Soft tissue sarcoma

Presented at AW Sjahranie General Hospital under supervision of dr. Elvis K. SpB

1. Soft Tissue Sarcoma Dr. Isa Basuki Department of Surgery, AW Sjahranie General Hospital

2. 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

3. Cytogenetic changes Divided into 2 catagories : One group has specific changes and relatively simple karyotypes eg . fusion gene or point mutation O ther 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. 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

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 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

9. 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

10. 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

11. 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

12. 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

13. Management Surgery Surgery is the principal therapeutic modality Controversy: extent of surgery required optimum combination of radio- and chemotherapy O bjective : 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

14. 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

15. 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

16. 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

17. 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

18. 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 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. Visceral and R etroperitoneal 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

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

26. 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

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

28. Differential diagnosis Important to exclude : lymphoma , germ cell tumours (young patients) adrenal gland tumours

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

30. 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 “ Enucl e ation ” along the pseudocapsule is associated with high recurrence Chemotherapy principles are the same as for extremity STS

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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, FLT ₃ A number of new drugs are being developed

37. Gastro I ntestinal S tromal T umour (GIST)

38. Gastro I ntestinal S tromal T umour (GIST)

39. 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

40. M alignant F ibrous H istiocytoma (MFH)

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

42. 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

43. 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

44. 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

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

46. 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

47. 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

48. 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

49. 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)

50. 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

51. 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

52. 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%)

53. 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

54. 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

55. 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

56. 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, Seref B. 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 . 18 th edition, 2007, Saunders Elsevier, Philadelphia.

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