Soft Tissue Sarcomas (STS)

1. Soft Tissue Sarcomas (STS) Author: Dr Francois Steyn Moderator: Dr Franzen

2. 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

3. 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)

4. 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

5. 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

6. Presentation (extremity sts) • Mostly asymptomatic mass • Pain in 33% due to destruction of surrounding tissues • Rarely paraneoplastic symptoms eg. fever

7. 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

8. Imaging • MRI modality of choice • Enhanced contrasts between adjacent structures • However, no statistically significant superiority could be proven above CT-Scan

9. 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

10. Management: Surgery • Amputations: - rarely required - reserved for patients with unresectable tumours, no metastasis and good propensity for rehabilitation

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. Presentation • Asymptomatic mass • Pain • Gastrointestinal bleeding • Incomplete obstruction • Neurological symptoms due to invasion of neurovascular structures

19. Imaging • CT-abdomen • Also allows evaluation of the liver, the most common site of metastasis

20. Staging • No official staging system • The same grading system applies as for extremity STS

21. Differential diagnosis • Important to exclude lymphoma, germ cell tumours (young patients) and adrenal gland tumours

22. Diagnosis • Laparotomy with open biopsy • CT guided biopsy has a limited role only • Only if: - unresectable tumour - doubtful diagnosis - neoadjuvent chemotherapy considered

23. 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

24. 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

25. Gastrointestinal stromaltumour (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-αboth tyrosine kinase transmembrane receptors • Normally expressed by hematopoietic cells, germs cells, interstitial cells of Cajal

26. 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

27. 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

28. 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

29. 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

30. Most common sts • Liposarcoma • LMS • Synovial Sarcoma • Angiosarcoma • Kaposi’s Sarcoma • GIST • Dermatofibrosarcoma Protruberans (DFSP) • Aggressive Fibromatosis/Desmoid Tumour • Alveolar Soft Part Sarcoma • Rhabdomyosarcoma

31. 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

32. 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

33. 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

34. Angiosarcoma • Strong environmental factor aetiology • Irradiation, lymphoedema, chemical • Scalp, face, post-irradiation areas • Vinyl chloride (plastic) – angiosarcoma of the liver • Surgery and paclitaxel treatment

35. 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, toplicalalitretinoin, liquid nitrogen cryotherapy • More extensive involvement of lower extremities: radiation, but leads to lymphoedema • Systemic disease: doxorubicin

36. DermatofibrosarcomaProtuberans (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

37. AggresssiveFibromatosis (af)/Desmoidtumour • 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

38. Aggressive fibromatosis (af)/ Desmoidtumour • Genetics: CTNNB1 pathwayand 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

39. 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

40. 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%)

41. 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

42. 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

43. 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!

44. References • Skubitz KM, D’Adamo DR. Sarcoma. Mayo Clin Proc 2007;82(11):1409-1432. • 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. • Atalay C, Altinok M, SerefB.The impact of lymphnode metastasis on survival in extremity soft tissue sarcomas. World J Surg 2007;31:1433-1437. • 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 • Woodall CE, Scoggins CR. Retroperitoneal and visceral sarcomas: Issues for the general surgeon. American Surgeon 2007;73:631-635 • Boyar MS, Taub RN. New strategies for treating GIST when Imatinib fails. Cancer Investigation 2007;25:328-335. • Singer S. Soft tissue sarcomas. In: Sabiston Textbook of Surgery. 18th edition, 2007, Saunders Elsevier, Philadelphia.