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Soft Tissue Sarcomas (STS)

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SOFT TISSUE SARCOMAS (STS) Author: Dr Francois Steyn Moderator: Dr Franzen ANGIOSARCOMA Strong environmental factor aetiology Irradiation, lymphoedema, chemical Scalp ... – PowerPoint PPT presentation

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Title: 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, Gardeners 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
    Kaposis 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
  • - gt 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 gt 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 gt 50 yrs
  • - Size gt 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 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-a
  • 5 no mutations on either of above
  • C-kit and PDGFR-a both 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 (lt 5cm)
    has high recurrence

27
GIST
  • Recurrence correlates with tumour size and
    mitotic index
  • lt 5cm with lt 5 mitosis/50 high power fields low
    risk
  • gt 10 cm with gt 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-a and ß, 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
  • Kaposis 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
Kaposis 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

36
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

37
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

38
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, NSAIDs, 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 lt20 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, DAdamo DR. Sarcoma. Mayo Clin Proc
    200782(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 2007245952-958.
  • Atalay C, Altinok M, Seref B.The impact of
    lymphnode metastasis on survival in extremity
    soft tissue sarcomas. World J Surg
    2007311433-1437.
  • 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 2007431927-1934
  • Woodall CE, Scoggins CR. Retroperitoneal and
    visceral sarcomas Issues for the general
    surgeon. American Surgeon 200773631-635
  • Boyar MS, Taub RN. New strategies for treating
    GIST when Imatinib fails. Cancer Investigation
    200725328-335.
  • Singer S. Soft tissue sarcomas. In Sabiston
    Textbook of Surgery. 18th edition, 2007, Saunders
    Elsevier, Philadelphia.
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