What is the diagnosis, prognosis, and treatment approach for patients presenting with sarcomas, including predisposing factors?

Diagnosis, Prognosis, and Management of Sarcomas

Sarcomas require multidisciplinary management in specialized centers with expertise in these rare tumors, with treatment decisions based on histological subtype, grade, size, and location to optimize patient survival and quality of life.

Diagnosis

Clinical Presentation

• Soft tissue sarcomas typically present as painless masses
• Bone sarcomas may present with pain, swelling, or pathological fractures
• Retroperitoneal sarcomas may present with abdominal pain, fullness, or organ compression symptoms
• Uterine sarcomas often present with abnormal bleeding or pelvic pain

Diagnostic Workup

1. Imaging:

   • MRI for extremity/trunk lesions (preferred for local staging)
   • CT scan for retroperitoneal/abdominal lesions
   • Chest CT scan (mandatory for all patients for staging) 1
   • Additional imaging based on histology:
     • Abdominal CT for myxoid liposarcoma
     • Brain CT for alveolar soft part sarcoma, clear cell sarcoma, and angiosarcoma 1

2. Biopsy:

   • Core needle biopsy is standard procedure 1
   • Incisional biopsy may be needed for larger/deeper lesions
   • Open biopsy only in selected cases
   • Biopsy should be performed at centers experienced in sarcoma management

3. Pathological Assessment:

   • Histological diagnosis according to WHO classification
   • Malignancy grading (FNCLCC system preferred in Europe) 1:
     • Grade 1 (low): score 2-3
     • Grade 2 (intermediate): score 4-5
     • Grade 3 (high): score 6-8
   • Scoring based on:
     • Tumor differentiation
     • Necrosis
     • Mitotic count 1
   • Expert second opinion pathology review is essential (45% of initial diagnoses are modified upon expert review) 2
   • Molecular pathology (FISH, RT-PCR) for specific subtypes or when diagnosis is doubtful 1

Predisposing Factors

1. Genetic Syndromes:

   • Li-Fraumeni syndrome (TP53 mutations)
   • Retinoblastoma (RB1 mutations)
   • Neurofibromatosis type 1 (NF1 mutations)
   • Werner syndrome
   • Familial adenomatous polyposis 3

2. Environmental Factors:

   • Prior radiation exposure (radiation-induced sarcomas)
   • Chronic lymphedema (lymphangiosarcoma)
   • Chemical exposure (vinyl chloride, arsenic)
   • Herbicide exposure (Agent Orange)

3. Molecular Alterations:

   • Specific gene fusions (e.g., NTRK gene fusions) 1
   • Complex genomic rearrangements
   • Mesenchymal stem cell origin with aberrant differentiation 4

Prognostic Factors

The three most important prognostic factors for sarcomas are:

1. Grade: Higher grade correlates with worse prognosis
2. Size: Tumors >5 cm have worse outcomes
3. Location: Deep-seated tumors have worse prognosis than superficial ones 1, 5

Additional prognostic factors:

• Presence of metastases (especially lung metastases)
• Histological subtype
• Patient age (very young and elderly have worse outcomes) 6
• Surgical margins (R0, R1, R2)
• Performance status

Treatment Approach

Localized Disease

1. Surgery:

   • Wide excision with negative margins (R0) is the standard treatment 1
   • Requires removal of tumor with rim of normal tissue
   • Should be performed by surgeons specifically trained in sarcoma management 1
   • Marginal excision may be acceptable in selected cases (e.g., extracompartmental atypical lipomatous tumors) 1

2. Radiation Therapy:

   • Standard for high-grade (G2-3), deep, >5 cm tumors
   • Options for administration:
     • Postoperative: 50-60 Gy with 1.8-2 Gy fractions (with possible boost to 66 Gy)
     • Preoperative: 50 Gy 1
   • Improves local control but not overall survival

3. Adjuvant Chemotherapy:

   • Not standard treatment for all soft tissue sarcomas
   • May be considered for high-risk patients (high-grade, deep, >5 cm)
   • Decision should consider histological subtype (some are more chemosensitive) 1
   • Meta-analysis showed limited but statistically significant benefit in survival and relapse-free survival 1

Management of R1/R2 Resections

1. R1 Resection (microscopic positive margins):

   • Re-operation if adequate margins can be achieved without major morbidity 1
   • Radiation therapy if re-excision not feasible

2. R2 Resection (macroscopic positive margins):

   • Re-operation is mandatory 1
   • Consider preoperative treatments if adequate margins cannot be achieved

Advanced/Metastatic Disease

1. Lung Metastases:

   • Chemotherapy is standard treatment for synchronous metastases 1
   • Complete surgical resection of metastases for selected cases with limited disease
   • Consider chemotherapy before surgery to assess response

2. Non-resectable Primary Tumors:

   • Options include:
     • Chemotherapy and/or radiotherapy
     • Isolated hyperthermic limb perfusion with TNF-α + melphalan (for extremity tumors)
     • Regional hyperthermia combined with chemotherapy 1

3. Systemic Therapy Options:

   • First-line: Anthracycline-based chemotherapy
   • Second-line options:
     • Gemcitabine (particularly for leiomyosarcoma)
     • Trabectedin (effective in leiomyosarcoma and liposarcoma)
     • Pazopanib
     • Targeted therapies for specific subtypes (e.g., TRK inhibitors for NTRK fusion-positive sarcomas) 1

Follow-up

• High-risk patients (high grade): Every 3-4 months for first 2-3 years, then twice yearly to year 5, then annually
• Low-grade sarcomas: Every 4-6 months for first 3-5 years, then annually
• Focus on local recurrence and lung metastases
• MRI for local recurrence assessment
• Chest X-ray or CT scan for lung metastases surveillance 1

Special Considerations

1. Retroperitoneal Sarcomas:

   • Standard treatment is surgery through retroperitoneal compartmental resection
   • May include en-bloc visceral resections 1
   • Consider preoperative radiation or chemotherapy

2. Uterine Sarcomas:

   • Standard treatment is total abdominal hysterectomy
   • For endometrial stromal sarcomas, bilateral salpingo-oophorectomy is typically performed
   • Radiation therapy may improve local control but not survival 1

3. Regional Lymph Node Metastases:

   • Rare in most sarcomas but more common in epithelioid sarcoma, clear cell sarcoma, and synovial sarcoma
   • More aggressive treatment approach warranted
   • Consider wide excision with adjuvant radiation and chemotherapy 1

4. Pediatric Sarcomas:

   • Different biology and treatment approaches than adult sarcomas
   • Require specialized pediatric oncology expertise

The complexity and rarity of sarcomas highlight the importance of referral to specialized sarcoma centers with multidisciplinary expertise to ensure optimal outcomes and quality of life for patients.