This document provides an overview of pediatric bone tumors, focusing on osteosarcoma and Ewing sarcoma. It discusses the epidemiology, clinical presentation, diagnostic workup, treatment, and outcomes of these two malignant bone tumors. Osteosarcoma most commonly affects the long bones of adolescents and is typically treated with neoadjuvant chemotherapy followed by surgery. Ewing sarcoma occurs in younger children and commonly involves the pelvis or long bones. It is treated with chemotherapy and local control with surgery or radiation therapy when possible. Both tumors require a multidisciplinary treatment approach to achieve long-term survival in approximately 60-75% of patients.

1. Bone and Soft
Tissue Sarcomas
Resident Education
Lecture Series

2. Pediatric Bone “Tumors”
Benign
 Osteochondroma
 Osteoid Osteoma
 Enchondroma
 Chondroblastoma
 Non-ossifying fibroma
aka
benign cortical defect
 Hemangioma
 Eosinophilic granuloma
 Osteomyelitis
Malignant
 Osteosarcoma
 Ewing sarcoma
 Malignant fibrous
histiocytoma
 Non-Hodgkin Lymphoma
 Eosinophilic granuloma

3. Malignant bone tumors
 Rare
 6% of all childhood malignancies
 Annual US Incidence in children < 20 yrs
 8.7 per million ~ 650 to 700 children/year
 For perspective, Annual US Incidence
 Overall 4697 per million
 Lung 610 per million
 Breast 633 per million
 Most often occur in young patients < 25 yrs
 Most common bone tumors ← will focus on these
 Osteosarcoma 56%
 Ewing sarcoma 34%

4. 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?

5. Cell of origin may be mesenchymal stem cell
Osteoblastic Fibroblastic
Chondroblastic
Telangiectatic
Small Cell

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

7. 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 1.4:1

9. 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

10. Clinical presentation OS
 Pain: dull, aching, constant, worse at
night, 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

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

12. Diagnostic Workup OS
 History and physical
examination
 Laboratory tests:
 Blood tests: include LDH,
Alkaline phosphatase
Also CBC, liver/kidney
function tests
 Pathology
 Biopsy (open preferred)
 Radiologic tests
 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,
GFR/creatinine clearance

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

17. Prognostic Factors OS
 Tumor Grade & Histology
 Parosteal favorable; telangiectatic unfavorable
 Disease Extent
 metastatic disease unfavorable
 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

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

19. 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, size, extramedullary extent, presence
of distant metastatic disease, age, skeletal
development, and life-style preference
 limb-sparing
 amputation
 Metastatic sites must also be resected
 If/when relapse occurs, retrieval therapy must
include resection

20.  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%

21. Treatment: Chemotherapy OS
 Bulky disease is considered somewhat
chemotherapy resistant
 Subclinical metastases are sensitive to
chemotherapy
 Most active agents include
 adriamycin, cisplatinum, high-dose methotrexate,
ifosfamide, 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

22. 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

23. 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

24. 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

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

26. Incidence EWS
 Occurs most commonly in 2nd decade
80% 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 1.3:1 < 10 yrs
1.6:1 > 10 yrs
 Rare in African-Americans and Asians

27. Associations or Risk Factors EWS
 ???
 Consistent cytogenetic abnormality,
t(11;22)(q24;q12) present in 90-95%
 resultant fusion gene is EWS/FLI-1
 Also seen:
 t(21;22)(q22;q12)  5-10%
EWS/ERG
 t(7;22) and t(17;22)  the remainder
EWS/ETV1 and EWS/E1AF respectively
 t(1;16)(q21;q13)
present along with t(11;22)

28. 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%)

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

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

31. Diagnostic Work-Up EWS
 History and physical
examination
 Laboratory tests:
 CBC, liver/kidney function
tests, LDH, ESR
 Urinalysis
 Pathology
 Bone marrow aspirate and
biopsy
 Biopsy (open preferred)
 Radiologic tests
 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

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

33. Radiographs EWS

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

35. 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

36. 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

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

38. 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

39. Surgical Indications EWS
 Expendable bone (fibula, 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. XRT

40. 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

41. Treatment: Chemotherapy EWS
 All patients require chemotherapy
 Active agents include
 Vincristine, cyclophosphamide, adriamycin,
dactinomycin,
ifosfamide, etoposide, topotecan, 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

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

43. Bone tumors:
“Compare & Contrast”

44. Soft Tissue
Sarcomas
Rhabdomyosarcoma
MOST COMMON

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

46. Rhabdomyosarcoma
Malignant tumor of mesenchymal origin,
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

47. Incidence and Etiology
 250 US cases/yr;
 most <9
 M:F ratio of 1.3:1.0
 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

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

50. 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, classified per tumor histology
 IRS Clinical Group Stage System

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

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

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

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

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

58. Credits
 Anne Warwick MD MPH