Approach to spindle cell tumors .docx

POSTGRADUATE NOTES

1. Approach to spindle cell tumors
Step 1: Age, size and site of tumor, growth characteristics
Step 2: Morphology of the tumor
Step 3: IHC application
Step 4: Molecular diagnostics
AGE
Children Elderly
Infantile myofibromatosis Limbs – undifferentiated spindle cell sarcoma
Fibromatosis colli Head & neck – spindle cell carcinoma, spindle cell malignant
melanoma, atypical fibroxanthoma, spindle cell angiosarcoma
Inclusion body fibromatosis Retroperitoneum – dedifferentiated liposarcoma
Calcifying aponeurotic fibromaExtremities – Kaposi sarcoma
Infantile fibrosarcoma Undifferentiated pleomorphic sarcoma (malignant fibrous
histiocytoma) is limited to adults
SITE
■Deep : sarcomas
–Exceptions include following are superficial soft tissue sarcoma.
DFSP – Dermatofibrosarcoma protuberans 
Epithelioid sarcoma
Kaposi sarcoma
Angiosarcoma
■Superficial : mostly benign
–Exceptions (metastatic carcinoma and melanoma)
MORPHOLOGY
1.Architectural pattern of the tumor
2.Encapsulation
3.Cellularity
4.Appearance of the cells
5.Amount and type of matrix formation
6.Tumor and adjacent tissue interfaces
7.Vascularity
8.Tumor necrosis
9.Mitotic activity
ARCHITECTURAL PATTERN
Storiform
Cart wheel like
1)DFSP
2)Malignant fibrous histiocytoma
3)Neurofibroma
4)Perineuroma
5)Nodular fasciitis
Fascicular 1)Fibromatosis
2)Cellular fibroma
3)Cellular schwannoma
4)Fibrosarcoma
5)Leiomyosarcoma
6)Spindle cell RMS
7)Synovial sarcoma
8)MPNST
9)Low-grade fibromyxoid sarcoma
Lobular/plexiform 1)Spindle cell lipoma
2)Liposarcoma
Palisading 1)Schwannoma

2. spindle 2)MPNST
3)Leiomyosarcoma
4)Extragastrointestinal stromal tumor - GIST
5)Rarely Synovial sarcoma
IHC
INTERMEDIATE FILAMENTS
1)Vimentin – mesenchymal tumors
2)Desmin – benign and malignant smooth muscle tumors
3)Glial fibrillary acid protein (GFAP) – gliomas
4)Cytokeratin - carcinomas
5)Neurofilaments – neural and neuroblastic tumors
CO-expression of vimentin and desmin – muscle cells
CO-expression of vimentin and GFAP – some Schwann cells
Cytokeratin expressed by:
1)Carcinomas
2)Epithelioid sarcoma
3)Synovial sarcoma
4)Mesothelioma
5)Rhabdoid tumor
6)Some angiosarcomas and leiomyosarcomas
Vimentin expressed by:
1)Sarcomas
2)Melanoma
3)Lymphoma
4)Some carcinomas
MARKERS OF MUSCLE DIFFERENTIATION
■Intermediate filament desmin
■Actin isoforms
■Myogenic transcription factors (MyoD family)
1.MyoD1
2.Myogenin
3.Myf5
4.MRF4
■Myoglobin – skeletal and cardiac muscle (not in smooth muscle)
■Others – myosin, creatinine kinase subunit M, titin.
Myogenic nuclear regulatory proteins (myogenin, MyoD1) - Specific for Rhabdomyosarcoma.
HHF35 expressed by benign and malignant skeletal muscle tumors.
Smooth and skeletal muscle actins (HHF35) & Smooth muscle actin (1A4)
Benign and malignant smooth muscle tumors
Myofibroblastc tumors
Pseudotumors
Epithelial membrane antigen
1)Synovial sarcoma
2)Perineuroma
MARKERS OF NERVE SHEATH DIFFERENTIATION
S-100 – Strong diffuse positivity in cellular schwannoma, malignant melanoma. Benign and malignant
peripheral nerve sheath tumors. Normal adipose tissue. Langerhan cells.
Claudin 1 – useful marker in perineurioma. Not in neurofibroma, schwannoma, low-grade fibromyxoid
sarcoma, desmoplastic fibroblastoma, DFSP and fibromatosis. Abberant expression in synovial sarcoma
and EFT
NEUROECTODERMAL MARKERS
CD99 – Plays a role in cellular adhesion and regulation of cellular proliferation.
oMost important use – EFT and many synovial sarcomas.
CD56 (Neural cell adhesion molecule)

3. oWidespread among sarcomas. Not useful in evaluating spindle cell soft tissue tumors.
MARKER OF MELANOCYTE DIFFERENTIATION
♠SOX10 - Neurofibroma (90%), Schwannoma (100%), MPNST (30%).
MARKERS OF ENDOTHELIAL DIFFERENTIATION
1)Factor VIII-Related antigen (von Willebrand factor)
2)CD34 (Human hematopietic progenitor cell antigen)  solitary fibrous tumor, synovial sarcoma, DFSP
and GIST
3)CD31 (Platelet endothelial cell adhesion molecule-1)
4)FLI-1 and ERG proteins
5)Claudin-5
6)VEGFR-3
7)Human Herpes virus-8 (HHV8)  Latency associated nuclear antigen (LANA)  Kaposi sarcoma.
OTHER MARKERS
TLE-1  Poorly differentiated synovial sarcoma showing TLE-1 expression, even in CK negative
synovial sarcoma.
MUC4
CD68
Bcl-2
PROGNOSTIC MARKERS
Ki-67
P53
p21W1
P16 and P27kip
♣Panel for monomorphic spindle cell tumors include cytokeratins, S-100, CD34 and SMA.
ANCILLARY TESTING SOFT TISSUE TUMORS
TUMOR TYPE TRANSLOCATION FUSION GENE
EWING SARCOMA / PNET t (11:22) EWSR1 – FLI1
t (21:22) EWSR1 – ERG
t (7:22) EWSR1 –ETV1
t (17:22) EWSR1 – ETV4
t (2:22) EWSR1 – FEV
DESMOPLASTIC SMALL
ROUNDCELL TUMOR t (11:22) EWSR1 – FLI1
t (21:22) EWSR1 – ERG
MYXOID ROUND CELL
LIPOSARCOMA t (12:16)
t (12:22)
ALVEOLAR
RHABDOMYOSARCOMA t (2:13) PAX3 – FOXO1
t (1:13) PAX7 – FOXO1
CLEAR CELL SARCOMA t (12:22) EWSR1 – ATF1
t (2:22) EWSR1 – CREB1
ANGIOMATOID FIBROUS
HISTIOCYTOMA t (12:22) EWSR1 – ATF1
t (2:22) EWSR1 – CREB1

4. EXTRASKELETAL MYXOID
CHONDROSARCOMA t (9:22)
ALVEOLAR SOFT TISSUE
SARCOMA t (X:17)
SYNOVIAL SARCOMA t (X:18) SS18 – SSX1
t (X:18) SS18 – SSX
t (X:18) SS18 – SSX4
DERMATOFIBROSARCOMA
PROTUBERANS t (17:22) COL1A1 - PDGFB
LOW GRADE FIBROMYXOID
SARCOMA t (7:16)
INFANTILE
FIBROSARCOMA t (12:15)
INFLAMMATORY
MYOFIBROBLASTIC
TUMOR t (1:2) TMP3 - ALK
t (2:19) TMP4 - ALK
NEW IN BONE AND SOFT TISSUE PATHOLOGY 2023
GUIDELINES FOR MOLECULAR TESTING
Fluorescence in-situ hybridization (FISH) –
Dual-color dual-fusion probes
Dual-color break-apart probes
EWSR1 fusion
MDM2 amplification
Reverse-transcriptase polymerase chain reaction (RT-PCR) –
Gene rearrangements
Genetic breakpoints
New fusion partners
Next-generation sequencing (NGS) –
For detection of both prognostic and therapeutic mutations.
New RNA-based method  hybrid-capture and anchored multiplex PCR  detects gene rearrangements.
Methylation testing - @CpG island.
ADIPOCYTIC:
Lipoma and well-differentiated/ dedifferentiated liposarcoma MDM2 amplification.
RB1 deletion  spindle cell/pleomorphic lipoma.
Myxoid liposarcoma  translocations involving DDIT3 and FUS.
FIBROBLASTIC/MYOFIBROBLASTIC :
Nodular fasciitis, myositis ossificans, fibro-osseous pseudotumor of the digit, aneurysmal bone cyst,
fibroma of tendon sheath  USP6 gene rearrangements.
Solitary fibrous tumor  NAB2::STAT6 fusion.
Dermatofibrosarcoma protuberans  COL1A1::PDGFB fusion.
Inflammatory myofibroblastic tumor: ALK rearrangement.
VASCULAR
Epithelioid hemangioma is defined by recurrent fusions involving FOS and FOSB.
Epithelioid hemangioendothelioma: WWTR1::CAMTA1 fusion or rarely TFE3::YAP1 fusion.
Pseudomyogenic hemangioendothelioma: FOSB gene fusions, usually with SERPINE1 or ACTB.

5. Angiosarcoma MYC gene amplifications. Glomus tumor  MIR143::NOTCH1/2/3
SKELETAL MUSCLE
Alveolar rhabdomyosarcoma: FOXO1 fusion with either PAX3 or PAX7.
Embryonal rhabdomyosarcoma - mutations in the RAS genes or DICER1 in some syndromic patients.
Gastrointestinal stromal tumor (GIST)
Mutations involving KIT (exons 9, 11, 13, 14, 17) and mutation in PDGFRA (exons 12, 14, and 18).
SDH-deficient GIST are negative for KIT and PDGFRA mutations in SDHA, SDHB, SDHC, SDHD.
UNCERTAIN DIFFERENTIATION AND ROUND CELL TUMORS
Angiomatoid fibrous histiocytoma: EWSR1::ATF1, FUS::ATF1, EWSR1::CREB1.
Ossifying fibromyxoid tumor: PHF1 rearrangements, rarely BCOR or SUZ12 rearrangement.
Extraskeletal myxoid chondrosarcoma: NR4A3 rearrangement, most commonly with EWSR1.
Phosphaturic mesenchymal tumor  FN1::FGFR1 or FN1::FGF1.
BONE AND CARTILAGE
Aneurysmal bone cyst: USP6 gene rearrangement.
Low-grade central osteosarcoma/parosteal osteosarcoma: MDM2 amplifications.
Giant cell tumor of bone/chondroblastoma: mutations in H3F3A or H3F3B.
Conventional chondrosarcoma: IDH1 or IDH2 mutations.
Mesenchymal chondrosarcoma: HEY1::NCOA2 fusion