Pediatric soft tissue sarcomas
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Pediatric Soft Tissue Sarcomas. Michael Weintraub, M.D. Hadassah University Hospital Jerusalem, Israel. Cancer Types in Children. Leukemia CNS tumors Lymphoma – Hodgkin’s & non-Hodgkin’s lymphoma Neuroblastoma Wilms’ tumor Sarcoma – Bone (Ewing, osteosarcoma)

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Pediatric soft tissue sarcomas

Pediatric Soft Tissue Sarcomas

Michael Weintraub, M.D.

Hadassah University Hospital

Jerusalem, Israel


Cancer types in children
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
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
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
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 sarcomas1
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



Rhabdomyosarcoma1
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
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



Rhabdomyosarcoma epidemiology1
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 pathogenesis i
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
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
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
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
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




Rhabdomyosarcoma

Sites of disease

Head & Neck

Orbit

Parameningeal

Non-Parameningeal

Genitourinary

Bladder

Prostate

Para-testicular

Vagina/uterus

Extremity

Others


Rms clinical presentation is site dependent
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




Rhabdomyosarcoma approach to diagnosis and staging
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
Rhabdomyosarcoma - Pathology

Two major histologic subtypes:

I. Embryonal RMS

(Botryoid and spindle cell variants)

II. Alveolar RMS

Undifferentiated sarcoma


Poorly Differentiated Embryonal RMSdifficult to distinguish from other small round blue cell tumors



Alveolar RMSSmall round cells floating in a pseudo-alveolar space representing fibrovascular septae


Small round blue cell tumors
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 tumors1
Small round blue cell tumors

  • Immunohistochemistry

  • Electron microscopy

  • Cytogenetics/Molecular Biology


Small round blue cell tumors immunohistochemistry
Small round blue cell tumorsImmunohistochemistry


Small round blue cell tumors2
Small round blue cell tumors

  • Immunohistochemistry

  • Electron microscopy – features of muscle differentiation -= actin-myosin bundles, z-bands

  • Cytogenetics/Molecular biology



Rhabdomyosarcoma approach to diagnosis and staging1
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
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)



Rhabdomyosarcoma evaluation of disease extent
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)


Rhabdomyosarcoma treatment
Rhabdomyosarcoma - Treatment

  • Local control – Surgery vs. Radiation

  • Systemic therapy – Chemotherapy

  • Pediatric sarcomas are systemic illnesses


Rhabdomyosarcoma local rx
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
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
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
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
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 V

A A

C C

Vincristine – 2 mg/M2/course

Actinomycin – 1.5 mg/M2/course

Cyclophosphamide – 1200 mg/M2/course


Pediatric cancer as a systemic illness the rule and the exceptions
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 exceptions1
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
Rhabdomyosarcoma - Outcome exceptions

  • 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
Rhabdomyosarcoma – Treatment of High Risk patients exceptions

  • 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
Rhabdomyosarcoma – Summary exceptions

  • 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
Rhabdomyosarcoma – Summary -2 exceptions

  • 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

Thank you exceptions


Rhabdomyosarcoma long term sequelae
Rhabdomyosarcoma – Long term Sequelae exceptions

  • 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
Risk-Adapted Therapy exceptions

  • 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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