michael weintraub, m.d. hadassah university hospital jerusalem, israel pediatric soft tissue...
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Michael Weintraub, M.D.
Hadassah University Hospital
Jerusalem, Israel
Pediatric Soft Tissue Sarcomas
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
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)
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
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
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
Rhabdomyosarcoma
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
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
Cancer Types by Age GroupTumor Type Ages 0-14 Ages 15-19
Leukemia 28% 10%
CNS 22% 10%
Neuroblastoma 8% 0.2%
NHL 6% 8%
Hodgkin’s 3.6% 16.8%
Wilm’s tumor 6% 0.3%
Rhabdomyosarcoma 3.6% 1.7%
NRSTS 3.5% 5.1%
Osteosarcoma 2.6% 4.2%
Ewing sarcoma 1.5% 2.4%
Germ cell/gonadal 3.5% 12.4%
Retinoblastoma 3.2% 0%
Hepatoblastoma 1.3% 0%
Thyroid 1.1% 7.3%
Melanoma 1.1% 7.6%
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
Genetics of Childhood cancer
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”
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
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
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)
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
RMS in Cancer Predisposition syndromes
Syndrome 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
Rhabdomyosarcoma- Clinical Presentations
RhabdomyosarcomaSites of disease
Head & Neck Orbit Parameningeal Non-Parameningeal
Genitourinary Bladder Prostate Para-testicular Vagina/uterus
Extremity
Others
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
Orbital rhabdomyosarcoma
Extremity RMS
Rhabdomyosarcoma – Approach to Diagnosis and Staging
• Evaluation of primary site – XR, CT, MRI
• Biopsy / surgery
• Metastatic workup – CT chest, bone scan, bone marrow, PET
Rhabdomyosarcoma - Pathology
Two major histologic subtypes:
I. Embryonal RMS (Botryoid and spindle cell variants)
II. Alveolar RMS
Undifferentiated sarcoma
Poorly Differentiated Embryonal RMSPoorly Differentiated Embryonal RMSdifficult to distinguish from other small round blue cell tumors difficult to distinguish from other small round blue cell tumors
Botryoid RMSBotryoid RMS
Alveolar RMSAlveolar RMSSmall round cells floating in a pseudo-alveolar space representing fibrovascular septaeSmall round cells floating in a pseudo-alveolar space representing fibrovascular septae
Small round blue cell tumors
• Lymphoma
• Neuroblastoma
• Rhabdomyosarcoma
• Ewing/PNET
• Desmoplastic small round cell tumor (DSCRT)
• Poorly differentiated synovial sarcoma
• Small cell osteosarcoma
Small round blue cell tumors
• Immunohistochemistry
• Electron microscopy
• Cytogenetics/Molecular Biology
Small round blue cell tumorsImmunohistochemistry
Tumor 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
Small round blue cell tumors
• Immunohistochemistry
• Electron microscopy – features of muscle differentiation -= actin-myosin bundles, z-bands
• Cytogenetics/Molecular biology
Cytogenetics in Pediatric Solid tumors
Tumor Cytogenetics Affected genesEmbryonal 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
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
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)
Wilms’ tumor - StagingStage
I Tumor confined to the kidney and completely resected. No penetration of renal capsule or sinus vessels.
II Tumor extends beyond kidney but completely resected; a) penetration of renal capsule b) invasion of renal sinus c) biopsy d) local spillage during removal
III Gross or microscopic residual (including gross spillage, positive margins, regional lymph nodes –renal hilar, para-aortic, or beyond, peritoneal implants, spillage beyond flank)
IV Metastatic disease outside abdomen (lungs, liver)
V Bilateral Wilms’ tumors
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)
Stage
Sites of Primary Tumor
Tumor Size
Regional Lymph Nodes
Distant Metastasis
1 Favorable sites Any size N0, or N1, or NXM0
2 Unfavorable sites T1a or T2a N0 or NXM0
3 Unfavorable sites T1a, T2a, or T1b, T2b
N1N0 or N1 or NX M0
4 Any site Any size N0 or N1M1
Group
Definition
I [Note: Approximately 13%] A localized tumor completely removed with pathologically clear margins and no regional lymph
node involvement.
II [Note: Approximately 20% ] 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.
III [Note: Approximately 48% ] A localized tumor with gross residual disease after incomplete removal or biopsy only.
IV [Note: Approximately 18% ] Distant metastases are present at diagnosis.
Risk Group Histology Stage Group
Low Risk Embryonal
Embryonal
1
2, 3
I, II, III
I, II
Intermediate Risk Embryonal
Alveolar
2, 3
1, 2, 3
III
I, II, III
High Risk Embryonal or Alveolar 4 IV
Rhabdomyosarcoma - Treatment
• Local control – Surgery vs. Radiation
• Systemic therapy – Chemotherapy
• Pediatric sarcomas are systemic illnesses
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
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
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
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
Rhabdomyosarcoma – Treatment- COG
VCR / Actinomycin D / Cyclophosphamide
3 Wk 3 wk 3 wk Local Rx.(Surg/XRT)Cycle 1 ↔ 2 ↔ 3 ↔ 4…………14………40
V VA AC C
Vincristine – 2 mg/M2/courseActinomycin – 1.5 mg/M2/course Cyclophosphamide – 1200 mg/M2/course
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
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
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
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
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
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
Thank you
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%)
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