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