Soft Tissue Sarcomas August 15, 2015

Introduction Rare: only 8300 new cases annually in U.S die annually from STS Mesodermal origin

Location and Type

Etiology h/o Radiation therapy increases grade of tumors and risk for metastasis Chemical exposure Thorotrast, vinyl chloride, arsenic for hepatic angiosarcoma Genetic syndromes Neurofibromatosis – nerve sheath tumors Familial gastrointestinal stromal tumor syndrome – KIT mutation Skin hyperpigmentation, uticaria, cutaneous mast cell dx

Classification Soft tissue and bone viscera (gastrointestinal, genitourinary, and gynecologic organs) nonvisceral soft tissues (muscle, tendon, adipose, pleura, and connective tissue) By differentiation (usually with IHC staining) adipocytic tumors fibroblastic/myofibroblastic tumors fibrohistiocytic tumors smooth muscle tumors pericytic (perivascular) tumors primitive neuroectodermal tumors (PNETs) skeletal muscle tumors vascular tumors osseous tumors tumors of uncertain differentiation

Biopsy Most present as painless mass leading to delayed diagnosis as lipoma or hematoma Core needle biopsy guided by palpation or by image guidance if not palpable Few cases of tumor seeding with closed biopsy so some recommend tattooing site for later excision with specimen Excisional biopsy for superficial small lesions if needle biopsy non-diagnostic Incision biopsy Longitudinal incision without tissue flaps with meticulous hemostasis to prevent tumor seeding in hematomas Send biopsy fresh and orientated

Tumor seeding after biopsy

Imaging MRI For extremity masses Gives good delineation between muscle, tumor and blood vessels CT for abdominal and retroperitoneal PET May help determine high vs. low grade May be helpful in recurrences

Staging AJCC/UICC Staging System for Soft Tissue Sarcomas T1: <5cm – T1a: superficial to muscular fascia – T1b: Deep to muscular fascia T2: >5cm – T2a: superficial to muscular fascia – T2b: Deep to muscular fascia N1: Regional nodal involvement Grading – G1: Well-differentiated – G2: Moderately differentiated – G3: Poorly differentiated – G4: Undifferentiated

Staging Stage IAG1,2T1a,bN0M0 Stage IBG2,2T2a,bN0M0 Stage IIAG3,4T1a,bN0M0 Stage IIBG3,4T2aN0M0 Stage IIIG3,4T2bN0M0 Stage IVAny GAny TN1M1 **Does not take into account extremity vs. visceral Staging system predicts survival and risk of metastasis, but not local recurrence

Survival by stage

Relative risk for recurrence and survival Age >50 years 1.6 Local recurrence at presentation 2.0 Microscopically positive margin 1.8 Size 5.0–10.0 cm 1.9 Size > 10.0 cm 1.5 High-grade 4.3 Deep location 2.5 Local recurrence 1.5

Surgery Limb-sparing vs amputation Comparison study with post-op radiation in limb sparing showed no difference in survival Amputation still may be indicated for neurovascular or bone involvement

Resection Arbitrary 2 cm margin if no plan for post-op radiotherapy Negative margins may be adequate for post- op radiation therapy Presence of positive margins increases local recurrence by 10-15% No need for lymph node dissection as only 2- 3% have nodal metastasis

Adjuvant radiotherapy Small, low grade tumors resected with 2 cm margins may not require radiation Improves local control but not survival Whether improved local control leads to improved survival is controversial

Local recurrence with post-op brachytherapy

Pre-op or post-op radiation? Some avoid pre-op use because of increased wound complications (although this is debatable) RCT looking at wound complication rate pre-op vs post- op radiation showed 35% vs 17% Risk confined to lower extremity Conclusions: pre-op may be better for upper extremity and head & neck because of equal wound complication risk and benefit of lower radiation doses to more vital tissues

Pre-op vs post-op radiotherapy

Chemotherapy Can improve local control, but not survival Doxorubicin and ibosfamide have response rates of 20% Use only in advanced disease Combination with radiation or neoadjuvant therapy are controversial Hypothermic isolated limb perfusion may be used for palliation

Treatment of Recurrence 20-30% of STS patients will recur More common in retroperitoneal and head & neck high grade tumors because hard to get clear margins 38% for retroperitoneal 42% for head and neck 5-25% for extremity After re-resection recurrence is 32% for extremity and much higher for visceral

Metastatic disease Lung most common site of mets, but visceral often go to liver Median survival from development of metastatic disease is 8-12 months Resection of pulmonary mets can give 5 year survival of 32% if all mets can be removed >3 mets is poor prognosticator

Case #1 64 y/o male with increasing abdominal girth

Retroperitoneal Sarcomas 15% of all sarcomas Liposarcoma 42% and leiomyosarcoma 26% CT scan can show cystic/solid/necrotic components and relation to surroundings CXR to r/o mets, chest CT if CXR abnormal Biopsy not necessary unless suspect a lymphoma or germ cell tumor or plan preop chemo or radiation En bloc resection is standard treatment bowel prep assess bilateral kidney function 50-80% need organ resection 78% of primary lesions can be completely resected

Liposarcoma

Survival after resection of primary retroperitoneal sarcoma

Prognosis for retroperitoneal sarcomas 5 year survival after complete resection of 54-65% Drops to 10-36% if incompletely resected Recurrence occurs in 46-59% of completely resected tumors

Radiation or chemotherapy for retroperitoneal sarcomas Radiation – GI and neurotoxicities limit delivery of sufficient doses – May improve local control – Recommended for use only in clinical trials given lack of data either way Chemotherapy – Use for recurrent, unresectable or metastatic disease

Case #2 49 y/o female with GERD undergoing EGD

GIST Separate subtype of sarcoma defined by expression of c-Kit (CD117) Surgery: complete resection without local or regional lymphadenectomy Very resistant to traditional chemotherapy Gleevec (imantinib mesylate) c-Kit is constitutively active tyrosine kinase receptor Drug is tyrosine kinase inhibitor used in CML Initial studies showed 54% response rates Two RCTs currently looking at adjuvant treatment

GIST

Extremity sarcomas MFH Synovial sarcoma

Breast sarcomas 1% of all breast neoplasms Wide excision with negative margins No clear role for adjuvant radiotherapy

Sarcoma after mastectomy

Vascular sarcomas Angiosarcoma, hemangiosarcoma, lymphangiosarcoma, hemangiopericytoma Key points: Hepatic angiosarcoma – thorotrast, vinyl chloride, arsenic Stewart Treve’s – lymphangiosarcoma in chronic lymphedema High risk for bleeding during excision No clear role for chemo or radiation