SOFT TISSUE SARCOMAS (STS)Author: Dr Francois SteynModerator: Dr Franzen

INTRODUCTION STS are part of a heterogenous group of

mesenchymal neoplasms 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 Common in STS 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

STAGING Based on tumour grade, size, depth and

presence or absence of metastasis Grade is the most important prognostic factor Due to the rarity of STS reproducibility of

grading between different pathologists is a problem.

Preferable that specimens be examined by an experienced pathologist

This staging system only applies to extremity STS

To date there is no official staging system for visceral and retroperitoneal STS

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 modality of choice Enhanced contrasts between adjacent

structures However, no statistically significant

superiority could be proven above CT-Scan

MANAGEMENT: SURGERY Surgery is the principal therapeutic modality Controversy: - extent of surgery required - optimum combination of radio- and

chemotherapy Surgical 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

MANAGEMENT: SURGERY Amputations: - rarely required - reserved for patients with unresectable

tumours, no metastasis and good propensity for rehabilitation

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

MANAGEMENT: CHEMOTHERAPY 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 assessment of therapeutic response or resistance to therapy

MANAGEMENT: CHEMOTHERAPY 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 Their use depends on the histological

subtype of STS High grade lesions respond better to therapy

than low grade lesions

RECURRENT AND METASTATIC DISEASE Local recurrence: mass or nodules in surgical

scar Isolated local recurrence: resection 50% recurrence of extremity STS in the lung If this is the only recurrence site, resectable

and patient fit for surgery: resection All unresectable or extrapulmonary

metastasis treated with chemotherapy Poor prognosis

RECURRENT AND METASTATIC DISEASE 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

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 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) and 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 Completeness of resection and grading of the

tumour are the most important prognostic factors

“Enucluation” along the pseudocapsule is associated with high recurrence

Chemotherapy principles are the same as for extremity STS

TREATMENT 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

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

GIST 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

GIST 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

GIST 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

OTHER COMMON STS 3 most common subgroups STS previously

considered to be malignant fibrous histiocytoma, liposarcoma (MFH) and 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

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 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) Gardner syndrome: intestinal polyposis,

oeteomas, fibromas, sebaceous and epidermal cysts

AGGRESSIVE FIBROMATOSIS (AF)/ DESMOID TUMOUR 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

Thank you!

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