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

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Presentation on theme: "Michael Weintraub, M.D. Hadassah University Hospital Jerusalem, Israel Pediatric Soft Tissue Sarcomas."— Presentation transcript:

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

2 Cancer Types in Children Leukemia CNS tumors Lymphoma – Hodgkins & non-Hodgkins 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 – Hodgkins & non-Hodgkins 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 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 TypeAges 0-14Ages Leukemia28%10% CNS22%10% Neuroblastoma8%0.2% NHL6%8% Hodgkins3.6%16.8% Wilms tumor6%0.3% Rhabdomyosarcoma3.6%1.7% NRSTS3.5%5.1% Osteosarcoma2.6%4.2% Ewing sarcoma1.5%2.4% Germ cell/gonadal3.5%12.4% Retinoblastoma3.2%0% Hepatoblastoma1.3%0% Thyroid1.1%7.3% Melanoma1.1%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 individuals 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% –Wilms tumor – 3-5% –Retinoblastoma – 40% –Optic gliomas – 45% –Adrenocortical Carcinoma – 50-80% However – the exceptions are instructive

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

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 TumorImmunohistochemical markers Ewing / ESFTPAS+ (Glycogen); NSE (Neuron specific enolase); CD99; Fli1 RhabdomyosarcomaDesmin, myosin, MyoD LymphomaLCA=Leukocyte common antigen=CD45 specific markers CD30-HD,ALCL; CD20-B cell; CD3-T cell; TdT NeuroblastomaNSE; 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 TumorCytogeneticsAffected genes Embryonal rhabdomyosarcoma LOH 11p15IGF-II Alveolar Rhabdomyosarcomat(2;13)(q35;q14) t(1;13)(p36;q14) PAX3-FKHR PAX7-FKHR Neuroblastoma1p36;17q; HSR;DM?;?; N-myc Ewing sarcoma-PNETt(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 sarcomat(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 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)


43 Distant Metastasis Regional Lymph Nodes Tumor Size Sites of Primary Tumor Stag e M0 N0, or N1, or NXAny sizeFavorable sites1 M0 N0 or NXT1a or T2aUnfavorable sites2 M0 N1 N0 or N1 or NX T1a, T2a, or T1b, T2b Unfavorable sites3 M1 N0 or N1Any sizeAny site4

44 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 I, II, III 2, 3 1, 2, 3 Embryonal Alveolar Intermediate Risk IV4Embryonal or AlveolarHigh 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 3 wk 3 wk Local Rx.(Surg/XRT) Cycle …………14………40VAC Vincristine – 2 mg/M 2 /course Actinomycin – 1.5 mg/M 2 /course Cyclophosphamide – 1200 mg/M 2 /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

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