STS

Yemisrach M. ( MD,Clinical
Oncologist)
Outline
• Introduction
• Epidemiology and etiologic factors
• Molecular biology
• Histologic classification(WHO)
• Anatomic distribution
• Diagnosis and Histologic Grading
• Staging

GTZ 2
 Introduction
STS comprise a group of relatively rare but anatomically and histologically
diverse group of malignant tumors that arising primarily from mesenchymal
tissue.

The histopathologic diversity is due to embryonic mesenchymal cells capacity

to mature into different soft tissue.

Soft tissue structures consist of

 Muscles
 Fat
 Fibrous tissues
 Blood vessels
Epidemiology and etiologic factors
Benign soft tissue tumors are 100 times common than malignant
tumor
malignant STT account for less than 1% of adult malignancies and
15% of pediatric malignancies.
more common with increased age, and the median age at diagnosis
is 65 years.
However, the median age varies significantly by histologic type and
molecular class.
Most soft tissue sarcomas are believed to be sporadic but small
proportion of cases are associated:
 Genetic factors
 Lymphedema
 Prior radiation therapy
no. Etiology Effects
Con..
1 Genetic factor APC mutation. E.g desmoid tumors
Mutations in the NF1. MPNST
Li- Fraumeni syndrom or GL P53 mutation is associated
with soft tissue or bone sarcomas of diverse histology.
2 Lymphedema Postmastectomy , postirradiated and filarial infection
associated ymphedema.
Angiosarcoma
3 Radiation  UPS, angiosarcoma, fibrosarcoma, LMS, malignant
peripheral nerve sheath tumor (MPNST) and
osteosarcoma.
 The median interval between radiotherapy and
development of a radiation-associated sarcoma was 10
years
4 Viral infection and  Human herpes virus infection is associated with
immunodeficiency development of Kaposi sarcoma.
 Epstein-Barr virus is associated with smooth muscle
tumor
 Molecular biology of STS
Most sarcoma subtypes demonstrate their own underlying biology because
sarcomas are diverse a set of tumors in terms of molecular biology.
From genetic change point of view sarcomas tend to fall into two major
subsets.
1. Simple karyotype:-This group of STS are cytogenetically simple and
consist of sarcoma with near diploid karyotype and simple genetic
alteration( translocation, inversion or specific activating mutation).
Typically occur in young adult with highest incidence b/n 30 and 50
2. Complex karyotype:-It is characterized by aneuploidy and the lack of
specific fusion genes. commonly have alterations in cell-cycle genes
TP53, MDM2, RB1 and defects in specific growth-factor signaling
pathways.
The peak incidence for these complex sarcoma types is in the 50s and 60s
 Con..
No. Simple karyotype STS Complex karyotype STS
1 Alveolar soft part sarcoma UPS
2 Myxoid liposarcoma Liposarcoma (types other than
myxoid)
3 Synovial sarcoma Fibrosarcoma (other than congenital)

4 Clear cell sarcoma Embryonal rhabdomyosarcoma

5 Ewing sarcoma and PNET Leiomyosarcomas

6 Desmoplastic small round cell tumor Angiosarcoma

7 Extraskeletal myxoid chondrosarcoma MPNST
 Pathologic Classification of STT
There are more than 70 histologic subtypes of STT with unique
molecular, pathologic, clinical, prognostic, and therapeutic
features.
WHO classifies most soft tissue neoplasms according to the
presumptive tissue origin (ie, the normal tissues the tumor most
closely resembles).
In some cases, histogenesis is uncertain, and the designation
reflects the architectural pattern. e.g
 Alveolar soft part sarcoma
 Epithelioid sarcoma
 Clear cell sarcoma.
 Con..
By WHO STT classified into four categories:
1. Benign tumor
2. Intermediate (locally aggressive)
3. Intermediate (rarely metastasizing)
4. Malignant tumors (soft tissue sarcomas)
 The common locally aggressive STT
N Behavior Histologic subtype
o-
1 Superficial Fibromatosis
Intermediate locally aggressive tumor Desmoid Tumor

2 1. Kaposi sarcoma
2. Dermatofibrosarcoma
Protuberans
Intermediate rarely metastasizing 3. Inflammatory
Myofibroblastic
tumor Tumor
4. Solitary Fibrous
Tumor/Hemangioperi
cytoma
5. Epithelioid
Hemangioendothelio
ma
The common histologic sub type of STS
There are more than 50 histologic subtypes of STS. The most common
subtypes include:
1. Undifferentiated pleomorphic sarcoma
2. Liposarcoma
3. Leiomyosarcoma
4. Myxofibrosarcoma
5. synovial sarcoma
6. Malignant peripheral nerve sheath tumor.
Together these tumor account for about 75% of STS cases.
 1. Liposarcoma
No.
WDLS It is LARMT with typical chromosome 12 amplification .it
has 3 to 20% of risk of dedifferentiation based of
location.
DDLS It is intermediate to high risk sarcoma that has non
lipodenic differentiation with area of necrosis and has
chromosom 11 copy no. alteration in addition to
chromosome 12 amplification of WDL
Myxoid or round cell The tumor consist of variable number of a fat cell, small
liposarcoma number of signet ring cell and multi vacuolated lipoblast.
The prognosis is deplaned on percentage of the round
cell.
It has an extraordinarily high response rate to
radiotherapy and their substantial sensitivity to
ifosfamide.
Pleomorphic It is high grad tumor account for 5% of LS. It commonly
liposarcoma occur in older individual at lower extremity.
 2. Leiomyosarcoma
It is highly aggressive STS arises from the smooth
muscle of blood vessels and visceral structures.

>50% occur at retroperitoneal or intra-abdominal and

pelvic area.

This tumor cxzed by genomic instability and numerous

copy number alterations including loss of TP53 and
PTEN.
 3. High-Grade Undifferentiated Pleomorphic
Sarcoma(UPS)

By using IHC technique more than 84% of this tumor are

reclassified into other histologic type such as :
 Myxofibrosarcoma
 myofibroblastic sarcoma
 liposarcoma
 soft tissue osteosarcoma
 MPNST
Therefore the term UPS is now reserved for pleomorphic
sarcomas that by current technology , it doesn’t show no
definable line of differentiation.
UPS typically has aggressive clinical course.
 4. Synovial Sarcoma

It is a spindle cell tumor with varying extents of epithelial differentiation,

including gland formation.
Synovial sarcoma generally does not originate from synovial tissue and may
be encountered in regions without apparent relationship to synovial
structures, including the head and neck.
It occur between 15 and 35 years of age and more common in males.
Nearly all synovial sarcomas contain (X;18) chromosomal translocation, so
this genomic signature has become the gold standard in diagnosis.
Histologically it may be monophasic or biphasic.
 5. Fibrosarcoma
It is a high grad or intermediate (rarely
metastasizing) tumor with homogenous spindle
cells, variable collagen production and rare
pleomorphisim.
It is usually involve the deep tissues of the
extremities, trunk, head, and neck.
Rarely fibrosarcomas arise in the ovary or other
unusual sites such as the trachea.
 6. Myxofibrosarcoma

Histologically it shows a fibroblastic lesion with pleomorphism and at least a

10% myxoid component.
Myxofibrosarcoma exhibits an infiltrative growth pattern and is associated
with higher rates of positive resection margins and local recurrence (LR)
compared to other STS
but the rate of distant recurrence to lung is lower than other STS.
 7. MPNST or neurofibrosarcoma

It is aggressive STS that rarely occur in the general population.

But the lifetime incidence is 8% to 13% in patient with NF1.
The lower extremity and the retroperitoneum (from major
nerves of the body wall and extremities) are the most common
sites
The majority of MPNSTs are high-grade and stain for the S-100
protein.
Patients with NF1-associated MPNST have a worse outcome than
sporadic MPNST.
Anatomic distribution
 Natural history
Local growth pattern
Soft tissue sarcomas grow at various rates depending on the aggressiveness
of the tumor.
Tumors tend to grow along tissue planes and rarely traverse major fascial
planes or bone.
Regional nodes spread
Unlike most solid tumors STS has only 1.8% to 3.7% of LN involvement .
But some HT of STS has higher incidence of LN involvement
1. Epithelioid sarcoma (20% to 35%)
2. Rhabdomyosarcoma (20% to 25%)
3. Clear cell sarcoma (10% to 18%)
4. Angiosarcoma (10% to 15%)
Pattern of distant speed or Metastasis
 Histologic Grading
Grading based on morphology only may evaluates the degree of
malignancy and predicts prognosis. The features that define grading of
STS include
 Mitotic index
 Necrosis
 Cellularity
 Pleomorphism
 Histologic type and subtype or differentiation.
Other molecular parameters such as mutation of p53 and a high Ki-67
are associated with high grade and poor survival.
Unfortunately the criteria for grading are neither specific nor
standardized and there is no general consensus on morphologic criteria.
 Clinical presentation
The most common presentation of STS is painless and rapidly
increase soft tissue a swelling .
On P/E the size, depth, fixation to underlying structures, the
presence of overlying skin changes, the potential evidence of
neurovascular compromise and LAP should be assessed.
The focus of the clinical evaluation is:
 To determine the likelihood of a benign or malignant
tumor
 To assesse the disease extent including metastasis
 To determine the type of biopsy we take with subsequent
excision in mind.
 Diagnosis
 Soft tissue mass of any size that is deep to the muscle
fascia
 Soft tissue mass >5 cm (golf ball size or larger)
 Soft tissue mass that is increasing in size rapidly.
 Recurrence soft tissue mass after previous excision
Should highly suspected and considered for tissue
diagnosis.
The histologic diagnosis of a soft tissue sarcoma is made
on the basis of morphologic pattern from cor needle or
incisional biopsy.
Staging
Prognostic factors for survival and local recurrence

There are many patient and tumor related prognostic factors that
determine for disease-free survival (DFS) or overall survival (OS) and local
recurrence (LR). This include:
 TNM staging
 Tumor site
 Histologic sub type
 Age
The most powerful predictor for DFS and OS is the TNMG stage of the
tumor. DFS rates for stage I, II, and III STS are 86%, 72%, and 52%,
respectively.
The single most important individual prognostic factor for survival is
grading.
Other significant predictors for DFS include tumor size, site and age.
 Con..
Tumors located in the head and neck or
retroperitoneal have lower survival rates than those
with tumors located in the extremity or superficial
trunk.
Significant predictors for local recurrence include
 Positive margins of resection
 Presentation with locally recurrent disease
 Older age
 head and neck or retroperitoneal location.
 Evaluation and Workup
• Essential Elements of Work-up include:
– History and Physical Examination

– Imaging of the Primary Tumor By MRI+/-CT-scan

– Imaging for Metastatic sites (CT-scan, CXR)

– Biopsy of the primary site after Imaging (Tru-

cut/CNB or Incisional Biopsy)
– All patients should be Evaluated in Sarcoma-MDT
 IMAGING
MRI with contrast+/-CT-scan for the Primary
tumor is preferred
To provide details about tumor size and
contiguity to nearby visceral structures and
neurovascular landmarks

Chest CT-Scan(preferred)for:-
large size High grade tumors
Deeply located tumors
CXR for Lung Met for
Small high grade tumors
Low grade tumors

Abdominal/pelvic CT for
Angiosarcoma,
LMS,
myxoid/round cell LPS, or
epithelioid sarcoma
• MRI of the total spine should be considered for
myxoid/round cell LPS
• Brain MRI (or CT if MRI is contraindicated) should be
considered for patients with
– alveolar soft part sarcoma
– Angiosarcoma
• PET scans may be useful in staging, prognostication,
grading, and determining histopathologic response to
chemotherapy.
 BIOPSY

• Pretreatment biopsy should be carefully planned

• Used for the diagnosis and grading of STS

• Core needle Biopsy(preferred) or incisional biopsy

• Biopsy placed along the future resection axis with

minimal dissection and careful attention to hemostasis

• FNAC- not accurate for primary diagnosis

• FNAC- used for confirmation of recurrence

• FNAC- discouraged in STS DX

• Avoid Excisional Biopsy especially for Tumor size

>3 cm
 Standard Pathology Report
should include:-
• Subtype of Primary STS (using WHO Classification)

• Status of excision margins

• Histologic grade of the tumor

• Depth, size ,organ and site of sarcoma

• Presence or absence of necrosis

• TNM stage

• Mitotic rate

• Presence or absence of vascular invasion

• Type and extent of inflammatory infiltration

General Principles of Treatment of
Localized STS of the Extremity

• Surgery

• Radiotherapy

• CCRT

• Chemotherapy
 SURGERY

• Gold standard primary Rx for STS of Extremity is WLE

with negative margin.
• Goal of surgery for STS of extremities should be
functional limb preservation with appropriate
oncologic resection.
 Surgery
• >1 cm negative margin is adequate
• <1 cm margin(close margins) for:
– Preserving uninvolved critical neurovascular
structures, bones, Joints
– Low Grade STS (e.g. Well Differentiated LPS)
• >2 cm margin for tumors with infiltrative borders –
DFSP, Myxofibrosarcoma, angiosarcoma
 Surgery
• The biopsy site should be excised en bloc with the
definitive surgical specimen
• If resections with positive margins are anticipated,
surgical clips should be placed to help guide future RT.
• If surgical margins are positive on final pathology, re-
resection to obtain negative margins should be strongly
considered
 Types of Surgery
• Limb sparing surgery +/-Adj.RT
– is an effective treatment for extremity STS.

– recommended for STS of extremities to achieve local

tumor control with minimal morbidity

• Amputation:
– reserved only for cases where resection or reresection
with adequate margins cannot be performed without
sacrificing the functional outcome.
Radiotherapy for Localized STS of
Extremity
 Radiotherapy

• RT can be administered either as primary,

preoperative, or postoperative treatment
• RT is not a substitute for definitive surgical
resection with negative margins, and re-
resection to negative margins is preferable
Pre-op RT Vs Post-OP RT. Which one is
better?
 Advantage and Dis-advantage
ADVANTAGE DIS-ADVANTAGE

Well defined RT target .1 1. Higher risk of Acute

Volume Wound complications
Intact Blood Supply which .2
Pre-OP RT increases sensitivity to RT
3.Short Course of treatment

Pathology Result and .1 Less precisely defined .1

margin status are available RT target volume
Post-OP RT to direct Rx
Higher late tissue .2
toxicity

Large RT target .3
volume
 Indications for Adjuvant RT
1. close soft tissue margins (<1 cm)

2. microscopically positive margin on bone, major

blood vessels, or a nerve
3. In selected cases with uncertain margin status

4. If Local Recurrence causes Amputation or

sacrifice of Critical structures
5. For locally Recurrent Tumors
• RT may not be necessary in patients with:-
– small low-grade lesions (5 cm or less)
– Atypical Liposarcoma or Well Differentiated LPS
– Superficial STS
• When the expected toxicity of RT is high and the risk of
LR is predicted to be low (based on surgical margins,
tumor size and location, or other parameters), surgery
without adjuvant RT may be the treatment of choice
 BRACHYTHERAPY
• Brachytherapy involves the direct application of
radioactive seeds into the tumor bed through catheters
placed during surgery.
• Options include
– low dose-rate (LDR) brachytherapy (Ir-192,I-125)
– fractionated high dose-rate (HDR)
– intraoperative HDR brachytherapy
 IORT

• IORT is the delivery of radiation during surgery

• It can be performed using electron beam RT or
brachytherapy.
• IORT-/+EBRT for STS involving neurovascular
structures
 CCRT for Localized STS of
Extremity
• Preoperative chemoradiation has been shown to improve
OS, DFS, and LC in high-grade STS of extremity and
trunk, although acute reactions must be considered

• CCRT is category 2B recommendation for localized STS

of the extremity
Chemotherapy for localized STS of the
Extremity

• The use of neoadjuvant and adjuvant chemotherapy in

soft tissue sarcomas is controversial
• Both Neo-adjuvant and Adjuvant Chemotherapy for
localized STS are Category 2B recommendations
 Neo-adjuvant Chemotherapy for
localized STS
• Neo-Adjuvant chemotherapy downstages large
high-grade tumors
• Indications for Neo-adjuvant Chemotherapy
– Large High grade tumors>10 cm (T3 and T4)
– Chemosensitive Histologies (Synovial Sarcoma,
Pleomorphic LPS, Myxoid LPS and Angiosarcoma)
 Adjuvant Chemotherapy for
localized STS
• Adjuvant chemotherapy improves relapse-free
survival (RFS) in patients with STS of extremities.
• However, data regarding OS advantage are
conflicting
• Adjuvant Chemotherapy is a Category 2B
recommendation for Stage III STS of extremity
Sarcoma Meta-analysis Collaboration
(SMAC meta-analysis)

Meta-analysis of 1568 patients from 14 trials

of doxorubicin-based adjuvant chemotherapy

Adjuvant
Chemo

There was improvement of Local RFS, distant

RFS and overall RFS but OS was not
significant
Summary Of management of Localized
STS of Extremity