Soft Tissue Sarcoma (STS)

Overview

Epidemiology & Distribution

• Most common site: Thigh (44% of extremity STS), followed by other proximal limb locations
• Extremity > retroperitoneum > intraperitoneal in frequency
• Age linked to histologic subtype: Rhabdomyosarcoma, alveolar soft part sarcoma, and neurofibroma affect children/young adults; most adult STS is sporadic in middle-aged to older patients
• Wide clinical spectrum: from indolent low-grade neoplasms (e.g., well-differentiated liposarcoma) to highly aggressive tumors (e.g., angiosarcoma, desmoplastic small round cell tumor)

Risk Factors

Germline / Hereditary Syndromes

Environmental / Acquired

• Radiation exposure - post-radiation angiosarcoma; Stewart-Treves syndrome (lymphangiosarcoma in chronic lymphedema post-mastectomy)
• Chemical carcinogens (vinyl chloride, arsenic, dioxin) - hepatic angiosarcoma

Classification: Major Subtypes

1. Undifferentiated Pleomorphic Sarcoma (UPS)

• Previously called malignant fibrous histiocytoma (MFH)
• Location: Deep soft tissues of extremities, especially the thigh; middle-aged/older adults
• Histology: Sheets of large anaplastic polygonal cells with hyperchromatic bizarre nuclei; storiform (cartwheel) pattern of spindle and histiocytic cells around slit-like vessels; abundant atypical mitotic figures
• Complex karyotype from genomic instability
• Metastases in 17-50% of cases; generally poor prognosis

2. Liposarcoma

• Rarely arise in the subcutaneous tissues
• Hallmark: lipoblasts (signet ring-shaped cells); IHC: MDM2-positive
• Subtypes:
  • Well-differentiated (low-grade, t(12;16) or 12q13-15 amplification)
  • Dedifferentiated
  • Myxoid/round cell - translocation t(12;16)(q13;p11) - FUS-DDIT3 fusion
  • Pleomorphic (high-grade)

3. Rhabdomyosarcoma (RMS)

• Most common pediatric STS
• Alveolar subtype: translocation t(2;13) - PAX3-FOXO1 fusion
• Treatment: chemotherapy ± limb salvage surgery (unlike most other STS)

4. Synovial Sarcoma

• Common in young adults; foot and lower extremity
• Translocation t(X;18) - SYT-SSX fusion products
• One of the ESARC tumors (lymph node metastasis risk)

5. MPNST (Malignant Peripheral Nerve Sheath Tumor)

• NF-1 associated or de novo
• Histology: spindle cells in sweeping fascicles, whorled/nodular areas; S-100 positive on IHC

6. Leiomyosarcoma

• Histology: fascicular growth with spindle cells intersecting at right angles; IHC: SMA and desmin positive

7. Angiosarcoma

• Cells resemble vascular endothelium
• Highly malignant; lymph node and cutaneous metastases common
• Associated with Stewart-Treves syndrome
• May require amputation for local control

8. Epithelioid Sarcoma

• Most common STS of the hand; occurs in young adults
• Part of ESARC group (lymph node metastasis)

9. Clear Cell Sarcoma

• Common tumor of lower extremity/foot; young adults
• Lymph node metastasis risk (ESARC)

Epithelioid sarcoma, Synovial sarcoma, Angiosarcoma, Rhabdomyosarcoma, Clear cell sarcoma

Staging

Diagnosis

Presentation

• Most common presentation: painless mass without prior evaluation
• Mimics include hypertrophic scar, myositis ossificans, hematoma, abscess, lipoma, cyst
• Red flags warranting workup: mass >5 cm, deep to fascia, fixed, growing

Imaging

• MRI - imaging modality of choice for trunk/extremity STS
  • T1: decreased signal
  • T2: increased signal
  • Characterizes tumor relationship to neurovascular structures
• Chest CT - most frequent site of metastasis is the lung
• Additional imaging per subtype: abdomen/pelvis CT for myxoid liposarcoma, epithelioid sarcoma, leiomyosarcoma; paraspinal MRI for myxoid liposarcoma; brain imaging for alveolar soft part sarcoma, clear cell, angiosarcoma

Biopsy

• Core-needle biopsy is the standard approach (percutaneous, image-guided)
• Open incisional biopsy if core needle is non-diagnostic
• Biopsy tract must be oriented so it can be resected en bloc with the specimen
• Small (≤2 cm), superficial, mobile masses may be excised upfront with wide margins in selective cases
• Molecular/NGS testing is increasingly routine - changed diagnosis in 13% of patients in one series; FISH/RT-PCR for specific translocations

Treatment

Trunk and Extremity STS

• Wide local resection with negative margins is the cornerstone of treatment
• Limb salvage surgery (LSS) has replaced amputation as the standard; equivalent survival outcomes with better functional results

• Lesions >5 cm: LSS + radiation (XRT) - pre- or postoperative
• Lesions <5 cm, subcutaneous: LSS alone may suffice
• Preoperative radiation: lower total dose, smaller field, higher rate of wound complications
• Postoperative radiation: lower wound complication rate, but larger field and higher total dose

• Standard first-line: doxorubicin ± ifosfamide
• Rhabdomyosarcoma: chemotherapy is a primary treatment modality (VAC regimen)
• Subtype-specific agents: trabectedin for leiomyosarcoma and myxoid liposarcoma; pazopanib for non-adipocytic STS; imatinib for GIST (KIT/PDGFRA mutation)

Retroperitoneal STS

• Surgery remains the cornerstone but complete resection is more challenging
• Higher local recurrence rates than extremity STS
• Role of preoperative radiation is being actively studied

Molecular Features Summary

Recent Evidence (2024-2025)

• Pembrolizumab + radiation + surgery vs. radiation + surgery for Stage III extremity STS (SU2C-SARC032, Lancet 2024, PMID 39547252) - evaluating immunotherapy integration in localized disease
• Doxorubicin-trabectedin + trabectedin maintenance vs. doxorubicin alone in leiomyosarcoma (NEJM 2024, PMID 39231341) - showed improved progression-free survival with combination therapy

Key Clinical Pearls (Miller's Orthopaedics)

• All STS subtypes share the same presentation, imaging, treatment, and differential - it is histology (and molecular signature) that distinguishes them
• ESARC = the 5 STS subtypes prone to lymph node metastasis
• NF-1 → MPNST; Stewart-Treves → angiosarcoma; FAP → desmoid
• Characteristic locations: Hand = epithelioid sarcoma; Foot = clear cell / synovial sarcoma
• Biopsy tract orientation is critical - must be excisable en bloc with the tumor

• Sabiston Textbook of Surgery, 21st ed., Ch. 64 (Soft Tissue and Retroperitoneal Sarcoma)
• Miller's Review of Orthopaedics, 9th ed., Ch. 9 (Table 9.19, ESARC)
• Robbins, Cotran & Kumar Pathologic Basis of Disease (Undifferentiated Soft Tissue Sarcoma)