Soft tissue sarcoma

1. Soft tissue sarcoma
Devita 2019
PEREZ 2019
UP TO DATE

2. Anatomic and Age Distribution
 Extremities : 45%
 Lower limb (most commonly in the thigh ) : 30%
 Intra-abdominal : 38%
 Visceral : 21 %
 Retroperitoneal : 17%
 Truncal : 10%
 Head and neck : 5 %
 STS become more common with increased age and the median age at
diagnosis is 65 years

3. Etiology and Risk Factors
Most STS : sporadic
predisposing factors :
 genetic factors,:
 FAP : Desmoid tumors
 NF1 with mutations in NF1 gene: MPNST
 Li-Fraumeni : germline mutation TP53
 Heritable retinoblastoma
 Lymphedemaangiosarcoma(postmastectomy, post RT lymphedematous )
prior RT ANGIOSARCOMA
 Carcinogens hepatic angiosarcomas : thorotrast , vinyl chloride, and arsenic

4. Clinical and Pathologic
Features of Specific
Soft Tissue Tumor Types

5. WHO classification :
 benign, intermediate (locally aggressive),
intermediate(rarely metastasizing), and malignant
o Fibroblastic and Myofibroblastic Tumors
o So-Called Fibrohistiocytic Tumors
o Adipocytic Tumors
o Smooth Muscle Tumors
o Skeletal Muscle Tumors
o Vascular Tumors
o Perivascular Tumors
o Neural Tumors
o Extraskeletal Chondro-Osseous Tumors
o Tumors of Uncertain Differentiation
o Undifferentiated/Unclassified Tumors

6. Fibroblastic & myofibroblastic tumors
Desmoid tumor
 Locally aggressive
 Do not metastasize
 most commonly in abdominal wall ,mesentery of the small bowel, and extremity.
 High local recurrence rate ( extremities / chest wall)
Management
 asymptomatic patients an initial period of observation is often recommended
 Surgical resection main treatment
 Systemic Therapy & RT:
Responses to any of these agents can be slow, with patients needing several months or
even 1 to 2 years of therapy
 Sulindac and other nonsteroidal anti-inflammatory drugs
 tamoxifen, gonadotropin-releasing hormone agonists, or aromatase inhibitors
 single-agent doxorubicin and liposomal pegylated doxorubicin

7. Desmoid tumor
 The role of adjuvant radiation in management of desmoid tumors is
controversial
 residual microscopic margins and negative margins
no benefit for adj RT
 definitive radiation is emerging as an alternative to surgery, particularly
when surgery would compromise function.
 5-year local control rate of 69% for patients treated with definitive radiation
(doses usually ranging from 56 to 60 Gy)

8. Fibroblastic & myofibroblastic tumors
DFSP
Management  Surgery with gross margin ( > 2cm)
 RT in :
 Positive or close surgical margins after surgery
 Unresectable disease
 Advanced & metastatic disease :
Imatinib

9. ADIPOCYTIC TUMORS
Liposarcoma
 Peak incidence : 50 and 65 years
 Most common sites : thigh and retroperitoneum
 3 main biological groups:
(1) Atypical lipomatous tumor/well-differentiated (ALT/ WD) liposarcoma
& dedifferentiated liposarcoma
(2) Myxoid round cell liposarcoma
(3) Pleomorphic liposarcoma

10. ADIPOCYTIC TUMORS
Liposarcoma , ALT/WD
 Locally aggressive , non metastasizing malignancy
 Location is an important predictor of outcome
 Extremity tumors rarely recur
 Retroperitoneal and mediastinal tumors may recur repeatedly and
eventually result in death from uncontrolled local effect
Liposarcoma , Dedifferentiated
 Co-existence of fatty & nonfatty solid components
 Lower risk of distant metastasis than other high grade pleomorphic
sarcomas

11. ADIPOCYTIC TUMORS
Liposarcoma (Myxoid or round cell )
 Usually in deep soft tissues of the extremities
 >66% in the thigh
 Rarely in the retroperitoneum or in the subcutaneous tissue
 Metastasize to unusual sites in soft tissue or bone
 Multifocal synchronous or metachronous spread to fat pad areas in the retroperitoneum and
axilla occurring even in the absence of pulmonary metastasis
Unusual among STS :
 Extraordinarily high response rate to RT
 Substantial sensitivity to ifosfamide & trabectedin
 adoptive T cell therapies or dendritic targeting with lentiviral vectors encoding NY-ESO-1
may be effective

12. ADIPOCYTIC TUMORS
Pleomorphic liposarcoma
 A high-grade, highly malignant sarcoma
 > 50 years
 Extremities (lower > upper)
 Metastasize early to Lung in > 50% of patients
 Sensitive to gemcitabine-based , and ifosfamide - based CHT

13. Smooth Muscle Tumors
Leiomyosarcoma
 Often in middle-aged
 >1/2 in retroperitoneal/intra-abdominal and pelvic, most commonly the uterus
 LMS can arise in any vessel :
 May present signs of venous outflow obstruction or pain related to encasement of nearby
nerves
 LMS of the IVC : Budd-Chiari syndrome
 treatment of choice :
 surgical resection, Arterial bypass may be performed for localized
 Doxorubicin / gemcitabine and docetaxel may be equivalent,
 But ifosfamide appears to add little to the response rate
 Pazopanib, trabectedin, and eribulin now have well-defined activity in LMS

14. Vascular tumors
Angiosarcoma
 Most in skin or superficial soft tissue;
 occurs most commonly in :
 the context of lymphedema(high rates of local and distant recurrence)
 after prior radiation(difficult to treat surgically because poor wound healing)
Features associated with poor outcome :
 age, tumor depth , size
Resection is rarely curative
Sensitive to anthracyclines and taxanes

15. Neural tumors
Malignant Peripheral Nerve Sheath Tumor
 Common sites : extremity & retroperitoneum
 adults between ages 20 and 50 years.
 NF1:the lifetime incidence is 8% to 13%.
 Stain for the S-100 protein
Weak S-100 is associated with fivefold higher risk of distant metastasis
 Treatment : Complete surgical resection +/- adjuvant RT
 Overall response rate to chemotherapy : 21%
 With improved outcomes when ifosfamide is added to Adriamycin
 Sorafenib has been tested in single cases
Worse prognosis:
1. Tumor size
2. p53 expression
3. NF1-related

16. Tumors of uncertain differentiation
Synovial sarcoma
 80% in deep soft tissue of the extremities
 t(X;18)gold standard in diagnosing
 high rates of response to chemotherapy
 Adjuvant or neoadjuvant ifosfamide-based chemotherapy should be considered in the
treatment high-risk primary synovial sarcoma of the extremities DSS
 Ifosfamide appears to be active in patients with advanced disease as
wellhigh dose of 14 to 18 g/m2 had a 100% response rate in small series
 novel agents: Pazopanib, trabectedin, immunotherapy

17. Tumors of uncertain differentiation
Alveolar Soft Part Sarcoma
 Prognosis is poor because :
 Metastasizes early
 Impervious to standard CHT
 Targeted inhibitors such as sunitinib and bevacizumab have some efficacy
 Ongoing trials  examining the efficacy of MET inhibitors such as crizotinib
in this tumor

18. Tumors of uncertain differentiation
Epithelioid Sarcoma
Distal-type volar aspects of hand and feet
Proximal type
 One of the few sarcomas in which lymph node metastases are fairly
common(20%)
 Gross nodal disease : biopsy if the disease is present and no apparent
distant metastases : complete lymph node dissection
 moderately sensitive to CHT
 Proximal type resistant to radiation & chemotherapy(worse prognosis)

19. Tumors of uncertain differentiation
Clear Cell Sarcoma (Melanoma of Soft Parts)
 Melanocytic differentiation
 typically involving the tendons and aponeuroses of young adults
Because of melanin and it tends to metastasize to regional LN :
 Behave more like a melanoma than a STS
Treatment of choice is surgical resection
 Gross disease in the LN basin is removed + wide resection of the primary tumor
 SNB can be considered
 Metastasis is common
• CHT has limited benefit : platinum-
containing regime
• recent reports suggest that :
anti angiogenic treatment (sorafenib
and sunitinib ) may have activity

20. DIAGNOSIS AND STAGING
 Sarcoma represent with a painless large mass
 1/3 : <5cm , 1/3 : 5-10 cm & 1/3 : > 10 cm
 DIAGNOSIS:
Biopsy with adequate amount of tissue :
 incisional biopsy or several Tru-Cut core biopsies
 Excisional biopsy should be avoided, especially for lesions > 3 cm
 FNA:used only for recurrence
IHC : vimentin,keratin,desmin,LCA,S-100

21. Imaging
 Must evaluate primary lesion and suspected sites of metastasis
 In extremity or head and neck : CT OR MRI(perez MRI superior)
 In chest , abdominal or retroperituneom : SPIRAL CT SCAN
PET  useful for :
 Determining early responses to systemic therapy for STS  For early prediction of
chemosensitivity in neoadjuvant CHT
 Identification of unsuspected sites of metastasis in patients with recurrent high
grade tumors
 fails to distinguish benign tumors from low-grade sarcomas

22. Imaging Sites of Metastasis
 Extremity : lungs (70%)
 Retroperitoneal and visceral : liver and secondary lung
So:
In Visceral and retroperitoneal : abdominal CT or MRI
Extremity : in low grades & small superficial high-grade ;
just chest film
In deep or large high grades ;
PET-CT limited in :
evaluating pulmonary
met <1cm

23. staging

24. Prognostic Factors for Primary
Extremity and Truncal Sarcoma
 Distant recurrence was associated with :
tumor size, depth, and grade, recurrent presentation, LMS histology,
any nonliposarcoma histology
 Factors that ↑ risk of LR :
age, recurrent disease at presentation, positive margin, and
fibrosarcoma or MPNST histology

25. Management of Extremity and Truncal Sarcoma
 Surgery  the principal therapeutic modality in STS
 Extent of Surgical Resection:
? wide enblock(CS) versus radical resection
 Although LR is greater in limb-sparing operation + RT than amputation , DFS is
not different
 Amputation should be reserved for ;
1. tumors that cannot be resected by any other means
2. without metastatic disease
3. with potential for good long-term functional rehabilitation

26. Management of Extremity and Truncal Sarcoma
 Wide en bloc resection
1-cm margin of uninvolved tissue in all directions
2-cm margins for histologic subtypes with infiltrative borders (DFSP or
myxofibrosarcoma)
For certain low-grade histologic types,( well diff. liposarcoma ) even 1-cm
margins are not required for excellent local control
 The limiting factor in obtaining wide margins :
neurovascular or bony juxtaposition

30. Postoperative Versus Preoperative
External Beam RT
Postoperative EBRT :
the first and the most widely practiced local adjuvant approach
 Advantages:
does not require that surgery be postponed
entire tumor and margins are available
 Disadvantages:
volume is larger and dose is higher : ↑ late tissue morbidity , higher
rate of bone fractures

31. Postoperative Versus Preoperative
External Beam RT
Preop RT
 Advantages:
treatment volume well defined
blood supply is intact
may decrease the dose needed
 DISADVANTAGES : Wound healing complication
Perez prefer preop RT

32. Radiation Therapy
Positioning the Patient
 patients are placed in the supine position
unless this places pressure on and deforms the tumor,
 in which case the prone position is used
 for upper extremity lesions
 include supine with abduction of the arm away
from the body with supination or pronation of
the arm by the location of the tumor
 Another good approach “swimmer position,”

33. Radiation Therapy
Positioning the Patient
 For treatment of a leg,
 The ipsilateral leg should be straight, and the
contralateral leg separated to create a gap
 If the target is in the proximal leg, the contralateral leg
can be in a frog-leg position with support under the knee
 For men with proximal tumors,
 the genitalia should be pulled to the contralateral side (using mesh or other )
 should consider sperm banking
Tumors in the true anterior or posterior compartments of the legmost challenging
for bone sparing
1. the supine position with external rotation of the leg
2. decubitus position

34. Radiation Therapy
Positioning the Patient
 patient must be immobilized
 immobilize the foot with a custom mold for all
lower extremity tumors
 immobilize the hand for all upper extremity
tumors
 use 3 anterior tattoos and 3 lateral tattoos.
 The 3 anterior tattoos are placed about 15 to 20
cm apart in the same sagittal plane
 and at each point, an additional lateral mark is
placed in the same axial plane

35. Target Volumes and Treatment Fields
Preoperative Radiation Therapy
 GTV: defined as the gross tumor delineated by the T1
postgadolinium MRI
 Fusion of the diagnostic MRI and planning CT is strongly
encouraged
 CTV : GTV plus 4-cm margins in the longitudinal directions and 1.5-
cm margins radially
 margins can be reduced if they extend beyond the compartment
or an intact fascial barrier, bone, or skin
 Editing target volumes 5 mm beneath skin surface to attain
superficial dose avoidance
 Peritumoral edema on T2 MRI will often be included within the
CTV
 PTV :CTV plus 5 to 10 mm

36. Dose
Preoperative Radiation Therapy
 The preoperative :50 Gy in daily fractions of 1.8 to 2.0 Gy over
approximately 5 weeks
 Postoperative boost :
only if the surgical margins +(16-20 GY)(efficacy has not been
proven)
EBRT,BRT,IORT

37. Target Volumes and Treatment Fields
Postoperative Radiation Therapy
 GTV: using gross tumor in preop MRI(T1+contrast)
 CTV :
 encompass all the tissues handled during the surgery including the incision and any
drain sites.
 additional longitudinal margin of 4 cm and a radial margin of 1.5 cm added to the
operative bed
Postoperative changes seen on MRI help define the operative bed
 PTV : CTV plus 5 to 10 mm
 A second course field reduction is typically used in the postoperative setting
 CTV margins for the reduced field (cone down) are generally 2 cm from the initial
GTV

39. Dose
Postoperative Radiation Therapy
 treatment usually commences about 4 to 6 weeks following surgery
and once the wound is fully healed
 60 to 66 Gy (delivered in 1.8- or 2-Gy fractions) :negative margins
 66 to 68 Gy : positive margins
The first course of treatment : 45 to 50 Gy
the balance of the dose is given in one reduced field.

40. Adjuvant BRT
 Focus dose directly on the tumor bed
 Treatment time : about 2 weeks
 BRT usually spares more normal tissue than EBRT, except IMRT
 As the sole RT : 45 Gy given over 4 to 6 days (LDR)/ 30-50GY(HDR)
 As a boost : 15 to 20 Gy (LDR)/ 12-20GY(HDR)from BRT + 45 to 50 Gy from EBRT
 The catheters are loaded no sooner than the sixth postoperative day
 CTV:
 American Brachytherapy Society: surgical bed + 2-cm longitudinal margin and 1- to
2-cm lateral
 MSKCC : margins of 1.5 to 2 cm + the tumor bed.

41. Definitive Radiation
 For unresectable disease or medical contraindications to operation
 The therapeutic window appears to be 63 to 68 Gy

42. CHT for Primary Localized Extremity/Truncal Sarcoma
 Surgery and RT : the mainstay for LC of STS
 > 1/2 of primary non-GIST sarcomas who achieve adequate local control of disease
will develop distant metastasis
 It was hoped that :
 adjuvant CHT would help to decrease the frequency of distant metastasis and
increase OS
 But All the trials were small and lacked statistical power
 Anthracyclines ;
 the agents most active against metastatic sarcoma
 they have been universally employed in adjuvant trials, alone or in combination

43. CHT for Primary Localized Extremity/Truncal Sarcoma
A large, randomized trial showed :
 some benefit to adjuvant cyclophosphamide, vincristine, doxorubicin, and dacarbazine
(CYVADIC) for STS in :
 the head, neck, or trunk
 not for in the extremities
Adjuvant doxorubicin + ifosfamide ;
 The trial had nonsignificant improvements in survival outcomes in
 grade III tumors, limb lesions, and tumors > 10 cm
Metanalyse in 2008 included 18 trials and1,953 patients:
 Chemotherapy was associated with significantly lower risk of local recurrence
 Overall survival was not significantly improved with single-agent doxorubicin
 but it was improved with doxorubicin combined with ifosfamide

44. Preop CHT for Primary Localized Extremity/Truncal Sarcoma
Preoperative chemotherapy :
 can make surgery easier and may treat micrometastatic disease.
 facilitating drug delivery, cause the primary vasculature is still intact
 can guide postoperative treatment based on pathologic review of the tissue response
A recent trial examined the role of neoadjuvant chemotherapy in 287 patients
 with high-risk tumors: >5 cm, deep, high-grade lesions including round cell
liposarcoma, LMS, synovial sarcoma, MPNST, and UPS
1. received three cycles of epirubicin and ifosfamide
2. or histotype-specific treatments
 patients receiving epirubicin and ifosfamide had better projected disease-free survival
Preoperative chemotherapy is very effective in predominantly pediatric sarcomas, such as Ewing sarcoma and
osteosarcoma
there is some evidence of benefit for synovial sarcomas and myxoid–round cell liposarcomas

45. Multimodal Management of Locally Recurrent
Extremity/Truncal Sarcoma
 Repeat resection :
 treatment of choice
 When surgical resection achieved  adjuvant RT should be considered in the vast majority of
patients with recurrent disease
 As a general principle , if RT is used in a previously irradiated field BRT is often recommended
 Other approaches: IMRT, preop RT to reduce dose and volume, fractionation in to small doses
,IORT
 Important factors in outcome for patients who undergo resection of their recurrent lesion
1. Size (> than 5 cm)
2. Timing of the recurrence (< 16 month)
45

46. Primary Retroperitoneal/Intra-Abdominal Sarcoma
 Asymptomatic abdominal mass
 GI bleeding , incomplete obstruction /Incidental diagnosis in CT or MRI
Dx :often is clear without Bx
 CT-guided core biopsy is indicated if :
 abdominal lymphoma, germ cell tumor, or carcinoma is suspected.
 who present with distant metastasis or advanced local disease that on imaging appears to be
difficult to completely remove surgically without substantial morbidity
 In most patient exploratory laparotomy should be performed and the diagnosis made at
operation unless ;
(1) The patient's tumor is clearly unresectable
(2) Neoadjuvant CHT or RT is needed to attempt to make the tumor more resectable

47. Management of Primary
Localized
Retroperitoneal Sarcoma
47

48. Retroperitoneal Sarcoma
Surgical Management
 Primary surgical resection :
 dominant therapeutic modality
 The primary factor in outcome :
1. Complete surgical resection
2. Grade
 Incomplete resection has been found to enhance survival relative to
biopsy or exploratory procedures for select sarcoma types
 Basis for unresectability :
Peritoneal implants
Extensive vascular involvement
48

49. RT for Primary Localized Retroperitoneal Sarcoma
Postop RT  not recommended(high toxicity & unproven efficacy)
Suitable for preop RT because
(1) local failure is a common cause of death for patients with retroperitoneal
liposarcomas, which is the most common histology;
(2) radiation therapy increases local control
(3) the tumor frequently displaces bowel from the target volume so that
radiation can safely be delivered
Preop RT dose :
49
 Conventional : 50.4
 IMRT : 60

50. CHT for Primary Localized Retroperitoneal Sarcoma
The most common histologic types :
 well-differentiated liposarcoma
 dedifferentiated liposarcoma
 Leiomyosarcoma
 MPNST
 chemotherapy is rarely indicated in the adjuvant setting for patients with
completely resected primary retroperitoneal sarcoma
 neoadjuvant chemotherapy may be indicated :
 For patients with locally advanced primary retroperitoneal sarcoma that is
unresectable or marginally resectable,
 enables assessment of response
50

51. 51

53. Multimodal Management of Locally Recurrent
Retroperitoneal Sarcoma
complete surgical resection remains the most effective treatment modality
 recommend surgery for patients whose:
1. recurrence is growing slower than 1 cm per month
2. symptomatic or whose local recurrence impinges on critical structures
3. has a solid appearance on CT scan (suspicious for dedifferentiation)
 systemic chemotherapy or novel targeted therapy trials:
 patients presenting with asymptomatic local recurrence
 and growth rates ≥1 cm per month
 Many asymptomatic patients with a differentiated-appearing local recurrence that is well
away from critical structures may be safely monitored
53

54. Multimodal Management of Locally Recurrent
Retroperitoneal Sarcoma
Radiotherapy
 No prior RT:
 Preop RT when complete gross resection appears technically feasible
 If prior RT has been used:
 IMRT , preoperatively
 IORT or proton beam may provide additional options
 Intraperitoneal chemotherapy after debulking of peritoneal metastases has been
advocated but remains an investigational approach.
54

55. Management of
Metastatic Disease
(up to date)
55

56. Multimodal Management of
Advanced Disease
1/2 of patients with non-GIST sarcomas :
 metastatic or locally advanced disease
 Median survival : 12 -19 months
 metastatic sarcoma :
 often feel well at the time that a radiograph or CT reveals metastases
 may remain free of symptoms for months
The primary tumors most likely to develop pulmonary metastases:
 PMFH (23 %)
 Synovial sarcoma (19%)
 LMS (15%)

57. Surgical Resection of Metastatic Disease
criteria for pulmonary metastasectomy :
1. No extrathoracic disease
2. The primary tumor is controlled or controllable
3. The patient is a medically appropriate candidate for intervention and pulmonary resection
4. Complete resection of all disease appears possible
In multivariate analysis associated with a lower risk of death:
 leiomyosarcoma subtype,
 primary tumor size ≤10 cm,
 greater time between primary resection and development of metastases,
 solitary lung metastases,
 minimally invasive resection

58. Systemic treatment of metastatic soft tissue sarcoma
 for the majority of patients with metastatic STS, chemotherapy is
administered with palliative intent to
1. decrease tumor bulk,
2. diminish symptoms,
3. improve quality of life,
4. prolong survival

59. OVERVIEW OF THE THERAPEUTIC APPROACH
Initial therapy
 First Patients should initially be assessed for their potential responsiveness
to doxorubicin
 The standard of care for many years for symptomatic patients has been doxorubicin
plus ifosfamide,
 with single-agent doxorubicin being considered for asymptomatic
 olaratumab + doxorubicin new first-line agent since 2016(toxicity is less with same
efficacy) except:
1. synovial sarcoma and myxoid/round cell liposarcoma could be more sensitive to
doxorubicin plus ifosfamide
2. If a patient is symptomatic and the immediate goal is tumor shrinkage
Exception: Angiosarcomas can also be highly sensitive to taxanes, and some clinicians
may choose a taxane-based regimen for initial therapy

60. Systemic treatment of metastatic soft tissue
Initial therapy
 poorer PS or extensive comorbidity:
 pegylated liposomal doxorubicin , gemcitabine alone, or a gemcitabine-
based combination.
 a gemcitabine-based combination may be considered for first-line
in a patient for whom an anthracycline is relatively contraindicated
(clinical heart failure, prior treatment with >400 mg/m2 doxorubicin in the
adjuvant setting)

61. Initial therapy
 For patients with STS histologies that are not sensitive to anthracyclines:
dvanced progressive alveolar soft part sarcoma, solitary fibrous
tumor (SFT)/hemangiopericytoma, and clear cell sarcoma
 pazopanib or sunitinib
For SFT/hemangiopericytoma, another option is
1. dacarbazine alone,
2. dacarbazine plus doxorubicin,
3. temozolomide plus bevacizumab.
unresectable DFSP imatinib

64. Treatment at progression
second line
 For most patients with progression on the first-line regimen, we prefer enrollment in a
clinical trial
 If not available for patients with good performance status base on histology:
Trabectedin LMS , Myxoid/round cell liposarcoma
Eribulin LMS and liposarcoma
Pazopanib is approved for advanced STS other than liposarcoma or
GIST
 weekly single-agent paclitaxel(choice) ,Single-agent gemcitabine or a
gemcitabine-based combination dvanced progressive angiosarcoma

65. Treatment at progression
second line
Other options for second-line treatment :
PLD,
ifosfamide-containing regimen,
 gemcitabine, or a gemcitabine-based combination
undifferentiated pleomorphic sarcoma responds better
to gemcitabine plus docetaxel than to other regimes,
So we would choose this combination for second-line therapy after
failure of initial doxorubicin plus olaratumab

66. Thank you