1. Pediatric Soft Tissue Sarcomas
Michael Weintraub, M.D.
Hadassah University Hospital
Jerusalem, Israel

2. Cancer Types in Children
Leukemia
CNS tumors
Lymphoma – Hodgkin’s & non-Hodgkin’s lymphoma
Neuroblastoma
Wilms’ tumor
Sarcoma – Bone (Ewing, osteosarcoma)
Soft-tissue –Rhabdomyosarcoma, NRSTS
Retinoblastoma
Hepatic tumors
Germ cell tumors

3. Major Cancer Types in Children
Leukemia
(CNS tumors)
Lymphoma – Hodgkin’s & non-Hodgkin’s lymphoma
(Neuroblastoma)
Wilms’ tumor
Sarcoma – Bone (Ewing, osteosarcoma)
Soft-tissue –Rhabdomyosarcoma, NRSTS
Retinoblastoma
(Hepatic tumors)
(Germ cell tumors)

4. Nomenclature of Tumors
Tumors are named after their cell of origin
and the embryonal layer that cell arose from
The middle embryonal layer – the mesoderm-
gives rise to mesenchymal tissues- bone,
muscle, cartilage, adipose tissue, blood
vessels and more
Mesenchymal tumors are called sarcomas

5. Mesenchymal tumors Tumors of bone (Osteosarcoma, Ewing sarcoma)
Tumors of soft tissues (Soft tissue sarcomas=STS)
Tumors of skeletal muscle (Rhabdomyosarcoma)
Tumors of smooth muscle (Leiomyosarcoma)
Tumors of adipose tissue (Liposarcoma)
Tumors of fibroblasts (Fibrosarcoma)
Tumors of cartilage (Chondrosarcoma, synovial sarcoma)
Tumors of blood vessels (Angiosarcoma)
MPNST, clear cell sarcoma, inflammatory myofibroblastic tumor, desmoid (fibromatosis), DSRCT, MFH

6. Pediatric soft tissue sarcomas
The most common form of soft-tissue sarcoma in childhood is rhabdomyosarcoma (50% of all STS)
For convenience – all other soft-tissue sarcomas of childhood are called non-rhabdo soft tissue sarcomas (NRSTS) – and account for the remaining 50% of STS

7. Rhabdomyosarcoma

8. Rhabdomyosarcoma
A tumor which arises from immature mesenchymal cells committed to skeletal muscle lineage
RMS can arise in multiple organs giving rise to a wide spectrum of clinical presentations, therapeutic approaches and prognoses
Some of these organs (e.g. – bladder) do not normally contain skeletal muscle

9. Rhabdomyosarcoma - Epidemiology
Most common type of soft tissue sarcoma in children
3.5% of childhood cancer
Incidence: 4.3/1,000,000 per year
USA ~ 350 new cases/year; Ethiopia? ~ 150? Less? (Lower
incidence of RMS in African-American girls and in
Southeast Asia)
2/3 of cases occur in children < 6 years of age
Genetic associations

10. Cancer Types by Age Group
Tumor Type
Ages 0-14
Ages 15-19
Leukemia
28%
10%
CNS
22%
Neuroblastoma 8%
0.2%
NHL 6%
Hodgkin’s
3.6%
16.8%
Wilm’s tumor
0.3%
Rhabdomyosarcoma
1.7%
NRSTS
3.5%
5.1%
Osteosarcoma
2.6%
4.2%
Ewing sarcoma
1.5%
2.4%
Germ cell/gonadal
12.4%
Retinoblastoma
3.2% 0%
Hepatoblastoma
1.3%
Thyroid
1.1%
7.3%
Melanoma
7.6%

11. Rhabdomyosarcoma - Epidemiology
Most common type of soft tissue sarcoma in children
3.5% of childhood cancer
Incidence: 4.3/1,000,000 per year
USA ~ 350 new cases/year; Ethiopia? ~ 150? Less? (Lower
incidence of RMS in African-American girls and in
Southeast Asia)
2/3 of cases occur in children < 6 years of age
Genetic associations

12. Genetics of Childhood cancer

13. Cancer – Pathogenesis I
Cancer is caused by the occurrence in a single, initial cell - of multiple genetic changes - “hits”- aberrations
The genetic aberrations that lead to the transformation of a normal cell into a cancer (malignant) cell involve genes which regulate cell proliferation, differentiation and apoptosis (Proto-oncogenes, tumor suppressor genes)
When a sufficient number of genetic “hits” have occurred in a single cell - that cell will have acquired the capacity to proliferate and metastasize – the “cancer cell”

15. Cancer – Pathogenesis - II
In most human cancers, the changes in genes that control cell proliferation are not inherited but acquired (somatic changes)
It is estimated that in order for a cell to transform into a cancer cell, changes must occur in 7-10 different genes
For a single cell to accumulate a sufficient number of mutations takes time, and thus cancer is largely a disease of old age

16. Cancer – Pathogenesis - III
If an individual inherits a mutation in one of the genes that control cell proliferation, than all the cells in that individual’s body have taken the first step in the path of malignant transformation
The cells in the bodies of these individuals have a “head start” on the malignant process: They have a higher risk of developing tumors, and develop tumors at an earlier age
The group of diseases in which individuals carry inherited/germline mutations in cancer genes are called cancer predisposition syndromes

19. Cancer predisposition syndromes (CPS)
In individuals with CPS only a very small fraction of the total cells in their body (or at risk organs) become neoplastic because other (somatic) mutations are required to develop a clinically detectable lesion (cancer phenotype)
Individuals with CPS often develop multiple tumors that occur at an earlier age than in individuals whose cancer gene mutations have all occurred somatically (The head start)
The tumor types are site specific (not all cancers are increased) – depending on the nature of the genetic “hit”
Not all individuals with CPS will develop tumors – in fact – in many CPS – most will not (Down syndrome vs. RB)

20. The role of heredity in childhood cancer
Most cancer cases in children do not have a hereditary basis
- Leukemia – 2%
Brain tumors – 1-3%
Wilm’s tumor – 3-5%
Retinoblastoma – 40%
Optic gliomas – 45%
Adrenocortical Carcinoma – 50-80%
However – the exceptions are instructive

21. RMS in Cancer Predisposition syndromes
Cancer Types
Beckwith-Wiedemann
Wilms (60%, 20% bilateral), RMS, HB, NB, ACC, Gonadoblastoma; (7.5 % of patients develop cancer by age 8)
Li-Fraumeni
RMS, OS, glioma, Breast, Adrenal, leukemia
50% cancer incidence by age 30 (cf. 1% in general population)
Costello syndrome
RMS

22. Rhabdomyosarcoma- Clinical Presentations

23. Rhabdomyosarcoma
Sites of disease
Head & Neck
Orbit
Parameningeal
Non-Parameningeal
Genitourinary
Bladder
Prostate
Para-testicular
Vagina/uterus
Extremity
Others

24. RMS – Clinical Presentation is Site Dependent
Orbit - Proptosis, ophthalmoplegia
Other head and neck/parameningeal – nasal or aural obstruction, cranial nerve palsies
Genitourinary tract – Bladder: Hematuria, urinary obstruction
Paratesticular – painless scrotal mass
Vaginal – Vaginal mass, discharge
Extremities – Swelling, pain, lymph node involvement

25. Orbital rhabdomyosarcoma

26. Extremity RMS

28. Rhabdomyosarcoma – Approach to Diagnosis and Staging
Evaluation of primary site – XR, CT, MRI
Biopsy / surgery
Metastatic workup – CT chest, bone scan, bone marrow, PET

29. Rhabdomyosarcoma - Pathology
Two major histologic subtypes:
I. Embryonal RMS
(Botryoid and spindle cell variants)
II. Alveolar RMS
Undifferentiated sarcoma

30. Poorly Differentiated Embryonal RMS difficult to distinguish from other small round blue cell tumors

31. Botryoid RMS

32. Alveolar RMS Small round cells floating in a pseudo-alveolar space representing fibrovascular septae

33. Small round blue cell tumors
Lymphoma
Neuroblastoma
Rhabdomyosarcoma
Ewing/PNET
Desmoplastic small round cell tumor (DSCRT)
Poorly differentiated synovial sarcoma
Small cell osteosarcoma

34. Small round blue cell tumors
Immunohistochemistry
Electron microscopy
Cytogenetics/Molecular Biology

35. Small round blue cell tumors Immunohistochemistry
Immunohistochemical markers
Ewing / ESFT
PAS+ (Glycogen); NSE (Neuron specific enolase); CD99; Fli1
Rhabdomyosarcoma
Desmin, myosin, MyoD
Lymphoma
LCA=Leukocyte common antigen=CD45
specific markers
CD30-HD,ALCL; CD20-B cell;
CD3-T cell; TdT
Neuroblastoma
NSE; S100

36. Small round blue cell tumors
Immunohistochemistry
Electron microscopy – features of muscle differentiation -= actin-myosin bundles, z-bands
Cytogenetics/Molecular biology

37. Cytogenetics in Pediatric Solid tumors
Affected genes
Embryonal rhabdomyosarcoma
LOH 11p15
IGF-II
Alveolar Rhabdomyosarcoma
t(2;13)(q35;q14)
t(1;13)(p36;q14)
PAX3-FKHR
PAX7-FKHR
Neuroblastoma
1p36;17q; HSR;DM
?;?; N-myc
Ewing sarcoma-PNET
t(11;22)(q24;q12)
t(21;22)(q22;q12)
EWS-FLI1
EWS -ERG
Malignant melanoma of soft parts
t(12;22)(q13;q12)
EWS-ATF1
Desmoplastic small round-cell tumor
t(11;22)(p13;q11-12)
EWS-WT1
Synovial sarcoma
t(X;18)(p11.2;q11.2)
SYT-SSX-1+2
Congenital fibrosarcoma and mesoblastic nephroma
t(12;15)(p13;q25)
ETV6-NTRK3

38. Rhabdomyosarcoma – Approach to Diagnosis and Staging
Evaluation of primary site – XR, CT, MRI
Biopsy / surgery
Metastatic workup – CXR/CT chest, bone scan, bone marrow, PET

39. Staging
A process that defines the local and distant (metastatic) extent of a tumor
Tumors have unique and consistent patterns of spread
Wilms’ tumor to lungs and liver (not to bone or bone marrow)
Neuroblastoma – bones, bone marrow, lymph, (not to lungs)
Stage is associated with prognosis (metastatic disease is rarely curable)

40. Wilms’ tumor - Staging Stage I II III IV V
Tumor confined to the kidney and completely resected. No penetration of renal capsule or sinus vessels. I
Tumor extends beyond kidney but completely resected; a) penetration of renal capsule b) invasion of renal sinus c) biopsy d) local spillage during removal II
Gross or microscopic residual (including gross spillage, positive margins, regional lymph nodes –renal hilar, para-aortic, or beyond, peritoneal implants, spillage beyond flank)
III
Metastatic disease outside abdomen (lungs, liver) IV
Bilateral Wilms’ tumors V

41. Rhabdomyosarcoma – Evaluation of disease extent
Extent of disease in primary site – CT, MRI, PET
Metastatic disease – Lungs, bones, lymph nodes
Stage
Clinical group (site and extent of resection)

42. Any site not considered favorable.
Term 
Definition 
Favorable site
Orbit; non-parameningeal head and neck; genitourinary excluding kidney, bladder, and prostate; biliary tract.
Unfavorable site
Any site not considered favorable. T1
Confined to anatomic site of origin. T2
Extension and/or fixative to surrounding tissue. a
Tumor ≤5 cm in maximum diameter. b
Tumor >5 cm in maximum diameter. N0
No clinical regional lymph node involvement. N1
Clinical regional lymph node involvement. M0
No metastatic disease. M1
Metastatic disease.

43. Distant Metastasis 
Regional Lymph Nodes 
Tumor Size 
Sites of Primary Tumor 
Stage   M0
N0, or N1, or NX
Any size
Favorable sites 1
N0 or NX
T1a or T2a
Unfavorable sites 2 N1
N0 or N1 or NX
T1a, T2a, or
T1b, T2b 3 M1
N0 or N1
Any site 4

44. I [Note: Approximately 13%]
Definition 
Group 
A localized tumor completely removed with pathologically clear margins and no regional lymph node involvement.
I  [Note: Approximately 13%]
A localized tumor that is grossly removed with: (A) microscopic disease at the margin, (B) involved, grossly removed regional lymph nodes, or (C) both A and B.
II  [Note: Approximately 20% ]
A localized tumor with gross residual disease after incomplete removal or biopsy only.
III  [Note: Approximately 48% ]
Distant metastases are present at diagnosis.
IV  [Note: Approximately 18% ]

45. Group 
Stage 
Histology 
Risk Group
I, II, III
I, II 1
2, 3
Embryonal
Low Risk
III
1, 2, 3
Alveolar
Intermediate Risk IV 4
Embryonal or Alveolar
High Risk

46. Rhabdomyosarcoma - Treatment
Local control – Surgery vs. Radiation
Systemic therapy – Chemotherapy
Pediatric sarcomas are systemic illnesses

47. Rhabdomyosarcoma – Local Rx
Local control options: Surgery and radiation therapy
The approach to local control of RMS depends on the site of origin
RMS tends to occur is sites that are surgically challenging where attempts at radical resections may lead to mutilating surgery as well as inadequate surgical margins
Use of radiation therapy is an important local control modality

48. Rhabdomyosarcoma – Surgery
Surgery in RMS is used with the aim of achieving complete resections with clear margins
Potentially relevant disease sites: Vagina, paratesticular, non-parameningeal, non-orbit head & neck, extremity
However – many children with RMS have tumors that cannot be excised or attempts at resection will lead to mutilation and loss of function (orbit, parameningeal, bladder)
Consider radiaiton
Late effects of radiation on young tissues

49. Rhabdomyosarcoma – Radiation Therapy
Required doses ~ Gy
Essential in non –resectable cases and where surgical margins are inadequate (orbit, parameningeal, bladder)
Tissue tolerance
Late effects of radiation on young tissues

50. Rhabdomyosarcoma –Systemic Therapy
20% of patients present with metastatic disease
Most patients (90%) who present without overt metastatic disease will develop systemic spread if not treated with chemotherapy (micro-metastatic disease)
All patients must receive systemic therapy
Active agents – Actinomycin, Cyclophosphamide/ifosfamide, vincristine,
Doxorubicin, VP-16, topotecan/irinotecan

51. Rhabdomyosarcoma – Treatment- COG
VCR / Actinomycin D / Cyclophosphamide
3 Wk wk wk Local Rx.(Surg/XRT)
Cycle ↔ ↔ ↔ 4…………14………40
V V
A A
C C
Vincristine – 2 mg/M2/course
Actinomycin – 1.5 mg/M2/course
Cyclophosphamide – 1200 mg/M2/course

52. Pediatric Cancer as a Systemic Illness – The rule and the exceptions
THE RULE- Pediatric solid tumors are always systemic – micrometastatic disease is present at diagnosis in the majority of patients
All patients – including those with apparently localized disease - must be treated with chemotherapy
Osteosarcoma, Ewing, RMS

53. Pediatric Cancer as a Systemic Illness – The rule and the exceptions
The exceptions: Tumors in which cure can be achieved with surgery alone
Unilateral Retinoblastoma
Stage I gonadal germ cell tumors
Stage I-II hepatoblastoma
Stage I – small – Wilms’ tumor
Stage I neuroblastoma
Supra-tentorial ependymomas
Low grade gliomas

54. Rhabdomyosarcoma - Outcome
With the combination of local and systemic therapy – 50-70% of patients are cured
Prognostic factors:
Metastatic disease 10-20% (Lung > bone)
Sites – favorable (orbit – 90%), unfavorable (extremity-60%)
Histology: embryonal> alveolar

55. Rhabdomyosarcoma – Treatment of High Risk patients
Dose intensification – Alkylators
Additional agents – doxorubicin, topotecan, irinotecan, ifosfamide, vinorelbine
High dose chemotherapy with stem-cell rescue
To date – none of these interventions have improved outcome

56. Rhabdomyosarcoma – Summary
RMS is the most common soft tissue sarcoma of childhood
RMS can occur at multiple sites resulting in a wide spectrum of clinical presentations:
The most common sites are 1) head and neck - including orbit and parameningeal, 2) genitourinary, including bladder, vagina and paratesticular 3) Extremities

57. Rhabdomyosarcoma – Summary -2
The diagnosis of RMS is made by a combination of clinical presentation, radiology and pathology
The treatment of RMS is site specific
Treatment of RMS must include a local component aimed at the primary tumor (surgery and/or radiation) and a systemic component (chemotherapy) aimed at micro-metastatic disease
For most children with RMS a combination of vincristine, actinomycin and cyclophosphamide is the best current therapy

58. Thank you

59. Rhabdomyosarcoma – Long term Sequelae
Site and treatment modality dependent
Fertility – High doses of alkylating agents
Cardiotoxicity – High doses of anthracyclines
Second malignancies – AML (Topoisomerase+alkylators – 8-10%)
Radiation field sarcomas (~5%)

60. Risk-Adapted Therapy Maximize benefit / Minimize risk
Patients with good-risk features and high cure rates – maintain good outcome, minimize toxicity (orbital, vaginal RMS)
Patients with poor-risk features and low cure rates – intensify therapy (extremity and metastatic RMS), consider interventions to reduce long term toxicity