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
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. 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
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 (2013) 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
MPNST
Smooth 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 Immunohistochemistry
Sarcomatoid
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
Wild Type 15%
KIT
75%
PDGFRA
10%
Exon 9
8%
Exon 12
2%
Exon 11
65%
Exon 14
Rare
Exon 13
1%
Exon 18
8%
Exon 17
1%
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
NERD
NERD
AE1/AE3
e D
Desmin
Vimentin
ERD
CD45
RD
Synaptophysin
Ne
CD56
Ne
Chromogranin
Ne D
S100
N
CD99
E
EMA
FLI1
E
Myogenin
WT1(c)
D
NSE
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, 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