Bone and Soft Tissue Sarcomas

Resident Education Lecture Series

Pediatric Bone “Tumors”
Benign
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Malignant
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Osteochondroma Osteoid Osteoma Enchondroma Chondroblastoma Non-ossifying fibroma aka benign cortical defect Hemangioma Eosinophilic granuloma Osteomyelitis

Osteosarcoma Ewing sarcoma Malignant fibrous histiocytoma Non-Hodgkin Lymphoma Eosinophilic granuloma

Malignant bone tumors

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Rare 6% of all childhood malignancies Annual US Incidence in children < 20 yrs
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8.7 per million

~ 650 to 700 children/year

For perspective, Annual US Incidence
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Overall 4697 per million Lung 610 per million Breast 633 per million

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Most often occur in young patients < 25 yrs Most common bone tumors ← will focus on these
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Osteosarcoma Ewing sarcoma

56% 34%

Osteosarcoma (OS)
Primary malignant tumor of bone  Derived from primitive bone forming mesenchyme  Malignant spindle cells produce immature neoplastic bone matrix – osteoid

 Can

look heterogeneous under the microscope  Cell of origin?

Cell of origin may be mesenchymal stem cell

Telangiectatic

Small Cell

Osteoblastic

Chondroblastic

Fibroblastic

Histologic subtype (WHO)  OS Central (medullary) tumors  Conventional  Surface tumors    OS (87%)    Parosteal (<5%) Periosteal High-grade surface OS Osteoblastic – 50% Chondroblastic – 25% Fibroblastic – 25%   Telangiectatic (3%) High grade vs. Low grade  Small cell  Intraosseous welldifferentiated (1%)  Multifocal .

4:1  .Epidemiology  OS Most common during 2nd decade  75%  between 10 and 20 yrs  Peak during adolescent growth spurt Taller than average  Occurs earlier in girls M:F 1.5:1  African-American:Caucasian 1.

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Associations or Risk Factors  OS Ionizing radiation  Hereditary retinoblastoma (Rb mutations)  Li-Fraumeni syndrome (p53 mutations)  Rothmund-Thomson syndrome   No environmental risk factors No consistent cytogenetic abnormality .

worse at night. constant. aching. often attributed to trauma  Average duration of symptoms prior to diagnosis is three months  May or may not have a mass  Diagnosis of pelvic lesions often delayed  20% have detectable metastases at diagnosis – most often (>90%) pulmonary .Clinical presentation  OS Pain: dull.

Location  OS Most common in long bones  May have altered gait or function cross growth  90% are metaphyseal  May plate  Location:  #1 distal femur  #2 proximal tibia  #3 proximal humerus .

Diagnostic Workup   OS History and physical examination Laboratory tests:   Radiologic tests  Blood tests: include LDH. GFR/creatinine clearance . Alkaline phosphatase Also CBC. liver/kidney function tests Biopsy (open preferred)       Pathology  Plain films of involved bone MRI of entire involved bone Whole body Bone Scan CXR and CT of Chest PET scan (in future) Pre-therapy evaluation also includes Audiogram. echocardiogram.

Radiographs   OS    Usually blastic May be lytic or mixed bone destruction and production Poorly marginated Cortical destruction Soft tissue ossification .

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telangiectatic unfavorable disease unfavorable Disease Extent  metastatic    Tumor Size / Site  axial skeletal primaries unfavorable Age < 10 yrs unfavorable Response of the primary tumor to pre-operative chemotherapy: very powerful predictor > 80-90% necrosis favorable .Prognostic Factors   OS Tumor Grade & Histology  Parosteal favorable.

Treatment: Multimodal  OS Surgery  control of bulk disease  Chemotherapy  control of micrometastases  Radiation  Tumors not very radiosensitive. so this usually reserved for palliation .

age. size. and life-style preference  limb-sparing  amputation   Metastatic sites must also be resected If/when relapse occurs. retrieval therapy must include resection . presence of distant metastatic disease.Treatment: Surgery  OS  Removal of all gross tumor with wide (>5cm) margins en bloc and biopsy site through normal tissue planes is required Type of surgical procedure depends on tumor location. skeletal development. extramedullary extent.

 Surgery alone 15-25% 5 year survival  Recurrence with local and (50%) metastatic disease within 6 months of resection  With multiagent chemotherapy  55-68%  No difference between adjuvant or neoadjuvant chemotherapy  Those with >90% tumor necrosis and complete resection  80-85% .

Treatment: Chemotherapy    OS Bulky disease is considered somewhat chemotherapy resistant Subclinical metastases are sensitive to chemotherapy Most active agents include  adriamycin. cisplatinum. etoposide  Best # and schedule of chemotherapy unclear  Role of intensification after local control unclear  Immune modulators under study  Role of adjuvant chemotherapy after thoracotomy for recurrent disease unclear . ifosfamide. high-dose methotrexate.

Outcomes  OS 60-68% of patients with nonmetastatic osteosarcoma of the extremity will survive without recurrence and be cured  20% of patients with metastatic disease will be cured  Therapy with curative intent is possible following relapse: 10-20% of these patients may achieve long term survival .

Ewing Sarcoma (EWS)  Represents a family of tumors including  Ewing sarcoma of bone  extraosseous Ewing sarcoma and  peripheral neuroectodermal tumor (PNET) of bone or soft tissue  2nd most common bone tumor in children .

Pathology  EWS  One of many „small round blue cell‟ tumors seen in pediatrics Thought to be of neural origin. derived from post-ganglionic parasympathetic primordial cells  tumor cells synthesize acetylcholine transferase .

Round. Blue Cell Tumor Differential Diagnosis       Lymphoma/Leukemia Rhabdomyosarcoma Metastatic Carcinoma Neuroblastoma PNET/Ewing Sarcoma Small Cell Osteosarcoma  Ewing  Tumor without differentiation Tumor with neural differentiation  PNET  .Small.

3:1 < 10 yrs 1.6:1 > 10 yrs  Rare in African-Americans and Asians  .Incidence   80% EWS Occurs most commonly in 2nd decade occur between ages 5 and 25  Most common bone tumor in children < 10 yrs  ~110 new cases/year < 15 yrs ~200 new cases/year < 20 yrs M:F 1.

22)  the remainder EWS/ETV1 and EWS/E1AF respectively t(1.q13) present along with t(11. t(11.22) and t(17.q12)  5-10% EWS/ERG t(7.22)(q22.q12) present in 90-95%  resultant fusion gene is EWS/FLI-1  Also seen:    t(21.16)(q21.22)(q24.Associations or Risk Factors   EWS ??? Consistent cytogenetic abnormality.22) .

Clinical Presentation   EWS Pain & swelling of affected area May also have systemic symptoms:  Fever  Anemia  Weight loss  Elevated WBC & ESR   Mean duration of symptoms 9 months 20-25% present with metastatic disease  Lungs (38%)  Bone (31%)  Bone Marrow (11%) .

chest wall.Location  EWS central axis (47%):  pelvis. spine. head & neck  extremities (53%) #1 Femur #2 Ilium #3 Tibia/Fibula .

Location EWS  Classical presentation is diaphyseal  Actually more common in metadiaphysis or metaphysis .

ESR Urinalysis Bone marrow aspirate and biopsy Biopsy (open preferred)  Pathology   Plain films of primary site CT/MRI of primary site CXR/CT of chest Whole body bone scan PET scan (in future)  Pre-therapy evaluation also includes echocardiogram/EKG . liver/kidney function tests. LDH.Diagnostic Work-Up   EWS History and physical examination Laboratory tests:    Radiologic tests      CBC.

Radiographs    EWS   Destructive Poorly Marginated Permeative Endosteal Cortical Erosion Layered periosteal new bone “Onion skinning”  .

Radiographs EWS .

Radiology  EWS Large soft tissue mass MRI necessary to determine  Soft  tissue extent  Intraosseous extent .

Prognostic factors  EWS Extent of disease  Metastatic disease unfavorable  Size of disease ???  Primary site  Pelvis least favorable  Distal bones and ribs most favorable   Age  Younger (<10) more favorable Histologic ???  Response to chemotherapy  Neural differentiation .

Treatment  EWS Multidisciplinary approach must provide both local control and systemic therapy  Local control measures should not compromise systemic therapy  When treatment fails. it is usually due to the development of distant metastatic disease .

Treatment: Multimodal  EWS Surgery  local control where possible  Radiation  local control where surgery not possible or incomplete  Chemotherapy  control of micrometastases .

Treatment: Local Control   EWS Surgery and/or Radiation therapy No randomized studies comparing surgery to radiation therapy  slightly more local recurrence when radiation used for local control  current suggestion for surgery where possible without loss of function and without mutilation   Combination therapy if incomplete resection Radiation doses usually 4500 – 5500 cGy .

rib. clavicle)  Bone defect able to be reconstructed with modest loss of function  May consider amputation if considerable growth remaining  Trend toward improved outcomes with chemo + surgery vs.Surgical Indications  EWS Expendable bone (fibula. XRT .

Radiation therapy Indications      EWS Unresectable without significant morbidity Pelvic lesions Spine lesions Lung metastases May consider chemo + XRT to allow for surgical resection or add XRT if surgical margins positive .

ifosfamide. melphalan   Effective chemotherapy has improved local control rates achieved with radiation to 85-90% Role of SCT for high risk Ewing sarcoma still under investigation . cyclophosphamide.Treatment: Chemotherapy   EWS All patients require chemotherapy Active agents include  Vincristine. dactinomycin. topotecan. etoposide. adriamycin.

as well as a higher rate of local failure and tumor recurrence .Outcomes  EWS Local Rx only  >80% distant failure Combination chemotherapy + local control EFS – localized tumors  20-30% EFS – metastases present at diagnosis  55-75%  Patients  with spine or paravertebral disease have a slightly worse prognosis overall.

Bone tumors: “Compare & Contrast” .

Soft Tissue Sarcomas Rhabdomyosarcoma MOST COMMON .

Staging Work-Up – What are we looking for?  CT/MRI (primary)   Bone Scan  Helpful to delineate soft tissue planes. pre-surgical evaluation Look for metastatic disease in the lungs (common site of metastases) Look for metastases to bone May give helpful information about tumor „activity‟ and response to therapy   CT (chest)  CT/PET   CT (body)  Look for lymph node involvement  Bone Marrow Evaluation  Look for metastatic disease .

generally in cells of skeletal muscle lineage  Small. round. blue cell tumor  Two main histological types: embryonal and alveolar  About 20% are undifferentiated or have other histological subtypes .Rhabdomyosarcoma  Malignant tumor of mesenchymal origin.

3:1.Incidence and Etiology  250 US cases/yr.0  higher in industrialized “West” Histology varies according to age at dx  Associated with familial syndromes such as Li-Fraumeni and neurofibromatosis  Genetic factors may be involved  .  most <9  M:F ratio of 1.

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Clinical Presentation  Detected by mass appearance or functional disturbance  ‘systemic’ symptoms are Rare .

classified per tumor histology  IRS Clinical Group Stage System .Diagnostic Workup/Staging H &P  Imaging studies of affected area and to determine mets. used as baseline data  Tumor biopsy is necessary for diagnosis  Formal „staging‟ to determine „risk group‟ a combination of  TNM system.

and bony erosion are associated with worse prognosis . potential for metastases  In general .Prognostic Indicators  Histologic subtype  Stage & Group  Site – often related to size.Better outcome with early response to treatment  For Localized tumors: older age. regional lymph node involvement.

with support of Chemotherapy and Radiation .per protocol  Surgery: resection where feasible.Treatment and Prognosis  Treatment multimodal . second surgery if residual disease after first surgery  Shift from more radical procedures to function-sparing procedures.

but with increased doses RT shown to be helpful  RT to all except completely resected Stage I patients.Treatment and Prognosis. IC meningeal extension . dose reduction for selected patients under study  Emergency RT for SC compression. cont‟d  Radiation therapy (RT): rhabdo initially thought to be radio-insensitive. hyperfractionated vs conventional treatment.

paravertebral. cranial. alveolar histology  Recurrence rare after 3-4 years. extremity. . non-bladder/prostate GU --Worse: pelvic.Treatment and Prognosis. retroperitoneal. mets at dx. truncal. parameningeal. for all  Prognosis: <20% to 95% stage & histology dependent --Better: orbital. cont‟d  Chemotherapy site.

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From ABP  Certifying Exam Content Outline Know that the presenting symptom of osteosarcoma is usually bone pain or swelling .

Credits  Anne Warwick MD MPH .