Sarcomas

Overview

• Sarcomas: rare mesenchymal malignancies; ~1% of adult cancers and ~15% of pediatric cancers. ~17,000 to 18,000 new cases/yr in US (~13,500 to 14,000 soft tissue, ~4,000 bone).
• Categories: soft tissue sarcoma (STS) ~80%, bone sarcoma ~20%; GIST is a separate entity and is the most common sarcoma (see GIST note).
• >100 histologic subtypes: STS (leiomyosarcoma, liposarcoma, undifferentiated pleomorphic sarcoma [UPS], synovial, MPNST, rhabdomyosarcoma, angiosarcoma, dermatofibrosarcoma protuberans [DFSP]); bone (osteosarcoma, Ewing, chondrosarcoma, chordoma).

Etiology / Associated Factors

• Often no defined cause; several factors are associated with different subtypes.
• Radiation: e.g., prior therapeutic RT (sarcomas arise in the field 5 to 20 yrs later; angiosarcoma after breast RT, sarcoma after Hodgkin mantle RT).
• Chemical: vinyl chloride, Thorotrast, and arsenic (hepatic angiosarcoma).
• Genetic: predisposition possible (TP53, APC, NF1, RB1 mutations); each subtype can carry complex unique alterations; more alterations may associate with higher STS risk.
• Chronic lymphedema: angiosarcoma (Stewart-Treves).
• Viruses: HHV-8 (Kaposi sarcoma); EBV (leiomyosarcomas).

Classification of Sarcoma

• WHO classifies STS by tissue of origin; if origin is uncertain, classification is by architectural pattern (e.g., alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma).
• Adult most common STS: GULL (GIST, UPS, Liposarcoma, Leiomyosarcoma).
• Pediatric most common: small round blue cell sarcomas (Ewing / PNET (EWSR1::FLI1 and related FET::ETS fusions), plus the now-distinct CIC-rearranged (CIC-DUX4) and BCOR-rearranged round cell sarcomas) and rhabdomyosarcoma (embryonal and alveolar).

• Vascular: angiosarcoma (hemangiosarcoma, lymphangiosarcoma are older synonyms), hemangioendothelioma. (Hemangiopericytoma is obsolete: now solitary fibrous tumor, a fibroblastic tumor with NAB2::STAT6.)
• Neural: MPNST (granular cell tumor is usually benign). Paraganglioma (neuroendocrine) and neuroblastoma (embryonal neuroblastic tumor) are not soft tissue sarcomas.
• Adipose: liposarcoma. Pleomorphic: pleomorphic liposarcoma, UPS.
• GIST: differentiates toward interstitial cells of Cajal (GI pacemaker cells); KIT/PDGFRA-driven. Smooth muscle: leiomyosarcoma (GI, GU, cutaneous, vascular). Skeletal muscle: alveolar / pleomorphic rhabdomyosarcoma.
• Fibrous: fibrosarcoma, fibromyxoid, desmoid, dermatofibrosarcoma, inflammatory myofibroblastic tumor.
• Unknown tissue: synovial sarcoma, ASPS, epithelioid sarcoma.
• Bone: osteosarcoma (and variants), chondrosarcoma (and variants), giant cell tumor of bone, Ewing sarcoma family. Extraskeletal: osteosarcoma, Ewing sarcoma.

Sarcoma Genesis (key oncogenic drivers)

• GIST: KIT, PDGFR, RAF.
• Myxoid liposarcoma: FUS::DDIT3 (CHOP) in ~90% (rarely EWSR1::DDIT3); PI3K/AKT/PTEN alterations are secondary.
• Dedifferentiated liposarcoma: MDM2, CDK4.
• Neuroblastoma (embryonal tumor, not a sarcoma; for contrast): N-MYC.
• Osteosarcoma: TP53 and RB1.
• Ewing sarcoma: EWS-FLI1.
• DFSP: COL1A1-PDGFB.
• Desmoid tumor: Wnt/beta-catenin activation (CTNNB1 sporadic, APC in FAP); ER expression may occur but is not the oncogenic driver.
• NTRK: infantile fibrosarcoma (>90% of cases).

Genetic Syndromes Associated with Sarcoma

General Workup

• Imaging: contrast-enhanced MRI of primary site (STS) or CT bone / MRI (bone sarcoma); CT chest (lung mets, the most common site of metastatic spread); for some subtypes, PET-CT, bone scan, abdominal/pelvic CT.
• Biopsy: CORE-NEEDLE preferred (or excisional only if planned definitive surgery); avoid violating compartments. Refer to a sarcoma center BEFORE biopsy, since an improper biopsy can compromise limb-sparing surgery.
• Pathology: morphology plus IHC plus cytogenetics / FISH / molecular (key fusion translocations are diagnostic).
• Genetic counseling: young pts, multifocal disease, syndromic features.

Diagnostic Translocations / Fusion Genes (reference)

Note: standard notation lists the 5' partner first: COL1A1::PDGFB (DFSP) and ASPSCR1::TFE3 (ASPS; ASPL = ASPSCR1). Older sources reverse the order, but the 5'/3' order is the convention and the table above is correct.

Key Targetable Molecular Features

• Well-differentiated / dedifferentiated liposarcoma: MDM2 amplification (12q14-15), often with CDK4; MDM2 IHC useful.
• DFSP: COL1A1-PDGFB, imatinib responsive.
• Inflammatory myofibroblastic tumor: ALK rearrangement, crizotinib responsive.
• Tenosynovial giant cell tumor (TGCT): CSF1 fusion. Two FDA-approved CSF1R inhibitors: Pexidartinib (Turalio), FDA Aug 2, 2019 (boxed warning for hepatotoxicity, REMS); Vimseltinib (Romvimza), FDA Feb 14, 2025 (MOTION, Gelderblom Lancet 2024; ORR 40% vs 0% placebo), better tolerated, no REMS.
• NTRK fusions: infantile fibrosarcoma, secretory carcinoma; larotrectinib / entrectinib.
• Epithelioid sarcoma: SMARCB1 (INI-1) loss; tazemetostat (EZH2 inhibitor).

Staging & Prognosis

• AJCC/UICC for STS: tumor size (T: 5/10/15 cm cutoffs, site-specific), grade (FNCLCC G1 to G3), lymph node (rare), distant mets (M); depth is no longer a T subcategory in AJCC 8th ed (still prognostic).
• Nodal spread is rare except in: rhabdomyosarcoma, epithelioid sarcoma, clear cell sarcoma, angiosarcoma.

FNCLCC Grading

• Differentiation score:
  • 1 = sarcoma closely resembling normal adult mesenchymal tissue.
  • 2 = sarcoma for which histologic typing is certain.
  • 3 = embryonal and undifferentiated sarcomas, sarcomas of doubtful type, synovial sarcoma, soft-tissue osteosarcoma, Ewing sarcoma / PNET of soft tissue.
• Mitotic count score: 1 = 0 to 9 mitoses per 10 HPF; 2 = 10 to 19 per 10 HPF; 3 = ≥20 per 10 HPF.
• Tumor necrosis score: 0 = none; 1 = <50% necrosis; 2 = ≥50% necrosis.
• The three scores are summed (total 2 to 8): grade 1 = 2 to 3; grade 2 = 4 to 5; grade 3 = 6 to 8. Grading is not applicable to MPNST (mostly high grade), angiosarcoma, alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, clear cell sarcoma, and epithelioid sarcoma.

Natural History / Prognosis

• ~25% of STS pts develop distant metastatic disease even after curative resection of the primary; this rises to ~50% in high-risk tumors that are >5 cm, deep to fascia, and intermediate or high grade.
• In ~70 to 80% of metastatic cases disease involves the lungs (higher for extremity primaries; other sites: bone, liver, soft tissue, skin, brain).
• Histologic grade is the most important prognostic factor for STS, predictive of distant metastasis and disease-specific OS.
• Coindre et al (FNCLCC, 1240 nonmetastatic STS pts): 5-yr metastasis-free survival 91% (grade 1), 71% (grade 2), 43% (grade 3).

General Treatment Principles

• Surgery: cornerstone, wide local excision with limb-sparing whenever possible; negative margins critical.
• Radiation: pre-op or post-op for high-grade, deep, large STS to ↓ local recurrence (pre-op less fibrosis but more wound complications).
• Adjuvant chemo: controversial in adult STS; consider for young pts, high-grade, >5 cm, deep, chemo-sensitive subtypes (synovial, myxoid liposarcoma, UPS).
• Pediatric / specific subtypes: rhabdomyosarcoma (VAC and alkylators), Ewing (VDC/IE), osteosarcoma (MAP) have chemo as standard.
• Targeted therapy: imatinib (DFSP, GIST), pazopanib (advanced STS, PALETTE), regorafenib (REGOSARC), tazemetostat (epithelioid sarcoma), larotrectinib / entrectinib (NTRK fusion), avapritinib (PDGFRA D842V GIST), selpercatinib (RET fusion).
• Immunotherapy: pembrolizumab has modest activity in select STS (UPS, dedifferentiated liposarcoma; SARC028). ASPS responds to checkpoint inhibitors per separate studies (e.g., atezolizumab).
• Atezolizumab (Tecentriq), ASPS: ML39345 / NCT03141684, NCI-sponsored phase 2 (Chen NEJM 2023, PMID 37672694) in unresectable/metastatic alveolar soft-part sarcoma ≥2 yr; FDA label data cut ORR 24% (12/49), mDOR NR; NEJM final analysis ORR 37% (19/52), mDOR 24.7 mo. FDA Dec 9, 2022. First IO with disease-specific approval in a rare STS subtype.
• TCR-T therapy: afami-cel (afamitresgene autoleucel, Tecelra): FDA Aug 2, 2024 (accelerated, adults); full approval and expansion to age ≥12 yr Jun 22, 2026; for unresectable/metastatic synovial sarcoma after prior chemo, MAGE-A4+ and HLA-A*02:01/02/03/06+ (SPEARHEAD-1, D'Angelo Lancet 2024; ORR 43%, mDOR 6 mo). First engineered cell therapy approved for any solid tumor.

High-Yield Pearls

• Refer to a sarcoma center BEFORE biopsy; improper biopsy can compromise limb-sparing surgery.
• Lung is the dominant metastatic site for most STS.
• FNCLCC grade (differentiation, mitoses, necrosis) is the most important prognostic factor.
• MDM2 amplification = well-differentiated / dedifferentiated liposarcoma.
• Stewart-Treves: angiosarcoma in chronic lymphedema (post-mastectomy).
• NTRK fusion is pan-tumor: larotrectinib / entrectinib.
• Nirogacestat (Ogsiveo), FDA Nov 27, 2023: first FDA-approved therapy for desmoid tumor.
• Afami-cel (Tecelra), FDA Aug 2, 2024 (full approval and age ≥12 yr Jun 2026): first engineered cell therapy for a solid tumor (synovial sarcoma).
• Vimseltinib (Romvimza), FDA Feb 14, 2025: CSF1R inhibitor for TGCT (no REMS, preferred over pexidartinib).