Pediatric Soft Tissue Sarcomas

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

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

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 RMSdifficult to distinguish from other small round blue cell tumors

31. Botryoid RMS

32. Alveolar RMSSmall 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 tumorsImmunohistochemistry

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

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

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)

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 ~ 40-50 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