Soft Tissue Tumors

Academy of Pathology and Laboratory Medicine of Puerto Rico April 2013

Bruce Horten, M.D.

Medical Director Integrated Oncology, New York

Part I  Sarcomas In My Consult Practice MFH Evaluation • IHC • Molecular   FISH RT∙PCR Part II   GIST • • IHC Molecular Small Round Cell Tumors • IHC • Molecular Brain Tumor Evaluation

Explosion of Interest in Soft Tissue Tumors

• WHO Classification of Tumors of Soft Tissue and Bone 4 th Edition 2013 Editors include C. Fletcher, J. Bridge • USCAP Annual Meeting, Baltimore 2013 * Long Course

Soft Tissue Tumors

C. Fletcher, C. Antonescu * Special Courses

Practical Guide to Molecular Testing in Cancer

J. Bridge

Advanced Molecular Pathology

F. Barr • New York Pathological Society, Saturday May 4

President’s All Day Symposium: Soft Tissue Neoplasms

C. Antonescu, C. Fletcher, M. Miettinen

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Most Common Sarcoma Diagnoses

Currently a very elusive statistic  Dependant on a site’s approach to malignant fibrous histiocytoma.

 As a result, very few current texts offer such a statistic.

• • Enzinger/Weiss or Rosai   In adults, spindle cell sarcomas dominate.

• 35-45% MFH and liposarcoma.

In childhood, round cell sarcomas dominate. • Rhabdomyosarcoma, neuroblastoma, PNET / Ewing’s.

Current WHO (20 13) on sarcomas    75% include undifferentiated pleomorphic sarcoma, liposarcoma, leiomyo-, myxofibro-, synovial sarcoma and MPNST.

75% highly malignant 75% in extremities (esp. thigh)

Malignant Fibrous Histiocytoma (MFH)

• Now considered a diagnosis of exclusion.

• The most high grade, poorly differentiated myofibroblastic or fibroblastic sarcoma.

• To properly evaluate such a tumor, it is now considered essential to exclude (usually via immunohistochemistry) more specific entities.

• If all investigations come up negative, the new term of choice is:

“Undifferentiated Pleomorphic Sarcoma (UPS)”

What Has Become of MFH?

• Fletcher Study (

AJSP

1992;16:213-228)  61% Pleomorphic sarcoma with specific differentiation  13% Pseudosarcoma  26% Remain MFH though now termed UPS

What Are The Specific Subtypes (61%)?

• About 1/3 are myogenic including:   Leiomyo- and rhabdomyo- sarcoma However the rhabdo subtype is very rare • Another 1/3 are liposarcomas including:  Dedifferentiated (abdomen) and pleomorphic • A final 1/3 includes:   Myxofibrosarcoma and Malignant peripheral nerve sheath tumor

Do These Subtypes Really Matter?

• The myoid subtypes are very aggressive with a highly metastatic rate (70% to >90%). 5 yr.

• The liposarcoma subtypes are less aggressive with a 5 yr. metastatic rate of 15% (dedifferentiated) to 40% (pleomorphic).

Pseudosarcomas (13%)

• Sarcomatoid carcinoma. Most common.

• Melanoma • Anaplastic lymphoma

How Are These MFH-like Entities Recognized?

• Principally By Immunohistochemistry

Myoid

Smooth Muscle Actin SMMHC Caldesmon

Lipoid

Dedifferentiated: CD34, MDM2/CDK4 Pleomorphic: Lipoblasts S∙100 S∙100

MPNST

CD34 Calponin Desmin Myogenin

• But Also By Using Molecular Techniques • Above all gene fusions  Translocations    Inversions Deletions Duplications • Examples   DDIT3 (CHOP) FISH break-apart probe • Myxoid liposarcoma FOX01 (FKHR) FISH break-apart probe • Alveolar rhabdomyosarcoma

How Are Pseudosarcomas Recognized?

• By Immunohistochemistry

Sarcomatoid Carcinoma

CAM 5.2

S∙100

Melanoma

CD30

Anaplastic Lymphoma

ALK-1 AE1/AE3 CK903 CK5/6 p63 HMB45 Melan A MiTF1

And What of the Remaining Undifferentiated Pleomorphic Sarcoma?

• By immunohistochemistry, focal smooth muscle actin may be seen but no desmin reactivity. The pattern for myofibroblasts.

• By molecular techniques, largely nonspecific. BUT by CGH (Comparative Genomic Hybridization) some shared factors with pleomorphic leiomyosarcoma.

Part II Gastrointestinal Stromal Tumors

 Most common mesenchymal tumor of the gastrointestinal tract  At least ½ in the stomach of which ¼ of these gastric tumors are malignant

Gastrointestinal Stromal Tumors Cell of origin: Interstitial cells of Cajal

• Immunohistochemistry:  DOG1 – Most sensitive marker. Also ANO-1.

   CD117 (KIT) CD34 With exclusions S100 and SMA • Prognostic Factors:   Tumor size: 2,5,10,>10 cm.

Mitotic activity: ≤ or > 5 per 50 hpf  Anatomic site: gastric vs. small intestinal

Mutations in GIST

Wild Type 15% KIT 75% Exon 9 8% Exon 11 65% Exon 13 1% Exon 17 1% PDGFRA 10% Exon 12 2% Exon 14 Rare Exon 18 8% Includes D842V

Predictive Value of Mutations

• Exon 11 mutation KIT (65%)  Favorable survival and response to Imatinib (Gleevec) • Exon 9 mutation KIT (8%)  Best response to Imatinib if dose is doubled to 800 mg.

• Exon 18 (D842V) PDGFRA (8%)  Resistent to Imatinib • Wild type (15%)  Regular dose of Imatinib but response variable

Small Round Cell Tumors of Childhood

• Neuroblastoma • Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) • Rhabdomyosarcoma • Desmoplastic small round cell tumor

IHC Analysis of Small Round Cell Tumors

AE1/AE3 Vimentin Synaptophysin Chromogranin CD99 FLI1 WT1(c) NERD e D ERD N e N e D E E D Desmin CD45 CD56 S100 EMA Myogenin NSE NERD RD N e N D R NE D

• • •

Neuroblastoma

The most common of the small round cell tumors outside the CNS.

 Grading systems At least 5 are proposed.

   Differentiation is key.

• 5%: Neuropil with ganglion cells Age: 2 yrs.

Mitotic rate: 10/10 hpf    Other prognostic factors IHC: CD45, S∙100 favorable CD44, BCL2, P-glyoprotein unfavorable Flow: Aneuploid and 100% S, G 2 , M phases favorable FISH: NMYC Amplification in 25%. Unfavorable .

• • • Ewing’s Sarcoma/ Primitive Neuroectodermal Tumor   Older and broader age range than neuroblastoma. Also broader sites of origin from bone to soft tissues.

 95% of cases feature the fusion of the EWS gene at 22q12 with another gene especially FLI-1 (80-90%).

Translocation: t(11;22) Fusion gene: EWSR1-FLI-1 Protein: FLI-1 (nuclear) IHC CD99 and FLI-1 versus NSE in neuroblastoma

EWSR1 And Its Partners

At Least 9 Different Partners In Ewing’s/PNET 3 in myoepithelial tumor of soft tissue 2 in clear cell sarcoma 1 in extraskeletal myxoid chondro sarcoma 1 1 in myxoid/round cell liposarcoma in desmoplastic small round cell sarcoma

Rhabdomyosarcoma

Embryonal versus Alveolar     Sites: • Head/neck and urogenital vs. extremities Cytology/Histology Prognosis IHC: • Myogenin, desmin, sarcomeric actin

Molecular Analysis of Rhabdomyosarcoma

• Embryonal  No distinctive genetic features • Alveolar  FOXO1 (FKHR)   Translocations 2;13 (PAX3-FOX) more aggressive than 1;13 (PAX 7-FOX) NMYC in about 50% of alveolar subtype

Brain Tumor Evaluation

• Immunohistochemistry CAM 5.2

EMA Vimentin GFAP Neu∙N Ki67 PR S∙100 CHROMOGRANIN GH Prolactin ACTH LH TSH FSH • FISH 1p/19q deletion