Comprehensive overview of soft tissue sarcoma: staging, diagnosis, risk stratification and treatment

1. Ahmed Zeeneldin
Associate professor of Medical Oncology

2. • US:
• In 2012: 11,280 new cases and 3,900 mortalities
• adults: 1%, pediatrics: 15%
• Egypt:
• GPBCR: adults: 2.5%, pediatrics: 10%
• NCI: adults: 2.8%, pediatrics: 10%
• RT is a risk factor

3. • Most common primary sites
• Extremities (60%),
• Trunk (19%),
• Retroperitoneum (15%)
• Head and neck (9%)
• Most common metastatic sites
• Generally : lungs
• With abdominal tumors: liver and
peritoneum

4. • Mesenchymal cell origin
• Fibrous: MFH, Fibrosarcoma, Myxofibrosarcoma,
fibromyxoid sarcoma
• Fat: liposarcoma
• Muscle: SM: Leiomyosarcoma, Sk m: Rhabdomyosarcoma,
• nerve and nerve sheath (Malignant peripheral nerve
sheath tumor),
• blood vessels (hemangioendothelioma, Angiosarcoma)
• Chondro-osseous Tumors (Extraskeletal chondrosarcoma,
Osteosarcoma)
• Uncertain origin:
• Synovial, Epithelioid, Alveolar, Clear cell , Desmoplastic small
round cell
• Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing
• Extraskeletal myxoid chondrosarcoma
• Extrarenal rhabdoid tumor
• Undifferentiated sarcoma;
• Sarcoma, not otherwise specified (NOS)

5. Most common subtypes of STS
• In children:
• Rhabdomyosarcoma
• in adults
• Pleomorphic sarcoma (MFH),
• GIST,
• liposarcoma,
• leiomyosarcoma,
• synovial sarcoma,
• malignant peripheral nerve sheath tumors

6. Molecular Diagnosis of STS
• (i) sarcomas with specific genetic alterations and usually
simple karyotypes (eg, chromosomal translocations or point
mutations); and
• (ii) sarcomas with non-specific genetic alterations and
complex unbalanced karyotypes.
• Methods:
• Conventional cytogenetic analysis,
• Fluorescence in-situ hybridization (FISH) and
• Polymerase chain reaction (PCR)

7. • EWSR1-ATF1 in clear cell sarcoma,
• TLS-CHOP (also known as FUS-DDIT3) in myxoid or round cell
liposarcoma,
• SS18-SSX (SS18-SSX1 or SS18-SSX2) in synovial sarcoma, and
• PAX-FOXO1 (PAX3-FOXO1 or PAX7-FOXO1) in alveolar
rhabdomyosarcoma].

8. Evaluation and Workup
• H&P: for DD
• Lab: limited role
• Bx:
• core or open biopsies by experienced members.
• FNA is generally inadequate
• Radiology:
• Local:
• MRI: most important particularly in extremity STS
• CT: most important particularly in retroperitoneal STS
• Plain XR: optional
• Possible metastatic sites:
• CT Chest: in all cases
• CT Abdomen and pelvis: myxoid round cell liposarcoma, angiosarcoma, leiomyosarcoma or
epithelioid sarcoma
• MRI spine: myxoid round cell liposarcomas
• CT/MRI brain Alveolar soft part sarcoma (ASPS)
• Local and Metastatic sites:
• PET or PET/CT

9. PET or PET/CT in STS
• Values:
• Prognosis and grading:
high SUVmax correlates
with higher tumor grade
and worse survival and
disease progression
• response to chemotherapy for
firm, and deep >3 cm, high-
grade extremity STS:
decrease SUVmax (35-40%
drop particularly after 1st
cycle) correlates with
response, RFS, DFS

10. • T1: <= 5 cm
• A: superficial ( to and not invading superficial fascia)
• Deep ( to or invading superficial fascia)
• T2: > 5 cm
• A: superficial ( to and not invading superficial fascia)
• Deep ( to or invading superficial fascia)
• No T3 or T4
• NB: ovary has no T4
T1 T2 N1 M1
• N1: regional LN (RARE) G1, GX IA IB III IV
• M1: distant mets G2 IIA IIB III IV
G3 IIA III III IV
• Low grade: G1
• High grade: G2,3
• Grade cannot be assessed: GX

11. • Surgery:
• Mainstay
• Problems: recurrence, incomplete resection for difficult sites
• RT:
• May be used pre, intra, or postoperative
• May be used as definitive Tx
• External beam, brachytherapy or radiosurgery
• Systemic therapy:
• May be used ad neoadjuvant or adjuvant
• May be combined with RT
• May be used alone in disseminated disease
• Includes: chemotherapy, targetd therapies

12. • Standard primary treatment for most sarcomas
• Extremity STS
• Limb sparing surgery (LSS) is recommended to preserve function
• Amputation for non-functional limb or infeasible LSS or patient
preference
• If adequate initial surgery cannot be done:
• Preoperative chemo or radio or chemoradio
• To decrease local recurrence
• Chemo or radio can be used (either pre or post)
• Negative SM is always desirable and may need re-resection
• Adjuvant RT in:
• Close SM (<1 cm; R0)
• Microscopic + SM (R1) on bone or major blood vessels

13. compartment resection is
not routinely necessary
• Resect the tumor with appropriate negative margins (>1 cm)
• Close margins (<1 cm) may be necessary to preserve uninvolved
critical neurovascular structures, bones, joints.

14. • Ideally, the biopsy site should be
excised en bloc with the definitive
surgical specimen
• Metalic clips can indicate suspiciuos
margins to help RT

15. Surgical margin (SM) and residual (R)
• Negative SM = R0
• Adequate: >1cm
• Close: < 1cm
• Close margins may be necessary to preserve uninvolved critical
neurovascular structures, bones, joints
• Adj RT is given in close margins
• Positive SM = R1 or R2
• R1 resection - Microscopic residual disease
• R2 resection - Gross residual disease
• surgical re-resection to obtain negative margins should strongly be
considered if it will not have a significant impact upon functionality
• Adj RT is given in microscopically positive margin (R1) on bone, major
blood vessels or a nerve
• Uncertain margin:
• Consult radiotherapist

16. • Because the risk of failure in the
surgical bed can be high, Many
clinicians augment surgery with
RT and chemotherapy, either
preoperatively or postoperatively,

17. • Source:
• EBRT: conventional or IMRT
• Brachytherapy
• Timing
• Preoperative: 50 Gy
• Easier surgery
• Poor wound healing
• Boost if close or positive SM
• Postoperative
• Improve local control in high-grade extremity STS with positive SM or
higher stage (III), old age
• May be partly given immediately (Intraoperative) and completed
later

18. Chemotherapy or chemoradiation
• Preop chemoradiation:
• Value: increase local control, DFS and OS
• CTàRT±CTàSurgery à±CT
• Regimens:
• Doxorubicin (30 mg/m2/d x 3) concurrent with RT (300 cGy x 10)
• IMAP x 2àRT±MAP on rest days (0, 21, 42) àIORT
• MAID+RT (44 GY split)àsurgery àMAID x 3 if SM+
• Preop chemotherapy:
• Value: inconsistent
• CTà surgery à±CT
• Regimens:
• MAID

19. Chemotherapy
• Postop (adjuvant) chemotherapy:
• Value: improve RFS and OS of extremity STS
• EORTC trials lack OS benefit??
• surgery àCT
• Regimens:
• Doxorubicin based (doxo-ifos)
• Epirubicin based (epi-ifo)
• Definitive chemotherapy:
• In advanced, unresectable or metastatic disease
• Single agents: dacarbazine, doxorubicin, epirubicin or ifosfamide,
gemcitabine, docetaxel, vinorelbine, pegylated liposomal
doxorubicin and temozolomide
• Anthracycline-based combination regimens: doxorubicin or
epirubicin with ifosfamide and/or dacarbazine

20. Definitive Chemotherapy/targeted
Therapy
• In:
• advanced, irrresectable or metastatic disease
• Approaches:
• Single agents CT:
• dacarbazine, doxorubicin, epirubicin or ifosfamide,
• gemcitabine, docetaxel, vinorelbine, pegylated liposomal doxorubicin
and temozolomide
• Trabectedin: good RR
• Combinations CT:
• Anthracycline-based combination regimens: first-line
• doxorubicin or epirubicin with ifosfamide and/or dacarbazine
• Non-antracycline combination regimens: after failure of anthracycline
• gemcitabine and docetaxel particulalry in LMS
• Targeted Tx:
• Pazopanib: after failure of doxo-based regimens, Prolongs PFS, No in
liposarcoma
• Ohers: sunitinib, imatinib, crizotinib, sirolimus, avastin

21. Treatment of STS of
extremities and trunk
G Obs Preop Preo Preop Surg Posto Posto Posto
erve RT pCT CRT p RT p CT p CRT
I T1 (small, <5) 1 √ may
T2 (large, >5) 1 √ √
II T1 (small, <5) 2,3 May May √ √ May
T2 (large, >5) 3 May May √ √ √ May
III T2 (large, >5) 3 May May √ √ √ May
N1 May May √+ √ May
Radical LND
IV Limited M1
Dissemin’d May if May MAY May
M1 Sym-
Post op RT if : SM <1cm, non-intact fascial plane

22. Treatment of STS of
retroperitoneum or intra-abdominal
Obs Preop Preo Surg Posto Posto
erve RT pCT p RT p CT
Resectable May May √ ± IORT May May
in R1
or
Boost
Unresectable √ √ √ if becomes resectable
Otherwise as M!
IV Limited M1
Dissemin’d May if May MAY May
M1 Sym-
Post op RT if : SM <1cm, non-intact fascial plane

23. Desmoid Tumors
(Aggressive Fibromatoses)
• Mesenchymal neoplasms
• Well-circumscribed, differentiated fibrous tissue with no
histopathological features of malignancy.
• However, they are often categorized as low-grade sarcomas
• locally destructive and infiltrative but rarely metastasize
• Need extensive surgery
• Tend to recur locally after excision with long natural history
• 10% of patients died of progressive disease.

24. • Abdominal wall of young
pregnant females
• Intra-abdominal
mesenteric masses, and
large extremity masses in
older men and women.

25. • Component of the familial adenomatous polyposis (FAP)
• may also arise through elective surgical intervention (eg,
colectomy) in susceptible patients.
• 85% have mutations in exon 3 of CTNNB1 gene encoding for β
catenin AND this was associated with more recurrences

26. Evaluation and Workup
• H& P
• Exclude Gardner’s syndrome
• Imaging:
• Local: CT or MRI
• Chest
• Biopsy

27. Resectable Tumors Irresectable Tumors
• Observation: • Observation
• small size, asymptomatic, • Definitive RT (54-58 Gy)
favorable sites • No prior RT only
• In extremity, head and neck or
• Surgery: superficial trunk
• Mainstay • Not in retroperitoneal/intra-
abdominal
• Large size, symptomatic, • very slow response (~2ys)
unfavorable sites • Systemic therapies:
• Preop RT or systemic therapy • NSAIDS
may be given • Hormonal therapies
• Postop RT if large tumors or • Biologic therapies
SM+ (R1) • Surgery
• Radical surgery if the above fails

28. Systemic treatment of desmoids
• Indications:
• advanced or unresectable desmoids
• Agents
• NSAIDS: sulindac or celecoxib
• Hormonal: tamoxifen, toremifene
• Biological agents: low-dose interferon
• Chemotherapy: methotrexate and vinblastine, doxorubicin-based
regimens
• tyrosine kinase inhibitors: imatinib and sorafenib

29. Rhabdomyosarcoma (RMS)
• histologic subtypes:
• Embryonal: children
• Alveolar: adolescents
• Pleomorphic: adults and aggressive
• extremities (26%)
• trunk (23%)
• genitourinary tract (17%) and
• head and neck (9%)

30. • Multidisciplinary
• Surgery, RT, chemotherapy
• Emberyonal and alvelar: May use pediatric protocols

31. • VD±C: vincristine and dactinomycin (with or without
cyclophosphamide),
• VAC: vincristine, doxorubicin and cyclophosphamide
• VAC alternating with ifosfamide and etoposide
• HD methotrexate with CNS and leptomeningeal invovlvment
when RT is not feasible

34. Amputation LSS+RT p
Number 16 27 2:1 randomization
Local Recs % 0 4 0.06
DFS% 78 71 0.75
OS% 88% 83% 0.99
Highest recurrence was for SM+
65 patients received postop: Adriamycin, cyclophosphamide, MTX
Chemotherapy No chemotherapy p
3-y DFS% 92 60 0.0008
3y- OS% 95 75 0.04