Soft Tissue SarcomaDR. ISA BASUKIDEPARTMENT OF SURGERY, AW SJAHRANIE GENERAL HOSPITAL

Introduction

• Soft tissue sarcomas are cancerous (malignant) tumors that originate in the soft tissues of your body

• Rare 1% adult, 15% paediatric neoplasms

• Can occur at any site:– Extermities 43%– Visceral 19%– Retroperitoneal 15%– Trunk/thoracic 10%– Other 13%

• Characterized by their genetic alterations, morphology under light microscopy and grade

Cytogenetic changes

• Divided into 2 catagories:– One group has specific changes and relatively simple karyotypes eg.

fusion gene or point mutation– Other group has non-spesific changes and complex karyotypes

• Genetic syndromes associated with STS include– neurofibromatosis, – retinoblastoma, – Li-Fraumenii syndrome, – Gardener’s syndrome (familial adenomatous poliposis)

Other aetiological factors

• Radiation exposure (osteosarcoma, angiosarcoma)

• Chronic lymphoedema

• Trauma

• Chemical exposure eg. arsenic, polyvinyl chloride (hepatic angiosarcoma)

• Infections eg. Herpes Human Virus-8: causes Kaposi’s Sarcoma in immunocompromized patients

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

Presentation (extremity STS)

• Mostly asymptomatic mass

• Pain in 33% due to destruction of surrounding tissues

• Rarely paraneoplastic symptoms eg. fever

Diagnosis• Open or large gauge core biopsies

• In which masses should biopsies be done: symptomatic Enlarging > 5 cm persists longer than 4 weeks

• Incision biopsies should not interfere with subsequent surgery, therefore: over most superficial part of mass no raising of flaps meticulous haemostasis to prevent haematomas

• FNA limited value, mostly to diagnose recurrence

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

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

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

Cont’d

Stage IA G1,2 T1a,b N0 M0

Stage IB G2,2 T2a,b N0 M0

Stage IIA G3,4 T1a,b N0 M0

Stage IIB G3,4 T2a N0 M0

Stage III G3,4 T2b N0 M0

Stage IV Any G Any T N1 M1

Staging system predicts survival and risk of metastasis, but not local recurrence

**Does not take into account extremity vs. visceral

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

ManagementSurgery

• Surgery is the principal therapeutic modality

• Controversy: – extent of surgery required– optimum combination of radio- and chemotherapy

• Objective: complete removal of tumour with negative margins with maximum preservation of function

• Neurovascular structures can generally be preserved with meticulous dissection

• Bone also mostly preserved as invasion of bone is rare and periosteum provides a good fascial plane

Cont’d

• Amputations:– rarely required– reserved for patients with unresectable tumours, no metastasis and

good propensity for rehabilitation

• 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

Management Radiotherapy

• Controversial

• Adjuvant radiotherapy proven to improve local recurrence and overall survival outcomes in high grade and > 5 cm lesions

• Still no consensus on neoadjuvent radiotherapy and differs between centers

• More studies are needed in this area

• Both brachytherapy and external beam radiation are used

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

ManagementChemotherapy• Opposite of radiotherapy

• Neoadjuvant chemotherapy proven to improve outcome

• Advantages:– subsequent surgery easier due to shrinkage of the tumour– may treat micrometastasis– leaves vasculature intact for improved drug delivery– enables assessm– ent of therapeutic response or resistance to therapy

• Can improve local control, but not survival

• Combination with radiation or neoadjuvant therapy are controversial

• Hypothermic isolated limb perfusion may be used for palliation

Cont’d

• Adjuvant chemotherapy still largely investigational and controversial

• Statistically significant improvement in overall survival has not been proven

• 3 most commonly used drugs are doxorubicin, ifosfamide and gemcitabine

• Doxorubicin and ibosfamide have response rates of 20%

• Their use depends on the histological subtype of STS

• High grade lesions respond better to therapy than low grade lesions

Recurrent and metastatic disease

• Lung most common site of mets, but visceral often go to liver

• 50% recurrence of extremity STS in the lung

• Local recurrence: mass or nodules in surgical scar

• Isolated local recurrence: resection

• If this is the only recurrence site, resectable and patient fit for surgery: resection

• All unresectable or extrapulmonary metastasis treated with chemotherapy

Cont’d• Resection of pulmonary mets can give 5 year survival of 32% if all

mets can be removed– > 3 mets is poor prognosticator

• Poor prognosis

• Relation between local lymphnode metastasis and survival controversial

• Studies: improvement in survival if local lymphadenectomy if no distant metastasis

• However, only true if done with initial curative surgery and not if done after

• Median survival from development of metastatic disease is 8-12 months

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

Prognosis

• Factors that negatively impact prognosis:– Age > 50 yrs– Size > 8 cm– Vascular invasion– Local infiltration (vs. pushing)– Tumour necrosis– Deep location– High grade tumours– Recurrent disease– Certain histological subtypes eg. non-liposarcoma histology

Visceral and Retroperitoneal sts

• 34% of all STS

• Most common RPSTS are liposarcoma (40%), leiomyosarcoma (25%), malignant peripheral nerve sheath tumour and fibrosarcoma

• Most common visceral STS are gastrointestinal stromal tumour (GIST), leiomyosarcoma and desmoid tumour

Presentation

• Asymptomatic mass

• Pain

• Gastrointestinal bleeding

• Incomplete obstruction

• Neurological symptoms due to invasion of neurovascular structures

Imaging

• CT-abdomen

• CT scan can show cystic/solid/necrotic components and relation to surroundings

• Also allows evaluation of the liver, the most common site of metastasis

Staging

• No official staging system

• The same grading system applies as for extremity STS

Differential diagnosis

• Important to exclude: – lymphoma, – germ cell tumours (young patients) – adrenal gland tumours

Diagnosis

• Laparotomy with open biopsy

• CT guided biopsy has a limited role only

• Only if:– unresectable tumour– doubtful diagnosis– neoadjuvent chemotherapy considered

Treatment• Surgery the mainstay of treatment

• 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

• Completeness of resection and grading of the tumour are the most important prognostic factors

• “Enucleation” along the pseudocapsule is associated with high recurrence

• Chemotherapy principles are the same as for extremity STS

Cont’d

• Radiotherapy controversial

• High morbidity and mortality due to radiosensitivity of surrounding organs

• Full-dose external beam radiation not possible due

• Intensity-modulated radiation showing promising results

• Targeted dose escalation to the area most at risk for recurrence

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

Gastrointestinal stromal tumour (GIST)

• STS arising from the gastrointestinal tract (GIT)

• Most common visceral STS

• 90% mutations in c-kit proto-oncogene

• 5-7% mutations in PDGFR-α

• 5% no mutations on either of above

• C-kit and PDGFR-α both tyrosine kinase transmembrane receptors

• Normally expressed by hematopoietic cells, germs cells, interstitial cells of Cajal

Cont’d

• Mostly discovered incidentally

• Occur most in stomach (50%) and proximal small bowel (25%)

• Can occur throughout the GIT including omentum, mesentery, peritoneum

• 50% metastatic at presentation, mostly to liver and peritoneum

• Surgery is primary method treatment

• Complete resection of even small tumours (< 5cm) has high recurrence

Cont’d

• Recurrence correlates with tumour size and mitotic index

• < 5cm with < 5 mitosis/50 high power fields = low risk

• > 10 cm with > 10 mitosis/50 high power fields = high risk

• Standard chemotherapy rarely effective

• High response rates to Imatinib – tyrosine kinase inhibitor

• Neoadjuvant therapy may enhance resectability and adjuvant therapy has shown increased disease free but not overall survival

Cont’d

• Some patients poor response to Imatinib

• Response depends on type of mutation and location of mutation on KIT

• Treatment of resistant patients include:– increasing dose of Imatinib– metastatectomy of liver/peritoneal metastasis or radiofrequency

ablation (reasonable results)– Sunitinib – inhibitor of multiple receptor kinases including tyrosine

kinase, VEGFR-1, 2 and 3, PDGFR-α and β, KIT, FLT₃

• A number of new drugs are being developed

GastroIntestinal Stromal Tumour (GIST)

GastroIntestinal Stromal Tumour (GIST)

Other common STS• 3 most common subgroups STS previously considered to be:

– malignant fibrous histiocytoma (MFH), – liposarcoma – leiomyosarcoma (LMS).

• MFH now considered to be pleomorphic STS without differensiation

• This is because many tumours previously thought to be MFH, share biochemical markers similar to other subtypes of STS

• Liposarcoma and LMS now considered 2 most common subgroups

Malignant Fibrous Histiocytoma (MFH)

Most common sts• Liposarcoma

• LMS

• Synovial Sarcoma

• Angiosarcoma

• Kaposi’s Sarcoma

• GIST

• Dermatofibrosarcoma Protruberans (DFSP)

• Aggressive Fibromatosis/Desmoid Tumour

• Alveolar Soft Part Sarcoma

• Rhabdomyosarcoma

Liposarcoma

• 20% of STS

• Types:– well-differentiated (retroperitoneum, low-grade)– myxoid (extremities, low-grade)– round cell (extremities)– dedifferentiated (retroperitoneum, high grade)– pleomorphic (extremities, high grade)

• Aetiology unknown, variety of cytogenetic abnormalities

Leiomyosarcoma (lms)

• Occur throughout the body

• Also in the uterus, but different gene expression pattern from non-uterine LMS

• Variety of cytogenetic changes

• Cutaneous lesions low risk for mets compared to subcutaneous and deep lesions

• Gemcitabine promising for treatment of mets

Synovial Sarcoma

• Unrelated to the synovium

• Histologic resemblance of synovial cells

• 2 types: monophasic, biphasic

• Fusion of genes between chromosome 18 and X chromosome – t(X,18)

• Sensitive to Ifosfamide regimes

Angiosarcoma

• Strong environmental factor aetiology

• Irradiation, lymphoedema, chemical

• Scalp, face, post-irradiation areas

• Vinyl chloride (plastic) – angiosarcoma of the liver

• Surgery and paclitaxel treatment

Kaposi’s Sarcoma

• HHV-8 important in pathogenesis

• Immunocompromized patients, AIDS

• Pink, purple, red, brown patches or nodules

• Mostly skin, oral mucosa

• Non-HIV: mostly lower extremities

• HIV: more wide spread, any organ, may lead to haemorrhage or organ dysfunction

Cont’d

• Indolent to aggressive course

• Local lesions: injection with vinblastine, toplical alitretinoin, liquid nitrogen cryotherapy

• More extensive involvement of lower extremities: radiation, but leads to lymphoedema

• Systemic disease: doxorubicin

Dermatofibrosarcoma Protuberans (DFSP)

• Occurs near body surface

• Metastasis unusual

• Surgery primary treatment, recognizing outer margins may be difficult

• Translocation of chromosomes 17 and 22

• This results in production of PDGFB. Therefore metastasis may respond to Imatinib

Aggresssive Fibromatosis (AF) /Desmoid tumour

• Monoclonal of myofibroblastlike cells with variable collagen disposition

• Locally invasive, rarely metastasize but can be multifocal

• Histological similarities with proliferative phase of wound healing, therefore trauma can cause AF

• Pregnancy, oral contraceptive also causes of AF

• Occurs 1000-fold more in patients with familial adenomatous polyposis (FAP)

Aggresssive Fibromatosis (AF) /Desmoid tumour

• Gardner syndrome: intestinal polyposis, oeteomas, fibromas, sebaceous and epidermal cysts

• Genetics: CTNNB1 pathway and WTC (APC)

• No consensus on optimal treatment

• High recurrence after surgery, can even be caused by surgery

• Variety of non-surgical treatments: methotrexate, vinblastine, NSAID’s, tamoxifen, radiation, Imatinib

Alveolar Soft-part Sarcoma

• Slow-growing tumour, late metastasis

• t(X,17), ASPSCR-TFE-3 fusion

• Low response to chemotherapy

• Responds well to surgery, can even resect metastasis due to slow growth

Rhabdomyosarcoma (RMS)• Most common paediatric STS

• Historically <20% survived with surgery alone due to rapid metastasis

• Today more than 70% cure with multimodal treatment (surgery, chemo- and radiotherapy)

• Arises from primitive precursor cells for striated muscle

• Types: embryonal (58%), alveolar (31%), botryoid, pleomorphic, anaplastic

• Variety of cytogenetic changes

• Presentation: mass with overlying erythema

• Most common sites: head and neck (35-40%), genitourinary tract (25%), extremities (20%)

Rhabdomyosarcoma (RMS)

• Staging according to tumour size, location, confinement to an anatomic site of origin (stage I and II), nodal spread (stage III), distant metastasis (stage IV)

• 5 year survival: 90% stage I

80% stage II

70% stage III

30% stage IV

• Most common sites metastasis are lungs and bone

• Staging workup: high-resolution imaging of primary, CT-chest and bone scan

Rhabdomyosarcoma (RMS)

• Complete resection best chance of local control

• Not always possible due to location (eg. orbital)

• Radiotherapy for residual disease and stage III

• Chemotherapy standard treatment for RMS and is plays the largest part in cure

• Vincristine, dactinomycin, cyclophosphamide

• Metastasis has poorer prognosis, but remissions and cure are possible with chemotherapy and radiotherapy of primary and metastatic sites

Conclusion

• STS are heterogeneous tumours

• They are uncommon and expertise are often lacking at all levels involved (pathologist, surgeon, oncologist etc.)

• Studies have shown significant improvement in survival and functional outcomes if treated at high volume centres

References1. Skubitz KM, D’Adamo DR. Sarcoma. Mayo Clin Proc 2007;82(11):1409-1432.

2. Gutierez JC, Perez EA, Moffat FL, Livingstone AS, Franceschi D, Koniaris LG. Should soft tissue sarcomas be treated at high-volume centers? Ann Surg 2007;245:952-958.

3. Atalay C, Altinok M, Seref B.The impact of lymphnode metastasis on survival in extremity soft tissue sarcomas. World J Surg 2007;31:1433-1437.

4. Engellau J, Samuelsson V, Anderson H, Bjerkehagen B, Rissler P, Sundby-Hall K et al. Identification of low-risk tumours in histological high-grade soft tissue sarcomas. Eur J Cancer 2007;43:1927-1934

5. Woodall CE, Scoggins CR. Retroperitoneal and visceral sarcomas: Issues for the general surgeon. American Surgeon 2007;73:631-635

6. Boyar MS, Taub RN. New strategies for treating GIST when Imatinib fails. Cancer Investigation 2007;25:328-335.

7. Singer S. Soft tissue sarcomas. In: Sabiston Textbook of Surgery. 18th edition, 2007, Saunders Elsevier, Philadelphia.

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