Tumor Patterns. Common Morphologic Patterns in Soft Tissue Tumors. Update on Lipomatous Tumors. MFH-like. Highly cellular spindle cell pattern

(1)

Update on Lipomatous Tumors

Common Morphologic Patterns

in Soft Tissue Tumors

John R. Goldblum, M.D.

Chairman, Department of Anatomic Pathology The Cleveland Clinic

Professor of Pathology Cleveland Clinic Lerner College of Medicine

Cleveland, Ohio

Tumor Patterns

• MFH-like

• Highly cellular spindle cell pattern

• Myxoid soft tissue lesions

(2)

MFH-like Pattern

• Pleomorphic sarcoma with a specific

line of differentiation

• Dedifferentiated sarcoma

• Pseudosarcoma with MFH-like pattern

(3)

Update on Lipomatous Tumors

Pleomorphic Sarcomas

• Pleomorphic liposarcoma pleomorphic lipoblasts

• Pleomorphic MPNST nerve origin; arises from NF S100+ in NF-1; EM

• Pleomorphic leiomyosarc diffuse SMA/MSA/desmin; EM

• Pleomorphic RMS skeletal muscle markers; EM

• Extraskeletal osteosarcoma malignant bone/osteoid

MFH-like Pattern

Dedifferentiated Sarcoma

• Well-differentiated liposarcoma

• Chondrosarcoma

• Chordoma

• Dermatofibrosarcoma protuberans

(4)

MFH-like Pattern

Pseudosarcomas

• Sarcomatoid carcinoma

• Sarcomatoid mesothelioma

• Melanoma

(5)

Update on Lipomatous Tumors

Pseudosarcomas

Tumor

Useful markers

Sarcomatoid CA

Cytokeratins

(multiple)

Sarcomatoid mesoth

CAM 5.2

Melanoma

S-100

(+/- melanocytic markers)

Anaplastic lymphoma CD30; ALK-1

MFH: Fact or Fiction?

159 Pleomorphic Tumors

Pleomorphic sarcoma

Pseudosarcomas

with specific

(N=20; 12.6%)

differentiation

(N=97; 61%)

Unclassifiable ?MFH

(N=42; 26.4%)

Highly Cellular

Spindle Cell Tumors

• Cellular schwannoma

• MPNST

• Fibrosarcoma

• Leiomyosarcoma

(6)

Cellular Schwannoma

Definition

• Highly cellular schwann cell

proliferation composed predominantly/

exclusively of Antoni A areas

• Absence of well-formed Verocay

(7)

(8)

S100

Cellular Schwannoma

Worrisome Features

• High cellularity

• Mitotically active (usual < 4/10HPF)

• Nuclear atypia

• Focal necrosis

• Bony erosion

* THE PERFECT PSEUDOSARCOMA*

Cellular Schwannoma

Behavior

Recurred Bony erosion Mets F/U (mean)

Woodruff

(14)

0%

7%

0% 2.2 yrs

Fletcher

(18)

5%

11%

0% 14 yrs

White

(58)

5%

19%

0% 7 yrs

(9)

Update on Lipomatous Tumors

Desmin

(10)

S100

Cellular Schwannoma vs MPNST

focal (60%) diffuse S-100 + (10%) -Divergent diff. 3+ 1+ - 2+ Mitoses 3+ 1+ - 2+ Pleomorphism common rare Necrosis 3+ 3+ Cellularity -+ Encapsulated MPNST Cellular schwannoma

(11)

(12)

AE1/3

(13)

Update on Lipomatous Tumors

Spindle Cell Sarcomas

Cytokeratin Subsets

2/28 (7%) 26/29 (88%) CK7 0/28 (0%) 26/29 (88%) CK19 10/28 (36%) 25/29 (86%) EMA or AE1/3 21/28 (75%) 10/29 (34%) S-100 MPNST Monophasic SS

TA Smith et al, AJCP, 1999

Synovial Sarcoma

t(x;18)(p11;q11)

SSX1

SYT

SSX2

SSX4

SYT (18q11) - Break Apart Probe

SYNOVIAL SARCOMA

POSITIVE

(14)

Cellular Spindle Cell Pattern

rare -Fibrosarcoma + -Leiomyosarcoma -+ 30% (focal) Synovial sarcoma -60% (focal) MPNST -+(diffuse) Cellular schwannoma SMA CK7/19 S-100

*CD99 and bcl-2 often in synovial sarcoma

Myxoid Soft Tissue Lesions

Benign • Nodular fasciitis • Myxoma • intramuscular • juxta-articular • cutaneous

• Nerve sheath tumors

• neurofibroma • neurothekeoma Malignant • Myxoid liposarcoma • Myxofibrosarcoma (“myxoid MFH”) • Myxoid chondrosarcoma

• Low-grade fibromyxoid sarcoma

• DFSP

• All other sarcomas

Evaluation of

Myxoid Soft Tissue Lesions

• Cellularity

• Cellular arrangement

• Pleomorphism

(15)

(16)

(17)

Update on Lipomatous Tumors

ARS slide to follow

Q: What is the best diagnosis?

1. Myxoma

2. Neurofibroma

3. Myxoid liposarcoma

4. Myxofibrosarcoma

(18)

Myxoid Soft Tissue Tumors

Tumor Defect Genes

Myxoma activating Gsαmutations

LGFMS/HSCT t(7;16)(q33;p11) CREB3L2/FUS t(11;16)(p11;p11) CREB3L1/FUS MLS/RCLS t(12;16)(q13;p11) DDIT3/FUS t(12;22)(q13;q12) DDIT3/EWS ESMCS t(9;22)(q22;q12) NR4A3/EWS t(9;17)(q22;q11) NR4A3/TAF2N MyxoFS None characteristic

Myxoid Soft Tissue Lesions

Random,thick Cords, chains Low Low-mod Myxoid CS Plexiform, fine Even cell distribution Low Low Myxoid LS Curvilinear; thick Perivascular cellularity Low-mod Low-mod Low-grade MFS Prominent in myxoid zones Abrupt myxoid collagen zones; swirling None-low Low Evans’ tumor Few Even cell distribution None Low Myxoma Vessels Architecture Atypia Cellularity Tumor

(19)

Update on Lipomatous Tumors

Round Cell Tumors

Benign

• Glomus Tumor

• Eccrine Spiradenoma

• Giant Cell Tumor

Round Cell Pattern

• ES/PNET

• Rhabdomyosarcoma

• Neuroblastoma

• Lymphoma

• DSRCT

• Mesenchymal

chondrosarcoma

• Round cell liposarcoma

• Small cell osteosarcoma

• Synovial Sarcoma

• Small cell/Merkel cell

(20)

PAS/D

(21)

Update on Lipomatous Tumors

ES/PNET: Histologic Spectrum

ES

PNET

Cell shape

regular

irregular

Chromatin

fine

coarse

Nucleoli

pinpoint

prominent

Glycogen

abundant

scant

Rosettes

absent

present

ES/PNET: Ultrastructure

_{ES/PNET: Ultrastructural Spectrum}

Feature

ES

PN

Organelles

scarce

abundant

Dense-core granules

absent

abundant

Neurotubules

absent

abundant

(22)

CD99

MIC - 2 Gene Product (CD99)

Diagnosis

Positive (%)

ES/PNET

93%

Small Cell Osteosarcoma

12%

Desmoplastic Round Cell Tumor

20%

Neuroblastoma

0%

Rhabdomyosarcoma

15%

Small Cell Carcinoma

9%

T-LL/ALL

92%

ES/

PNET

: Cytogenetics

t(11;22)(q24;q12) –

FLI1;EWS

Translocation

EWS FLI1

NH2 COOH

ETS DNA binding domain

t(21;22)(q22;q12) ERG;EWS t(7;22)(p22;q12) ETV1/EWS t(17;22)(q12;q12) FEV/EWS t(2;22)(q33;q12) E1AF/EWS

EWS (22q12) Break-apart probe

t(11;22), t(21;22) – EWS/PNET (FLI1/EWS, ERG/EWS) t(11;22) - DSRCT (WT-1/EWS)

t(12;22) – Clear Cell Sarcoma (ATF1/EWS) t(9;22) – ES Myxoid Chondrosarcoma (NR4A3/EWS) t(12;22) – Myxoid/Round Cell Liposarcoma (DDIT3/EWS)

(23)

(24)

Rhabdomyosarcoma

Classification

Conventional Scheme

• Embryonal

• Botryoid

• Alveolar

• Pleomorphic

(25)

Update on Lipomatous Tumors

Rhabdomyosarcoma

Classification

Scheme K (inter) K (intra)

Modified Conventional

0.451

0.605 SIOP

0.406

0.573 NCI

0.384

0.579 Cytohistologic

0.328

0.508

Asmar L et al. Cancer, 1994

Rhabdomyosarcoma

International Classification

Favorable Prognosis

• Botryoid

• Spindle cell

Intermediate Prognosis

• Embryonal

Poor Prognosis

• Alveolar

Newton WA et al, Cancer 1995

Rhabdomyosarcoma

Myogenic Markers

Desmin HHF-35 Sarcomeric actin SMA

Embryonal (n=61) 58 58 44 9 Alveolar (n=19) 19 19 12 2

Botryoid (n=9) 9 9 6 0

Spindle cell (n=6) 6 6 5 0

Total (n=95)

97% 97% 71% 12%

(26)

MyoD1/Myogenin

• part of the Myo-D superfamily of genes

• encode for DNA binding proteins which

activate transcription of skeletal

muscle-specific genes

• results in commitment to skeletal muscle

differentiation

• can detect skeletal muscle differentiation

at an earlier stage than with markers

currently available

Myogenin

Myogenin in Pediatric Tumors

Tumor

Cases stained

Rhabdomyosarcoma (69)

69/69 (100%)

• Alveolar (48)

• Embryonal (20)

• Spindle cell (1)

Other pediatric sarcomas (50)

0/50 (0%)

• ES/PNET (16) • DSRCT (6) • Neuroblastoma (4) • Others (24)

Alveolar Rhabdomyosarcoma

t(2;13)(q35;q14)

t(1;13)(q36;q14)

PAX3/FKHR

PAX7/FKHR

(27)

Update on Lipomatous Tumors

Alveolar Rhabdomyosarcoma

Fusion Transcript Subtype

PAX3/FKHR PAX7/FKHR

Age Adolescents Young children Site Wide distribution Extremities Stage Metastatic Localized Prognosis Poor Better

(28)

Desmin

Desmoplastic Round Cell Tumor

• Gender: 90M / 19F

• Age: 6-49 years (mean: 22 years)

• Sites:

• Abdominal cavity

103

• Thoracic region

4

• Cranial fossa

1

• Extremity

1

• Prognosis: poor, but may respond to

aggressive therapy

Gerald W et al, J Clin Oncol 1998

Desmoplastic

Round Cell Tumor

CK

86%

Vim

97%

WT-1

95%

Des

90%

NSE

81%

CD99

20%

Desmoplastic Small Round Cell Tumor

(29)

Update on Lipomatous Tumors

Round Cell Pattern

CD99 TdT Myo CAM5.2 CK20 Des

ES/PNET 95% - - 20% -

-RMS 15% - + - - +

DSRCT 20% - - + - + (dot-like)

Lymphoma 90% + - - - -Small Cell <10% - - 35% Rare -Merkel Cell <10% - - + +