Molecular pathology in soft tissue tumors

Pathologie Sylvia Höller

When do we perform molecular testing?

• Morphology and IHC are not clearly fitting

with an entity

– some translocations are entity specific e.g.

synovial sarcoma (SS18(SYT)- SSX)

• Morphology and IHC is fitting with an entity

but entity is defined molecularly

• Some translocations are not entity specific:

– FUS-CREB3L1/2 translocation: low grade fibromyxoid sarcoma, sclerosing epitheloid fibrosarcoma

• Consider only molecular results in the light of the rest of the findings: clinics, morphology, immunohistochemistry etc.

CAVEATS

translocation > point mutation > amplification

Molecular pathology in soft tissue tumors

• FISH for specific translocations and amplifications

• ARCHER («scattershot method»)

• NGS oder Sanger sequencing for specific point mutations (e.g. IDH1/2, GNAS1)

How do we test?

Advantages and disadvantages

• FISH:

– quick - only one «shot»

– specific - partner not known (BAP)

– cost effective

• ARCHER:

– many potential translocations - expensive

– partner known - time consuming

- good material needed (RNA)

http://archerdx.com/fusionplex-assays/sarcoma

IMFT

EHE ELS ELS

* RMS ESS

Perizytoma ESS

Lipoma ESS

LGFMS, MLS

IMFT: inflammatory myofibroblastic tumor, EHE: epitheloid hemangioendothelioma, ELS: Ewing like sarcoma, ESS: endometrial stroma sarcoma, RMS: rhabdomyosarcoma, LGFMS: low grade fibromyxoid sarcoma, MLS: myxoid liposarcoma, MCS: mesenchymal chondrosarcoma, CFS: congenital fibrosarcoma, DFSP: dermatofibrosarcoma protuberans, SS: synovial sarcoma, SFT: solitary fibrous tumor, ESMC: extraskeletal myxoid chondrosarcoma, ASPS: alveolar soft part sarcoma, ABC: aneurysmal bone cyst, NF: nodular fascitits

Chondroid lipoma MCS

CFS

DFSP

Lipoblastoma IMFT SS

SFT ESMC ASPS

ABC, NF ESS

http://archerdx.com/fusionplex-assays/sarcoma

Angiomatoid fibrous histiocytoma, clear cell sarcoma, angiosarcoma, myoepithelial tumor: EWSR1–ATF1 Clear cell sarcoma: EWSR1–ATF1, EWSR1–CREB1 Desmoplastic round cell tumor: EWSR1–WT1, EWSR1–ERG Extraskeletal myxoid chondrosarcoma: EWSR1–NR4A3 Ewing sarcoma/PNET:

EWSR1–FLI1 EWSR1–ERG EWSR1–NFATC2 EWSR1–FEV EWSR1–ETV1 EWSR1–E1AF EWSR1–SP3 EWSR1–ZNF278 EWSR1–POU5FI

Myxoid–round cell liposarcoma: EWSR1–DDIT3 Low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma: EWSR1-CREB3L1

Fisher C. Histopathology. 2014 Jan;64(1):134-50, Romeo S, Dei Tos AP. Virchows Arch. 2010 Feb;456(2):219-34.

Diagnostically useful markers in dedifferentiated sarcomas

• Dedifferentiated Liposarcoma:

– MDM2 amplification

• Dedifferentiated Chondrosarcoma:

– IDH point mutation (in 60% of cases)

Le Guellec S et al. Am J Surg Pathol. 2014 Mar;38(3):293-304. Amary MF et al. J Pathol. 2011 Jul;224(3):334-43.

Molecular pathology of bone lesions

• USP6 translocation: aneurysmal bone cyst

• H3F3A mutation: giant cell tumor

• H3F3B mutation: chondroblastoma

• GNAS1 mutation: fibrous dysplasia

• BRAF: Erdheim Chester disease

Molecular pathology of adipocytic tumors

• PLAG1 translocation: lipoblastoma

• MKL2 translocation: chondroid lipoma

• MDM2 amplification: atypical lipomatous tumor, dedifferentiated liposarcoma

• FUS-DDIT3 translocation: myxoid liposarcoma

Molecular pathology of fibroblastic/myofibroblastic tumors

• USP6 translocation: nodular faciitis

• B-Catenin mutation: desmoid type fibromatosis

• PDGFRB-COL1A1 translocation: giant cell fibroblastoma, dermatofibrosarcoma protuberans

• ALK, ROS translocation: inflammatory myofibroblastic tumor

• ETV6-NTRK3 translocation: infantile fibrosarcoma

• FUS-CREB3L1/2 translocation: low grade fibromyxoid sarcoma, sclerosing epitheloid fibrosarcoma

• CSF1-COL6A3: tenosynovial giant cell tumor • CAMTA1-WWTR1: epitheloid haemangio-endothelioma • GNAS1 mutation: intramuscular myxoma • HMGA2 translocation: deep angiomyxoma • EWSR1-CREB1 translocation: angiomatoid fibrous

histiocytoma • PHF1 translocation: ossifying fibromyxoid tumor • EWSR1 translocation: myoepithelioma • SS18-SSX translocation: synovial sarcoma • SMARCB1 mutations, deletions: epithelioid sarcoma,

extrarenal rhabdoid tumor • TFE3-ASPSCR1: alveolar soft part sarcoma • EWSR1-ATF1: clear cell sarcoma • EWSR1-WT1: desmoplastic small round cell tumor

Molecular pathology of fibrohistiocytic, vascular and other tumors