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SOFT TISSUE SARCOMASDr. Nikhil S.
Rare 1% - 2 per 100,000 persons (US)
Derived from mesenchymal tissue.
Diverse anatomically, histologically and by risk of metastasis.
Male: female = 1.1 : 1.0
Median age 50-55 years
Natural history determined by:
Anatomic location Size Depth Pathological
characteristics.
Extremities and torso: Local control good; death from lung mets 2-3 years later.
H&N: LC more difficult than extremity.
Retro peritoneum: Continued local recurrence many years after treatment.
ETIOLOGY
Herbicide exposure Constitutional and
hormonal factors during childhood puberty and adulthood.
HIV: non-AIDS defining neoplasm.
Chemical: Thorotrast, Vinyl Cl, As.
Trauma: Study in THR patients.
Radiation exposure: poor survival as compared to sporadic. Children: RB.
Usually in the perimeter. RT in breast cancer: 1.5
fold increased chance of STS.
9 fold increase for angiosarcoma and MFH.
Lymphoedema: lymphangiosarcoma.
Molecular Pathogenetic mechanisms Simple Karyotypic
sarcomas with specific genetic alterations: 1/3rd.
Translocations Only 1 cytognentic
abnormality. Synovial sarcoma
t(X;18)(p11;q11) distinguishes from MPNST.
Complex Karyotypic sarcomas without specific genetic alterations- 2/3rd.
Lacks genetic signatures Most adult spindle cell,
pleomorphic sarcoma, LMS.
High prevalence of TP-53, MDM-2 amplification, deletion of CDKn-2A
Clinical features
Extremities and superficial trunk: 60%
Painless primary soft tissue mass.
Retroperitoneum: 15%
Abdominal mass Pain:50% Grows to large size
before symptoms.
Viscera:15% GIST: anemia, malena,
abd pain, wt loss. Uterine LMS: painless
P/V bleed.
H&N: 10% Smaller Mechanical problems:
compression or invasion of adjacent critical structures.
WHO classification
I. Fibrous tumors
A. Fibromatoses
1.Superficial fibromatoses
i. Palmar and plantar(dupuytren’s contrcture)
ii. Penile(peyronie’s disease)
iii. Knuckle pads
2. Deep fibromatoses
i. Abdominal fibromatoses(Desmoid)
ii. Extra abdominal desmoid
iii. Intra abdominal desmoid
iv. Mesenteric
v. Infantile
B. Fibrosarcoma
1. Adult fibrosarcoma
2. Inflammatory fibrosarcoma
3. Myxofibrosarcoma.
Classification (contd.)
II. Fibrohistiocytic tumors
1. Dermato Fibro sarcoma Protruberans
2. Heterogenous tumors without specific differentiation(Formerly MFH)
i. Undifferentitaed pleomorphic sarcoma.
ii. Undifferentiated pleomorphic sarcoma with giant cells with inflammation.
iii. Angiomatoid MFH.
Classification (contd.)
III. Lipomatous tumors
1. Atypical lipoma
2. Liposarcoma
i. Well differentiated
a. Lipoma like
b. Sclerosing
c. Inflammatory
ii. Dedifferentited liposarcoma
iii. Myxoid or round cell LS
iv. Pleomorphic LS
IV. Smooth muscle1. Leiomyosarcoma2. Epitheloid LMS V. Skeletal Muscle3. RMSi. Embryonalii. Botryoidiii. Spindle calliv. Alveolarv. Pleomorphic2. RMS with ganglionic
differentiation(Ectomesenchymoma)
Classification (contd.)
VI. Blood and lymph vessels1. Epitheloid
hemangioendothelioma.2. Angiosarcoma nd
lymphangiosarcoma3. Kaposi’ s sarcoma
VII. Malignant perivasular tumors
4. Malignant glomus tumor or glomangiosarcoma.
5. Malignant hemangio pericytoma
VIII. Malignant synovial tumors1. Malignant GCT of tendon
sheath.
IX. Malignant neural tumors2. MPNST
(Neurofibrosarcoma)2. Malignant granular cell
tumor3. PNET(primitive NET)i. Neuroblastomaii. Ganglioneuroblastomaiii. nauroepithelioma
Classification (contd.)
X. Paraganglionic tumors1. Malignant
paraganglioma
XI. Extra skeletal Cartilaginous and oseeous tumors
2. Extra skeletal chondrosarcoma
a. Myxoidb. Mesenchymal2. Extraskeletal
osteosracoma
XII. Pluripotential malignant mesenchymal tumor
1. Malignant mesenchymoma2. Alveolar soft part sarcoma3. Epitheloid sarcoma4. Malignant extra renal
rhabdoid tumor5. Desmoplastic small cell
tumor6. extraskeletal Ewing s
sarcoma7. Clear cell sarcoma8. GIST9. Synovial sarcoma
Myxofibrosarcoma Myxoid variant of
MFH. Malignant
fibroblastic lesion with variable myxoid stroma.
One of the MC sarcomas
Arising in the limbs of elderly adults.
Slowly enlarging painless mass.
MC sites of metastases are lung, bone and lymph nodes.
So- called fibrohistiocytic tumors:
This concept is challenged now.
Merely in histological appearance.
None of them show histiocytic differentiation.
DFSP Low grade- recur
locally, but rarely metastasize.
Slow and persisitent growth.
Unpredicted radial extensions.
Stains positive for CD34.
Response with Imatinib.
High grade undifferentiated pleomorphic sarcoma/ pleomorphic MFH.
Was the MC diagnosed STS in some series in past.
Now reserved for those undifferentiated Pleomorphic sarcomas with no line of differentiation by current technology.
Aggressive course Many develop
metastasis within 3 years of diagnosis.
Liposarcoma 20% of all STS MC in thigh and
retroperitoneum. Three principal
groups:1. Atypical
lipomatous tumour/ WD LS and dedifferentiated LS
a. Adipocytic (lipoma like)
b. Sclerosingc. Inflammatoryd. Spindle cell.2. Myxoid or round
cell LS3. Pleomorphic LS
Leiomyosarcoma Malignant tumors
composed of spindle cells
Showing smooth muscle features.
Location: Retroperitoneal, intra abdominal pelvic sites, MC uterus.
Smooth muscle actin and desmin.
Grading of LMS difficult.
Large tumor size, high grade and high mitotic rate are the prognostic factors.
Rhabdomyosarcoma Embryonal: Small cell tumor. Orbit or genito urinary
tract of children. Botyriod type usually
in the mucosa lined visceral organs- vagina and urinary bladder- polypoid tumour.
Also seen in adults. But poorer
prognosis than in chidren.
Alveolar type: Extremities Young adults and
adolescents.
Angiosarcoma: Malignant tumor with
cells that resemble morphologically and functionally endothelial cells.
No clear distinction of those from lymphatics and capillaries.
Sometimes assoc with lymphedema.
Stewart treve syndrome: lymphangiosarcoma of skin in the lymphedematous arm post mastectomy and XRT.
MPNST: Rare sporadically But 8 to 13% in
those with NF-1 Affect major nerves
of extremities or chest wall.
Originate from nerve sheath.
Most are high grade
Stain positive for S-100
MPNST with RMS elements termed Triton tumor.
Synovial sarcoma: Spindle cell tumor Young adults 15-35 yrs
of age 80% in extremities, 10
% in H&N Unrelated to synovium. Monophasic or biphasic. Stain positive for
keratin, vimentin, S-100+/-
Epitheloid sarcoma Unknown lineage Adolescent and young
adults Extremity and perineal
area Tends to propogate
along tendon and nerve sheaths.
Lung and lymph nodal metastasis common.
5 year survival 66%.
Staging AJCC 7th Ed.
T1: </= 5 cm T1a: Superficial
tumor T1b: deep tumor T2: >/= 5cm T2a: superficial T2b: Deep
Stage IA: T1a/1b N0M0 Gx/G1
Stage IB: T2a/2b N0M0 Gx/G1
Stage IIA: T1a/1b NoM0 G2/G3
Stage IIB:T2a/2b N0M0 G2
Stage III: T2a/2b NoM0 G3 or N1
Stage IV: M1
Prognostic factors
1. Tumor grade2. Anatomic site3. Tumor size4. Depth5. Histological
subtype6. Age
Sarcoma specific nomogram (Kattan et al)
Risk stratification in GIST by AFIP strategy(Armed Forces institute of pathology)
These staging systems prognostify patients for the risk of distant metastasis and/or mortality.
Risk of local recurrence is not predicted by these factors.
Grading
Grading more significant than histo subtype
French federation of cancer centre three tire system (FNCLCC)
Parameters:1. Differentiation score2. Mitoses3. Necrosis.
Greatest limitation is the differentiation score.
NA in case of undiff. tumors.
In some tumors no adnl info e.g. w/d LS, ewing
Some ungradable e.g. epitheloid, clear cell, angiosarcoma.
No diff in prognosis- MPNST.
US national cancer institute(NCI) system
AJCC uses French system.
Screening and diagnosis
No screening tests. Incidence too low.
Physical exam:1. Size of the mass2. Mobility3. Superficial vs deep4. Relation to nearby
NV and bony structures.
5. Regional lymph nodes.
Biopsy Symptomatic,
enlarging, >5cm or beyond 4to 6 weeks.
1. Percutaneousa. FNA- sub optimalb. Core biopsy2. Open biopsy.a. Incisionalb. Excisional: <3cm
Retroperitoneal mass: Usually biopsy not required if
radiographically resectable or suspecting GIST.
Biopsy indicated:1. Unresectable disease2. Suspicion if lymphoma or GCT.3. Tissue diagnosis for NACT or RT.4. Suspected mets from another primary.
Imaging: primary site
Primary: CT or MRI of the local site-
extremity or H&N. MRI preferred: enhances
the contrast btw tumor and muscle; and with blood vessels.
Also provides multi planar definition of the lesion.
Abdominal- Spiral CT to know the relation with neuro-vascular structures.
Pelvic lesions: MRI may provide superior single modality imaging.
Role o f PET not well defined. Correlates well with CECT.
PET frequently fails to distinguish benign lesions from low grade sarcomas.
Imaging: metastatic sites
Chest X ray: for low grade lesions <10 cm or intermediate or high grade<5cm.
CT to look for lung Mets.
Common in extremity lesions.
Retroperitoneal lesions- liver Mets.
Lymph node mets rare 3.7%
Higher in RMS, epitheloid, angiosarcoma.
Treatment
Rx localized disease
Surgical resection Earlier radical
ablative surgeries- amputation and compartmental resection
Now limb sparing surgeries- Wide local Excision with pre-op and/or post op XRT.
Newer advances in Sx- Micro vascular tissue transfer
Bone and joint replacement.
Vascular reconstruction.
STS tend to expand and form a pseudo capsule with normal tissue and tumor fimbriae.
So WLE with a rim of normal tissue required- 30% LR without adj. Rx.
If small T1, low grade extremity lesion, LR<10%.
Though high grade, <5cm tumors, No diff seen with adj. XRT.
Large T2- limb sparing Sx + irradiation.
Surgical details
Skin, sub cut. Tissue, soft tissue adjacent to tumor (2 to 3 cm margin if possible)
Any assoc drainage sites should be resected.
Bone, NV structures if adjacent may be spared adj. XRT.
If grossly involved resected en-bloc and reconstructed.
Metal clips. Regional
lymphadenectomy has no role.
If clnically or radiographically nodes are detected, should be resected in C/O embyonal RMS, angio, epitheloid ,synovial.
radiotherapy
Pre-op RT Advantages:1. Small RT portals2. Produce tumor
encapsulation, allowing easy resection from vital structures.
3. Easier to spare a strip of skin.
4. Size decreased. So less amount of resection needed.
5. Lower XRT dose. 50Gy
Drawbacks6. Precise staging not
possible.7. Increased wound
healing issues.
Post Op XRT 60 to 65 Gy over 6
to 7 weeks. Local control 70 to
90% Survival 70% Limb preservation
85% Similar rates as
that of amputation.
Interstitial therapy Ir192 As boost after
EBRT 20 to 25 GY or in place of EBRT
40 to 45 Gy. Local control 82%
vs.69% for surgery alone.
Indications for post op XRT1. Limb conservation or limited
surgery.2. Gross residual tumor or inadequate
excision margins.3. Grade 2 and 3 histology4. Tumor 5 cm or more in any
dimension.5. Virtually all tumors in H&N.
comparison
Comparable LC rates ~ 90% with pre-op, post-op or interstitial XRT.
Wound complications increased with Pre-op XRT.
If interstitial, adv is the short Rx time. 10-12 days.
Post OP EBRT takes 10 to 12 weeks (post op gap of 4-6 wk + XRT for 6-7 wk)
Primary radiation therapy
In unresectable cases.
5year survival of 25-40% ad LC 30%.
LC depends primarily on the size.
Atleast 65 to 70Gy Location of the
tumor important
Because of the potential for damage to sensitive structures like spinal cord.
Retroperitoneal sarcomas
Only 50 % able to undergo complete resection.
Of these, 50% develop local recurrence.
Role of RT remains controversial due to lack of data, rarity and low doses used in many studies.
Pre-op XRT Adv: Bowel is
displaced by the tumor.
Hence less of bowel is treated, less GI toxicity.
Conformal techniques may also be used.
Intra-op XRT Prospective trial by
NCI IORT foll by low
dose EBRT(30-40Gy) vs. post op EBRT 35 to 40 Gy and 20 Gy boost.
Absolute LR rates were lower (p<0.05)
Post OP XRT Doses used in
extremities cannot be used here.
Most tumors are large 10 to 15cm.
3D planning and conformal techniques can be used to minimze bowel in field.
Isolated limb perfusion
Agents MC used are melphalan and TNF-a
With or without interferon-Y-1b.
Extrapolated from protocols for melanoma.
Now approved in europe for treatment of grade 2/3 extremity sarcomas.
Netherlands Cancer institute: 63% of patients had overall response.
Toxocity was frequent but mild.
Chemotherapy
Pre-operative Generally ifosfamide
and adriamycin containing regimes.
1. Reduction in tumor size surgical resection with less morbidity
2. Better compliance
Masachussets general hospital: 5 year freedom from distant metastasis 75% vs 44%(p=0.001)
5 year disease fee survival and overall survival was also significant.
Increased wound healing problem with chemo arm.
RTOG phase II study also with similar results.
Post operative chemo
Six studies- adriamycin.
All studies with patients<100
CyVADIC regime used in most.
No survival advantage could be demonstrated d/t inadequate statistical power.
Ifosfamide not studied in studies before 2000. only 1 study.
Italian co-operative group: 104pts- closed.
interim analysis showed sign. Survival advantg for chemotherapy patients.
Not reproduced in the EORTC or SMAC trials.
Treatment of local recurrence LR in 10 to 50% of
patients after ~24 months.
Higher for Retroperitoneal(40%) and H&N(50%) vs low for extremity(10%).
Re-operation after staging evaluation.
2/3rd of patients experience longterm survival.
Adjuvant RT: if previous RT was
not given or previous dose was
sub-therapeutic or previous fields
allow further treatment.
Isolated limb perfusion.
Treatment of limited pulmonary metastasis Thoracotomy and
metstatectomy 3 year survival is 23 to 42
% Indicated if:1. Primary tumor is
controlled or controllable2. Complete resection
appears to be possible3. No extra thoracic
disease4. No medical C/I.
Pre- resection chemotherapy- sometimes recommended.
No definitve proof that it helps in better resection.
Unresectable and metastatic
Chemotherapy is the mainstay.
Single agents:1. Doxorubicin2. Pegylated lipodox3. Ifosfamide4. Dacarbazine5. Ecteinascidin
(trabectidin)
Combination chemotherapy:
Anthracycline plus an alkylating agent, dacarbazine or both.
Doxorubicin plus ifosfamide
CyVADIC MAID
Combination vs single agent:
Superior response But no survival
advantage. Pts can achieve
more benefit when these agents are given sequentially than by combinations.
Gemcitabine plus docetaxel
Gemcitabine plus vinorelbine
Kinase targeted agents.
Prognostic factors for response to therapy1. absence of liver
metastasis.2. Younger age3. High grade4. liposarcoma
Better survival with;
1. Good PS2. Absence of liver
mets3. Low grade4. Young age5. Long time to
metastasize after primary treatment.
THANK YOU
