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MDM2 IN SOFT TISSUE AND BONE SARCOMAS

Raf Sciot, M.D., PhD.Department of Pathology, University HospitalsKatholieke Universiteit Leuven, LEUVEN, Belgium

NO CONFLICT OF INTERESTS

WHAT IS MDM2? (MDMTWOMICS)

MDM2 IN SARCOMAS?(MDMTWOMAS)

MDM2MICS?

n Murine Double Minute clone 2: oncogene in double minutes of spontaneously transformedmouse fibroblasts

n 12q15n Controls/blocks p53 activity:

°p53: nucleus → cytoplasm, ubiquitination°inhibits p53 transactivation domain

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MDM2MICS?

n MDM2 amplification/overexpression for cancercells is an elegant means to block p53

n 7% of human cancers show MDM2 amplificationn Molecules that block the MDM2-p53 interaction

can reestablish wild type p53 activity

MDM2MAS?

n Atypical lipomatous tumor/well differentiatedliposarcoma

n Dedifferentiated liposarcoman Intimal sacoman Low grade osteosarcoma

(parosteal/intramedullary)

ATYPICAL LIPOMATOUS TUMOR/WELL DIFFERENTIATED LIPOSARCOMAn Synonymsn 40-45% liposarcoman Middle-aged adults, extremities (deep) >

retroperitoneum, paratesticulum, mediastinumn Variation adipocyte size/hyperchromatic/atypical

nuclei/lipoblasts(+/-)n Lipoma- like/sclerosing/inflammatoryn Prognosis: extremities >>> retroperitoneum

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ATYPICAL LIPOMATOUS TUMOR/WELL DIFFERENTIATED LIPOSARCOMA

n Giant markers/supernumerary ring chromosomes: 12q13-15

n Amplification of MDM2, CDK4, HMGA2, GLI1…n FISH to detect MDM2 amplification is very usefuln Cave MDM2 immunohistochemistry:

°focal to negative°nuclear°macrophages often false +

n MDM2/CDK4/p16 immuno: sensitivity ↑**Thway et al. Am J Surg Path 2012;36: 462-469.

lipoma-like sclerosing

inflammatory spindle cell

MDM2

MDM2

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MDM2

MDM2

MDM2

MDM2

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CD68

FISH probes: MDM2-SO (red) + CEP12-SG (green) as a reference probe (coveringcentromeric region of chromosome 12)

ProbesMDM2/12q15-BIOCDK4/12q14.1-DIG

Well differentiated fatty tumor

FISH test for MDM2 recommendedn Recurrent lesionn Deep extremity lesion >10 cm, pt > 50

yearsn Equivocal atypian Retroperitoneum/abdomen/pelvisn None of the above criteria but

worrisome clinical/radiological features

FISH test for MDM2 not recommendedn Superficial locationn Hands/feet

Clay et al. Am J Surg Path 2015;39:1433-1439.

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DEDIFFERENTIATED LIPOSARCOMA

n Transition of WDL/ALT towards a nonlipogenicsarcoma in 1e tumor or recurrence

n The well differentiated component may be lackingn 90% de novo, +/- 10% of WDL/ALT

dedifferentiaten Retroperitoneum (80%) > extremities

→ most frequent retroperitoneal sarcoma→ extremity undifferentiated pleomorphic sarcoma

with MDM2 amplification = dediff. Liposarc*.*Le Guellec et al. Am J Surg Path 2014;38:293-304.

DEDIFFERENTIATED LIPOSARCOMA

n Usually looks like a high gradespindle/pleomorphic sarcoma

n …but also: myxoid, low grade looking, heterologous differentiation (chondro-, osteo-, myogenic…)

n Recurrence ≥ 40%n Metastasis: 15-30%n Correlation between grade and outcome?*

*Dantey K et al. Human Pathol 2017;66:86-92.

DEDIFFERENTIATED LIPOSARCOMA

n Giant markers/supernumerary ring chromosomes: 12q13-15 (MDM2, CDK4, HMGA2…)

n MDM2 immuno usually strongly +n 6p23, 1p32 (JUN!) co-amplification

*Barretina et al. Nat Genetics 2010;42:715-721.

Well differentiatedliposarcoma/atypical lipoma

12q amplification (MDM2, CDK4,…): low → high level

Dedifferentiated liposarcoma

12q amplification (MDM2, CDK4,…): high level

+JUN, YEATS4*

*

*

Male, 66 yrs, retroperitoneal tumor (35 cm)…

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Ring chromosome

Ring

FISHMDM2/12q15-BIOCDK4/12q14.1-DIG

…dod 3 yrs after resection: recurrences and inoperability

Male, 83 yrs, retroperitoneal tumor (26 cm)…

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MDM2

MDM2…dod 5 yrs after resection (inoperable recurrence)

Female, 58 yrs, retroperitoneal tumor…

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MDM2

MDM2…awd, inoperable recurrence after 3 yrs, chemotherapy

MDM2

Male, 52 yrs, tumor lower pole kidney: punction biopsy

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MDM2

FISH probes: MDM2-SO (red) + CEP12-SG (green) as a reference probe (coveringcentromeric region of chromosome 12)

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INTIMAL SARCOMA

n Very rare, adults with broad age rangen Wall of large blood vessels, proximal pulmonary

arteries most frequentn Most frequent primary cardiac sarcoma*n Very poor prognosis (embolic dissemination)n Histology very heterogeneous: spindly/anaplastic/

myxoid/sclerotic/osteoid…→ any weird looking intraluminal sarcoma: thinkintimal sarcoma!

*Neuville et al. Am J Surg Path 2014;38:461-469.

INTIMAL SARCOMA

n Amplification of 12q12-15: MDM2/CDK4n Amplification/activation of PDGFRα/KIT (4q12)

and EGFR (7p11)

Male, 51 yrs, tumor pulmonary artery*

*Cuppens et J Thorcic Oncol 2014;9:897-899

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Boy, 4 yrs, tumor left ventricle

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MDM2

Case 3

Case 2

Case 1

1 3 5 7 9 11 13 15 17 19 21 X2 4 6 8 10 12 14 16 18 20 22

Chromosomes

244k Agilent CGHarray analysis

Log2

(rat

io)

Log2

(rat

io)

Log2

(rat

io)

PDGFRA/KIT/VEGFR-2 MDM2/CDK4

PDGFRA

MDM2/CDK4

CDKN2A/CDKN2B

EGFREGFR

MDM2/CDK4

Dewaele et al. Cancer Research 2010;70:7304-7314

PAROSTEAL OSTEOSARCOMA

n 4-5% of osteosarcoma, most frequent surfaceosteosarcoma

n Peak incidence in 3rd decade, slight femalepredominance

n 70%: posterior surface of distal femur, tibia, humerus also rarely involved

PAROSTEAL OSTEOSARCOMA

n Looks often benign. Fascicles of non-atypicalspindle cells admixed with parallel bone trabeculae, +/- osteoblastic rimming. 50%: cartilage islands

n MDM2 and CDK4 expression/amplification byimmuno/FISH

n Complete resection: 5 yr survival 91%. No chemotherapy, unless dedifferentiated (15-20%), then prognosis as in conventional type.

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male, 14 yrs, increasing problems with kneeflexion…

…ned 14 yrs after resection

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Female, 19 yrs, slowly increasing pain in shoulder since 6 months, and palpable mass…

…resection, after 3 yrs recurrence?

…resection, after 3 yrs recurrence?

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MDM2

= recurrence of parosteal osteosarcoma! MDM2

Male, 24 yrs, car accident 4 yrs ago, knee pain since then, recently increasingpain and swelling above the knee, biopsy and resection…

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…dedifferentiation…

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MDM2

MDM2

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FISH: MDM2-SO + CEP12-SG (Kreatech)

LOW GRADE CENTRAL OSTEOSARCOMA

n 1-2% of osteosarcoman 50% in 2nd-3rd decaden Long bones lower extremity, mainly distal femur

and proximal tibian Fascicular moderately cellular fibroblastic

proliferation with minimal/no atypian Curved bone trabeculae (fibrous dysplasia-like) or

long longitudinal seams of bone (parostealosteosarcoma-like)

LOW GRADE CENTRAL OSTEOSARCOMA

n Permeation of pre-exsiting bone or soft tissue extension may be only clue for malignancy

n MDM2 and CDK4 expression/amplification by immuno/FISH

n Upon resection 5 yr survival = 90% Chemotherapy only in cases with progression to high grade osteosarcoma (10-36%)

Female, 57 yrs, painless swelling of knee…

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…ned 12 yrs after resection

FISH: MDM2-SO + CEP12-SG (Kreatech)

100x 60x

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M

D

M

2

eaningful, molecular mechanism

iagnostic, FISH>Immuno

aybe drugable

make the life of a pathologist easier…

CONCLUSIONS