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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