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 ISarcomas 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 4th 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. BridgeAdvanced 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

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 Lipoid MPNSTSmooth Muscle Actin

Dedifferentiated:CD34, MDM2/CDK4

S∙100

SMMHC Pleomorphic:Lipoblasts

CD34

Caldesmon S∙100

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 ImmunohistochemistrySarcomatoid Carcinoma

Melanoma Anaplastic Lymphoma

CAM 5.2 S∙100 CD30

AE1/AE3 HMB45 ALK-1

CK903 Melan A

CK5/6 MiTF1

p63

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

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

Wild Type 15%

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

NERD NERD

AE1/AE3 e D Desmin RD

Vimentin ERD CD45

Synaptophysin

N e CD56 N e

Chromogranin N e D S100 N

CD99 E EMA D

FLI1 E Myogenin R

WT1(c) D NSE 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, G2, 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 in myxoid/round cell liposarcoma

1 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 CHROMOGRANIN

Vimentin PR GH

GFAP S∙100 Prolactin

Neu∙N ACTH

Ki67 LH

TSH

FSH

• FISH 1p/19q deletion