Soft Tissue Sarcoma

Dr Junaid Ahmad

∗ A heterogeneous group of tumors of connective tissue

∗ Two third of Soft tissue sarcomas in extremities∗ Constitute 1% of cancers in adults but 15% in children∗ The overall 5-year survival rate 50% to 60%.∗ Most of die with lung metastasis

Sarcomas

∗ Malignant fibrous histiocytoma is most common type in elderly

∗ Liposarcoma in middle age∗ Leimayosarcoma in young∗ Embryonal/alveolar rhabdomyosarcomas are the

most common type in children

Histological Subtypes

∗ I. Fibrosarcoma∗ 1. Adult fibrosarcoma∗ 2. Inflammatory fibrosarcoma∗ 3. Myxofibrosarcoma

∗ II. Fibrohistiocytic tumors∗ 1. Dermato Fibro sarcoma Protruberans∗ 2. Heterogenous tumors without specific differentiation(Formerly MFH)

∗ i. Undifferentitaed pleomorphic sarcoma.∗ ii. Undifferentiated pleomorphic sarcoma with giant cells with inflammation.∗ iii. Angiomatoid MFH

∗ III. Lipomatous tumors∗ 1. Atypical lipoma∗ 2. Liposarcoma

∗ i. Well differentiated∗ a. Lipoma like∗ b. Sclerosing∗ c. Inflammatory

∗ ii. Dedifferentited liposarcoma∗ iii. Myxoid or round cell LS∗ iv. Pleomorphic LS

∗ IV. Smooth muscle

Classification

∗ 1. Leiomyosarcoma∗ 2. Epitheloid LMS

∗ V. Skeletal Muscle∗ 1. RhabdoMayoSacroma

∗ i. Embryonal∗ ii. Botryoid∗ iii. Spindle call∗ iv. Alveolar∗ v. Pleomorphic

∗ 2. RMS with ganglionic differentiation (Ectomesenchymoma)

∗ VI. Blood and lymph vessels∗ 1. Epitheloid hemangioendothelioma.∗ 2. Angiosarcoma nd lymphangiosarcoma∗ 3. Kaposi’ s sarcoma

∗ VII. Malignant perivasular tumors∗ 1. Malignant glomus tumor or glomangiosarcoma.∗ 2. Malignant hemangio pericytoma

∗ VIII. Malignant synovial tumors∗ Malignant GCT of tendon sheath.

∗ IX. Malignant neural tumors∗ 1. MPNST (Neurofibrosarcoma)∗ 2. Malignant granular cell tumor

Classification

∗ 3. PNET(primitive NET)∗ i. Neuroblastoma∗ ii. Ganglioneuroblastoma∗ iii. nauroepithelioma

∗ X. Paraganglionic tumors∗ Malignant paraganglioma

∗ XI. Extra skeletal Cartilaginous and oseeous tumors∗ 1. Extra skeletal chondrosarcoma∗ a. Myxoid∗ b. Mesenchymal∗ 2. Extraskeletal osteosracoma

∗ XII. Pluripotential malignant mesenchymal tumor∗ 1. Malignant mesenchymoma∗ 2. Alveolar soft part sarcoma∗ 3. Epitheloid sarcoma∗ 4. Malignant extra renal rhabdoid tumor∗ 5. Desmoplastic small cell tumor∗ 6. Extraskeletal Ewing s sarcoma∗ 7. Clear cell sarcoma∗ 8. GIST∗ 9. Synovial sarcoma

Classification

∗ Liposarcoma ∗ Leiomyosarcoma ∗ Unclassified sarcoma ∗ Synovial sarcoma ∗ Malignant peripheral nerve sheath tumor ∗ Rhabdomyosarcoma ∗ Fibrosarcoma ∗ Ewing sarcoma ∗ Angiosarcoma ∗ Osteosarcoma ∗ Epithelioid sarcoma ∗ Chondrosarcoma ∗ Clear cell sarcoma ∗ Alveolar soft part sarcoma ∗ Malignant hemangiopericytoma

Common Histological Subtypes

∗ 20% of all Soft tissue sarcomas∗ Thighs and retroperitoneum.∗ Three principal groups:

∗ 1. Atypical lipomatous tumour/ WD LS and dedifferentiated LS

∗ Adipocytic (lipoma like)∗ Sclerosing∗ Inflammatory∗ Spindle cell.

∗ 2. Myxoid or round cell LS∗ 3. Pleomorphic LS

Liposarcoma

∗ Malignant tumors composed of spindle cells∗ Showing smooth muscle features.∗ Location: Retroperitoneal, intra abdominal pelvic

sites, uterus∗ Smooth muscle actin and desmin.∗ Grading of LMS difficult.∗ Large tumor size, high grade and high mitotic rate are

the prognostic factors.

Leiomyosarcoma

∗ 1. Embryonal∗ Small cell tumor

∗ Orbit or genito urinary tract of children.∗ Botyriod type usually in the mucosa lined visceral organs

vagina and urinary bladder∗ Polypoid tumour∗ Also seen in adults but poorer prognosis

∗ 2. Alveolar type:∗ Extremities∗ Young adults and adolescents.

Rhabdomyosarcoma

∗ Malignant tumor with cells that resemble morphologically and functionally endothelial cells.

∗ No clear distinction of those from lymphatics and capillaries.

∗ Sometimes associated with lymphedema.∗ Stewart treve syndrome

∗ Lymphangiosarcoma of skin in the lymphedematous arm post mastectomy

∗ Radiation therapy

Angiosarcoma

∗ Rare sporadically∗ But 8 to 13% in those with NF-1∗ Affect major nerves of extremities or chest wall.∗ Originate from nerve sheath.∗ Most are high grade∗ Stain positive for S-100∗ MPNST with Rhabdomayosarcoma elements termed

Triton tumor

Malignant Peripheral Nerve Sheath Tumor

∗ This concept is challenged now.∗ Merely in histological appearance.∗ None of them show histiocytic differentiation.∗ Low grade- recur locally, but rarely metastasize.∗ Slow and persisitent growth.∗ Unpredicted radial extensions.∗ Stains positive for CD34.∗ Response with Imatinib

Fibrohistiocytoma

∗ Spindle cell tumor∗ Young adults 15-35 yrs of age∗ 80% in extremities, 10 % in Head and Neck∗ Unrelated to synovium∗ Stain positive for keratin, vimentin, S-100+/-

Synovial sarcoma

∗ Epitheloid sarcoma∗ Unknown lineage∗ Adolescent and young adults∗ Extremity and perineal area∗ Tends to propogate along tendon and nerve

sheaths.∗ Lung and lymph nodal metastasis common.∗ 5 year survival 66%.

Synovial sarcoma

∗ Reserved for those undifferentiated Pleomorphic sarcomas with no line of differentiation by current technology.

∗ Aggressive course∗ Many develop metastasis within 3 years of

diagnosis.

High grade undifferentiated pleomorphic sarcoma/ pleomorphic MFH

∗ Most of time cause is unknown∗ Few known etiologies are

∗ Radiation Exposure∗ Occupational Chemical Exposure∗ Trauma∗ Chronic Lymphedema∗ Genetic Conditions (NF, RB)

Cause

∗ Different type of known mutations are∗ Point Mutations∗ Translocations∗ Amplifications∗ Oncogenic Mutations∗ Complex Genomic Rearrangements

Molecular Basis

∗ Asymptomatic painless masses∗ Venous thrombosis in extremities∗ Compress adjoining structures ∗ Sometimes painful, edema and swelling when

bone or nearby neurovascular bundle involved∗ Sometimes a traumatic even draws attention

to it

Clinical Picture

∗ Lipoma∗ Lymphangioma∗ Leiomyoma∗ Neurinoma∗ Primary or metastatic carcinoma∗ Melanoma∗ Lymphoma

Differential Diagnosis

∗ Superficial small lesions (<5 cm) that are new or that are not enlarging as indicated by clinical history can be observed.

∗ Enlarging masses and masses larger than 5 cm or deep to the fascia should be evaluated with a history, imaging, and biopsy.

Assessment

∗ Size of tumor and skin involvement (defect)∗ Pulses and sensation (for vascular and nerve

reconstruction)∗ Involved muscle groups (for

tendon/vascularized muscle transfer)∗ Age and fitness for surgery∗ Lifestyle (for limb preservation)

Clinical Assessment

∗ Should be before any invasive procedure∗ MRI is the choice in extremities∗ An x ray may help in bone involvement∗ CT may be helpful in intra abdominal and few

types of sarcomas∗ CT chest and MRI brain may be required to

see metastasis∗ Ultrasonography if MRI is contraindicated

Diagnostic Imaging

∗ PET scan is only a slight better than CT∗ Follow up 3 monthly MRI are done to

see recurrence

Diagnostic Imaging

∗ Fine-Needle Aspiration∗ Core Needle Biopsy (choice)

∗ Incisional Biopsy (25% changed plan)

∗ Excisional Biopsy

Biopsy Techniques

∗ Light Microscopy/Morphology (25-40% disagree)

∗ Electron Microscopy∗ Cytogenetics; immunohistochemistry and molecular

genetic testing.∗ Other molecular diagnostic techniques include Flow

cytometry, fluorescence in situ hybridization (FISH), and polymerase chain reaction–based methods.

Pathologic Assessment and Classification

∗ Pathological classification is more important∗ Type of tumor∗ Histologic Grade of Aggressiveness∗ Nodal Metastasis (Rare in adult sarcomas)∗ Distant Metastasis (CT chest)

Staging and Prognostic Factors

∗ Parameters by French federation of cancer centre three tire system (FNCLCC)∗ Differentiation score∗ Mitoses∗ Necrosis

∗ Some ungradable e.g. epitheloid, clear cell, angiosarcoma

Grading

∗ Primary:∗ T1 tumour 5 cm or less in greatest dimension (a superficial, b

deep).∗ T2 tumour more than 5 cm in greatest dimension (a

superficial, b deep).

∗ Regional nodes:∗ N0 none.∗ N1 regional nodes.

∗ Distant metastases:∗ MX, M0, M1

TNM G Staging

∗ Histological grade G∗ GX cannot be assessed∗ G1 well differentiated∗ G2 moderately differentiated∗ G3 poorly differentiated

∗ G4 undifferentiated

∗ G1/2 would be low grade tumors

TMN G

∗ Kattan et al studied Prognostic Factors∗ Age∗ Histology∗ Grade∗ Location∗ Depth∗ Size

Prognostic Factors.

∗ The treatment algorithm for soft tissue sarcomas depends on tumor stage, site, and histology.

Treatment

∗ Surgery∗ Limb sparing surgery / Wide Local Excision∗ Locoregional Lymphadenectomy.∗ Amputation.∗ Isolated Regional Perfusion.

∗ Radiation Therapy∗ Systemic Therapy

∗ Standard Chemotherapy.∗ Novel Chemotherapeutic Agents.∗ Targeted Therapies.

Treatment Modalities

∗ Limb Salvage Technique ∗ 1-2 cm margins (Dermatofibrosarcoma Protuberance require 2-4cm)

∗ Biopsy site is resected∗ Nerve and vessels are usually preserved by narrowing

the margins∗ NV bundle if very near to tumor then epineurium and

adventitia are removed∗ Tumor encircling NV bundles should be removed∗ Nearby veins are not be spared usually

Wide Local Excision

∗ Enucleation is discouraged and dissection must be in grossly normal planes (even with radiation)

∗ Lin and colleagues studied that in absence of frank cortical margins periosteum is the adequate surgical margin with radiation

∗ Bone involvement is poor prognostic factor∗ NV bundles reconstructed∗ Free flaps and tendons/muscle transferred∗ Skin covered

Wide Local Excision

∗ Early physical therapy is essential∗ Large sarcomas of distal parts of

extremities are difficult to treat and amputations are considered

Wide Local Excision

∗ Also limb sparing surgery∗ Differ from wide local excision that

involved muscles are removed from origin to insertion

Compartectomy

∗ FNAC should be done US guided∗ If involved selected lymphedenectomy done∗ Proved increase survival rate∗ Sentinel lymph node biopsy is controversial

Lymphedenectomy

∗ 5% cases of extremity sarcomas∗ Have no survival advantage∗ Avoids local recurrence∗ Large unresectable tumors∗ Reserved only for cases when Limb

Salvage cannot be done

Amputations

∗ Palliative treatment∗ Artery and Veins of region involve are dissected and

connected to a pumping device∗ Branches are ligated∗ Perfused with TNF-alpha and Malaphalan∗ Limb is kept warm with heater at 40C∗ Systemic leakage checked with Tc labelled albumin∗ Artery and vein repaired∗ Expensive and controversial

Isolated Regional Perfusion

∗ Indications∗ Limb conservation or limited surgery∗ Gross residual tumor or inadequate excision

margins∗ Grade is high on histology∗ Tumor 5 cm or more in any dimension∗ Virtually all tumors in H&N

Radiation

∗ Smaller than 5cm tumors with clear margins can avoid radiation even if high grade

∗ Pre operative post operative and intra operative techniques have debates

∗ Metallic clips during surgery help define margins

Radiation

∗ Post operative∗ Large doses required∗ Reconstruction is less

complicated∗ Long time to complete∗ Local Cure is comparable

Radiation

∗ Pre operative ∗ Difficulty in pathologic

assessment of margins∗ Wound complications

increased∗ Low doses required∗ Better long term results

fibrosis∗ Difficult reconstructions

∗ No survival benefit ∗ Synovial and Myxoid sarcomas are most sensitive∗ For those with significant risk of death

∗ Metastasis∗ Non extremity tumors (unresectable)∗ Intermediate to high grade with size larger than 5cm

∗ Docurubicine and ifosfamide are standard∗ Hemorhagic cystitis, real tubular acidosis,

neurotoxicity are side effects of ifosfamide

Systemic Chemotherapy

∗ Anti vascular endothelial growth factor is particularly effective against angiosarcoma

∗ Trabectedin for leiomayosarcoma∗ Imitanib for GI stromal tumor∗ Use is contorversial as many trials even failed

to show benefits in disease free interval

Systemic Chemotherapy

∗ Increase wound complications∗ Decrease the size of tumor∗ Tumors with high pathological necrosis on CT

respond better to neoadjuvant chemotherapy

Neoadjuvant (Preoperative) Chemotherapy.

∗ Theoratical benefit is short total treatment time in high risk patients

Concurrent Chemoradiation Therapy

Thoracotomy and metstatectomy3 year survival is 23 to 42 %Indicated if

Primary tumor is controlled or controllableComplete resection appears to be possibleNo extra thoracic diseaseNo medical complicated disease

Lung Metastatic Disease

∗ History Physical Chest CT or radiograph every 3 to 6 months

∗ Tumor site should be evaluated with MRI first at 3 months then every 6 months

∗ First 2-3 years are most important∗ Some prefer less aggressive radiological

approach for asymptomatic patients

Post treatment Surveillance

∗ Biospy of any suspicious nodule∗ Redical excision with or without

radiation is treatment for tumor

Management of Recurrent Sarcoma

Thank you