Soft tissue sarcoma

MANAGEMENT OF SOFT TISSUE
SARCOMA
DR KIRAN KUMAR BR

Natural History
STS can occur anywhere in the body.
The most common site of presentation is an
extremity, specifically the thigh.
The approximate distribution of STS sites at presentation is extremity,
60% (lower extremity, 45%, upper extremity, 15%); trunk, 15% to 20%;
retroperitoneum, 10% to 15%; and head and neck, 8%.
Perez and Brady’s 6TH

Clinical presentation
• Extremity:-
• M.C symptom:- a painless swelling.
• Other symptoms – d/t involvement of surrounding structures.
• Pain  due to invasion of neurovascular
structures.
• Distal edema  pressure effect on vascular
structures.
• Joint compliants  restriction of joint movements
and bone # can occur .

Retroperitoneal:-
• Usually asymptomatic until reaching large sizes.
• Identified on imaging for unrelated complaints.
• May present with
i. Nonspecific abdominal pain
ii. Palpable abdominal mass.
iii. Anorexia and
iv. Chronic subacute intestinal obstruction
with subsequent weight loss.

Patterns of spread
• Local spread :
• Tends to invade longitudinally along musculoaponeurotic planes
• Rarely transgress fascial boundaries or invade bone
• Compresses surrounding normal tissue to form a pseudocapsule –
• Contains a compression zone and a reactive zone
• The Reactive zone consists of edema, inflammatory cells and tumor cells

LN SPREAD
• STS rarely spread to lymph nodes 1.8% to 3.7% of lymph node involvement at the
time of initial presentation.
• Notable lymph node involvement rates have been demonstrated for epithelioid
sarcoma (20% to 35%), clear cell sarcoma (10% to 18%), rhabdomyosarcoma
(20% to 25%), and cutaneous angiosarcoma (10% to 15%).
• 23% of patients had metastatic disease at presentation.
• The single most common site of distant metastasis (34%) lung,
Bone(24%),liver(16%),brain(2%).
• Retroperitoneal sarcoma and intra-abdominal visceral sarcomas1st site is Liver.

Imaging workup
• MRI is the preferred modality
• T1 weighted images – For disease extent
• T2 weighted images – For peritumoral edema
• CT scan
• Not good soft tissue delineation
• Chest CT scan is recommended to rule out pulmonary metastases for all cases
except low-grade tumour's or small (<5 cm) high-grade lesions
• CT of the abdomen and pelvis : Myxoid liposarcoma (predilection for spread
to the retroperitoneum)

CT MRI(T1)
MRIScanvs CTScan(Demas et al. compared MRI and CT for STS lesions in the
extremity and reported that for 23% of cases, the MRI scans showed tumor
involvement in muscles that appeared normal on CT scan)

Imaging Workup
• PET CT
• Used in cases of recurrence
• Also used for follow up purposes.
• Potential utility to help distinguish malignant peripheral nerve sheath tumors
from benign neurofibromas in patients with neurofibromatosis.
• the detection of malignant transformation in neurofibromatosis.
• the presence of regional or distant metastases
• the response to initial (i.e., neoadjuvant) treatment as a surrogate to
prognosticate on future outcome.
Gunderson

Investigation:
• Following appropriate imaging assessment, the standard approach to
diagnosis consists of multiple core needle biopsies.
• However, an excisional biopsy may be the most practical option for < 3 cm
superficial lesions.
( Excisional biopsy should be avoided, especially for lesions >3 cm in size, as the contamination of
surrounding tissue planes may require the definitive resection to be more extensive.)-DEVITA
• An open biopsy may be another option in selected cases.
• A biopsy may underestimate the tumor malignancy grade. Therefore, when
preoperative treatment is an option, radiological imaging [PET] may be
useful, in addition to pathology, in providing the clinician with information
that helps to estimate the malignancy grade
ESMO-2018

Gunderson
Cytogenic abnormalities

WHO Classification
• Benign
• Do not recur locally, and those that do recur usually are not locally invasive
and can be cured with complete surgical excision.
• Intermediate, locally aggressive soft tissue tumors
• often recur locally and are associated with a locally infiltrative growth pattern.
• Do not have any potential to metastasize but typically require wide excision
with a margin of normal tissue for good local control.
WHO 2013

• Intermediate rarely metastasizing tumors
• Often locally aggressive but in addition can occasionally give rise to distant
metastases. The risk of metastasis, usually to lymph nodes or lung, is typically
less than 2%, but is not reliably predictable based on histology
• Malignant
• potential for local invasion and recurrence, have a significant risk of distant
metastasis, ranging in most instances from 10% to 100%, depending on
histological type and grade.
• Some low-grade sarcomas have a metastatic risk of only 2% to 10%, but these
tumor types may progress to more aggressive tumors
WHO 2013

Histologic Diagnoses
•Malignant Fibrous Histiocytoma (MFH)
a) Undifferentiated pleomorphic sarcoma.
b) Myxofibrosarcoma
c) With inflammation
d) Angiomatoid malignant fibrous
histiocytoma
•Low-grade Fibromyxoid Sarcoma
(Fibrosarcoma)
Sarcomas of Fibrous Tissue Sarcomas of Blood and Lymph Vessels
•Angiosarcoma
•Hemangiosarcoma
•Lymphangiosarcoma
•Epithelioid Hemangioendothelioma
•Hemangiopericytoma
•Kaposi’s Sarcoma
Sarcomas of Peripheral Nervous Tissue
•Malignant Peripheral Nerve Sheath Tumor
(Neurofibrosarcoma).
Malignant granulosa cell tumour
Primtive neuroectodermal tumour.(PNET)
Sarcomas of Unknown Tissue
•Synovial Sarcoma
•Monophasic
•Biphasic
•Alveolar Soft Part Sarcoma
•Epithelioid Sarcoma
•Unclassified Sarcoma
Extraskeletal Sarcomas of Bone
•Extraskeletal Osteosarcoma
•Extraskeletal Chondrosarcoma
•Extraskeletal Ewing’s Sarcoma (PNET)
•Dermatofibrosarcoma Protruberans
•Desmoid Fibromatosis
•Nodular Fasciitis
SOFT-TISSUE SARCOMA
WHO 2013

• Leiomyosarcoma
• GI
• GU
• Skin
• Vessel
• Other
Sarcomas of Smooth Muscle
•Liposarcoma
•Atypical Lipomatous Tumor
•Myxoid Liposarcoma
•Cellular Myxoid Liposarcoma
•Dedifferentiated Liposarcoma
•Pleomorphic Liposarcoma
Sarcomas of Adipose Tissue
Sarcomas of Skeletal Muscle
•Embryonal Rhabdomyosarcoma
•Botryoid RMS
•Spindle cell RMS
•Alveolar Rhabdomyosarcoma
•Pleomorphic Rhabdomyosarcoma
Soft-tissue Tumors of Melanocytic Tissue
•Melanoma of Soft Parts
•AKA - Clear Cell Sarcoma
WHO 2013

Histological subtypes
• Most common subtypes :
• High-grade pleomorphic sarcoma
• Liposarcoma
• Leiomyosarcoma
• Synovial sarcoma
• Malignant peripheral nerve sheath tumor

Grading
• Under histological grading , the two most important criteria appear to be the mitotic
index and the extent of tumor necrosis.
• The two systems most favoured by pathologists are those designated as
 the French Federation of Cancer Centres Sarcoma Group (FNCLCC)
[tumour differentiation , mitotic count and necrosis]
 The National Cancer Institute (NCI)
[tumor histology and amount of tumor necrosis ]

Staging
• AJCC 8th edition
• Based on
• Size of tumor
• Extent of tumor (Superficial / Deep)
• Lymph node status
• Presence or absence of metastasis
• Grade of tumor

Soft Tissue Sarcoma of the Head and Neck
AJCC 8TH

Abdomen
and Thoracic Visceral Organs Gastrointestinal Stromal Tumor
AJCC 8TH

Prognostic Factors for Survival and Local Recurrence
• The most powerful predictor for DFS and OS is the TNM stage of the
tumor.
• Five-year DFS rates for stages I, II, and III STS are 86%, 72%, and
52%, respectively.
• Grade.
• Tumor size, depth, and site.
Poor Prognostic factors :
- Age > 50 years
- Size > 8 cm
- Vascular invasion
- Local infiltration
- Tumour necrosis
- Deep location
- High grade tumors
- Recurrent disease

Significant predictors for LR include positive margins of resection,
presentation with locally recurrent disease, older age, and head and neck
or retroperitoneal location.
Patients who present with locally recurrent disease are at higher risk for
LR (25% to 47%)

Management and Outcome for Soft Tissue
Sarcomas of Extremity and Trunk

SURGERY
Firstintervention
Most effective treatment to ensure cure.
Functionpreservation
Adequate Oncologicclearance

• Marginal resection-simple removal of the tumor with its pseudocapsule.
(LR-42% to 93%)
• Radical resection-removal of all of the muscles and neurovascular structures
within the compartment where the tumor resides or amputation. (LR-0% to
18%)
• Wide resection (conservative surgery (CS) limb-sparing surgery, or function
sparing surgery)-
It involves en bloc removal of tumor with a rim of normal tissue varying in
width from about 1 cm to several centimeters depending on anatomic
constraints. (LR- 25% to 60%)

Radiation Therapy
• Historically, all patients underwent amputation for extremity sarcomas
• NCI randomized study demonstrated that high grade lesions could be
treated with limb-sparing surgery with concurrent adjuvant RT.
• Rates of amputation fell to <10% as postop RT became widely used
after limb-sparing surgery

Conservative Surgery and Radiation Therapy

Wide resection/CS combined with pre- or postoperative
radiation therapy (RT) is the current standard of care for most
high-grade STS.
Most low-grade STS of the extremity and trunk is wide
excision alone.

TIMING OF RADIATION THERAPY
PRE OPERATIVE OR POST OPERATIVE ???

Preoperative Versus Postoperative EBRT:
• Recently, examination of data from 27,969 patients with extremity STS in
the NCDB identified both preoperative and postoperative RT as factors
associated with increased OS.
• However, that data showed that preoperative RT was predictive of achieving
R0 resection.
• In a phase III randomized study conducted by the Canadian Sarcoma
Group, local control and progression-free survival (PFS) rates were similar
in patients receiving either preoperative or postoperative RT in patients with
localized primary or recurrent disease.
• However, preoperative RT was associated with a greater incidence of acute
wound complications (35% vs 17% for postoperative RT), especially in
lower-extremity tumors (43% vs 5% for upper extremity tumors).
• Late-treatment–related side effects were more common in patients receiving
postoperative RT, which is believed to be related to the higher RT dose (66
vs 50 Gy for preoperative RT) and the larger treatment volume.
NCCN 2018

Updated Results of NCI Trial
• 2005
• Late radiation morbidity following randomization to preoperative
versus postoperative radiotherapy in extremity soft tissue sarcoma Davis
AM, Radiotherapy Oncol.2005 Apr;75(1):48-53
• Post-op RT associated with worse fibrosis as well as joint stiffness (although
not statistically significant).
• Outcome: Grade 2+ fibrosis pre-op RT 31% vs. post-op RT 48% (p=0.07)
• Edema, and joint stiffness also more severe in post-op arm
• Joint stiffness and fibrosis worse with larger field size

• 5 studies (1 RCT and 4 retrospective cohort) -1098 patients
• Localized, resectable, STS.
• Comparis5 studies (1 RCT and 4 retrospective cohort) -1098 patients
• Localized, resectable, STS.
• Comparison of pre operative versus and post operative Radiaotherapy
• Outcome:
• Local recurrence better in pre operative group (HR = 0.6, Significant)
• Survival : Pre operative - 76% vs Post operative - 67%
• Conclusion:
Delay in surgical resection for pre operative Radiation therapy does not increase mortality
Local recurrence lower after pre operative Radiation therapy
Annals of Surgical Oncology
May 2010, Volume 17, Issue 5, pp 1367-1374

Indications for Radiotherapy
• Post Operative :
• All Deep seated tumors
• All High grade tumors
• Intermediate grade tumor, size >5cm
• Low grade tumors :
• Positive or close (<1cm) resection margins
. Tumor location that would not be
amenable to subsequent salvage surgery
Recurrent disease following
initial wide excision
Pre Operative
• Unresectable disease
• Resectable disease but resection
will lead to significant functional loss

•Radiation Therapy Techniques

Radiation Therapy
• Positioning the Patient: the limb is positioned as far away from the
trunk (for upper extremities) or from the opposite limb (for lower
extremities) as possible.

Target Volumes and Treatment Fields
Preoperative Radiation Therapy:
• Fusion of the diagnostic MRI and planning CT for optimal target definition is
strongly encouraged.
• GTV is defined as the gross tumor delineated by the T1 postgadolinium MRI.
• Clinical target volume (CTV) is defined as the GTV plus 3-cm margins in the
longitudinal directions and 1.5-cm margins radially.
• PTV: CTV plus 5 to 10 mm

Postoperative Radiation Therapy
• The CTV should encompass all the tissues handled during the surgery including the
incision and any drain sites. (Postoperative changes seen on MRI help define the
operative bed.)
• An additional longitudinal margin of 2 to 4 cm and a radial margin of 1.5 to 2 cm is
generally added to the operative bed to form the CTV.
• The PTV is typically CTV plus 5 to 10 mm.
• A second (and sometimes third) course field reduction is typically used in the
postoperative setting. CTV margins for the reduced field(s) vary and can include about 2
cm on the operative bed or on the initial GTV.
(Baldini et al. found no recurrences in 36 patients with resection margins ≥1 cm compared to an
actuarial 10-year LR rate of 13% (4 of 38) for those with margins <1 cm.)

Are large CTV Expansions necessary ?
• 2 Prospective Randomised controlled trials are addressing this issue
• VORTEX Trial : Volume Of post-operative RadioTherapy given to
adult patients with eXtremity soft tissue sarcoma
• RTOG 0630 : A Phase II Trial of Image guided pre operative
Radiotherapy for Primary Soft tissue sarcomas of the extremity

Results: Two hundred sixteen patients were randomized, 108 in each arm.
• Tumor/normal tissues were collected from 206 randomized and 301 registered
patients.
Median follow-up was 4.8yr (C and R).
The 5-year local recurrence free survival (LRFS) rates were; for C: 86% and for R:
84%.
For C the 5-year overall survival was 72% and for R 67%.
There were no statistical differences between the arms in late radiation toxicity
grade 2+ at 2 years.
Conclusion: There was no difference in limb function at 2 years between control and
research arms. Because of the small number of events it was not possible to state
whether or not the research arm was inferior for LRFS.

Doses
• The standard dose for preoperative external-beam RT is 50 Gy
delivered in 2-Gy fractions. In the situation of positive margins, a
postoperative external-beam RT boost of 16 to 20 Gy (delivered in
1.8- to 2-Gy fractions) is sometimes delivered.
• For postoperative external-beam RT, treatment usually commences
about 4 to 6 weeks following surgery and once the wound is fully
healed. Recommended total doses are 60 to 66 Gy (delivered in 1.8- or
2-Gy fractions) for the case of negative margins and 66 to 68 Gy for
positive margins

Principles of Treatment Planning
• Basic tenets for treating the extremity are to “spare a strip” of the limb
circumference (to prevent subsequent lymphedema and pain), to avoid
treating the whole thickness of bone to high doses (to diminish risk of
fracture), and to avoid treating an entire joint to high doses (to
decrease joint stiffness).
• With IMRT, in order to achieve more dose conformality, the tradeoff is
that the volume of tissue that receives a low dose is increased; for
some of these cases, the entire circumference of the limb may receive
some low dose.

Radiation Therapy Toxicity
• Chronic Toxicity :
• Edema
• Subcutaneous fibrosis
• Decreased muscle
strength
• Decreased range of
motion and pain
• Bone fracture
• Peripheral nerve
damage
Acute Toxicities
• skin erythema and possible
desquamation in high-dose areas,
• problems with wound healing,
• localized alopecia,
• fatigue.
• Moist desquamation can be quite
uncomfortable,

Pre Operative Radiation Therapy
Advantages
• Smaller RT fields
• Lower RT doses
• Reduced treatment time
• Tumor down staging
• Radiobiological advantage
Disadvantages
• Higher risk of major wound
complications

Post Operative Radiation Therapy
Advantages
• Complete tumor specimen is
available for pathology review
for determination of histology
and margin status
• Lower risk of major wound
complications
Disadvantages
• Larger treatment volumes
• Higher doses
• More hypoxic tissue –
Radiobiological disadvantage
• High incidence of late toxicity

Chemotherapy
• There is no clear evidence showing that chemotherapy, adjuvant or neoadjuvant
showing significant improved OS or PFS.
• Drugs tried are
1) Doxorubicin
2) Ifosfamide
• Chemotherapy is effective only in
i. Rhabdomyosarcoma
ii. Ewing’s sarcoma.
ESMO 2018

Locally recurrent sarcomas
• Sarcomas have high local recurrence.
• The treatment modalities available are
1. Radical re-excision(amputation).
2. Limited resection with adjuvant RT(if previously not given).
• Brachytherapy is preferred over EBRT as it decreases dose to normal
tissues.

Metastatic disease
• Chemotherapy is the main modality for treating metastatic disease.
• Anthracycline based regimens were found to be effective.(doxorubicin
with ifosfamide and Mesna).
• Recent evidence showed gemcitabine in combination with docetaxel
showed increased survival.
P=0.005
P=0.009

Management of advanced/metastatic disease
• Metachronous (disease-free interval1 year), resectable lung metastases without extrapulmonary
disease are managed with surgery as standard treatment, if complete excision of all lesions is feasible.
• Standard ChT is based on anthracyclines as the first-line treatment [I, A]. Multi-agent ChT with
adequate-dose anthracyclines plus ifosfamide may be the treatment of choice, particularly in subtypes
sensitive to ifosfamide, when a tumour response is felt to be potentially advantageous and patient PS
is good [I, B]
• The combination of doxorubicin with an anti-PDGFRA agent, olaratumab, is option.
• Gemcitabine/docetaxel combination is not generally recommended as a first-line therapy for
advanced STS patients [I, D]
• Imatinib is standard medical therapy for those rare patients with dermatofibrosarcoma protuberans.
• Trabectedin is an option for second line and is approved for advanced previously treated STS.
• Pazopanib is an option in non-adipogenic STS.
• Eribulin is an option in patients with liposarcomas and LMS.
• Regorafenib is an option in doxorubicin-pretreated advanced, non-adipogenic STS patients.
• Crizotinib in inflammatory myofibroblastic tumours associated with ALK translocations.
Sunitinib and cediranib in alveolar soft part sarcoma, where the molecular target is as yet unclear and
Sunitinib in solitary fibrous tumours [IV, C]
ESMO 2018

Fallow up
Surgically-treated intermediate-/high-grade patients may be followed
every 3–4 months in the first 2–3 years, then twice a year up to the fifth
year, and once a year thereafter.
Low-grade sarcoma patients may be followed for local relapse every 4–
6months, with chest X-rays or CT scan at longer intervals in the first 3–
5 years, then annually.
ESMO 2018

Soft tissue sarcoma

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