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
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%
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)  Surface tumors

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

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

 Usually blastic
 May be lytic or mixed
bone destruction and
production
 Poorly marginated
 Cortical destruction
 Soft tissue
ossification
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
Treatment: Multimodal OS

 Surgery
 control of bulk disease

 Chemotherapy
 control of micrometastases

 Radiation
 Tumors not very radiosensitive, so this usually
reserved for palliation
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
 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, 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
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
Small, Round, Blue Cell Tumor
Differential Diagnosis
 Lymphoma/Leukemia
 Rhabdomyosarcoma
 Metastatic Carcinoma
 Ewing
 Neuroblastoma  Tumor without differentiation
 PNET/Ewing Sarcoma  PNET
 Small Cell Osteosarcoma  Tumor with neural
differentiation
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
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)
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%)
Location EWS

 central axis (47%):

 pelvis,chest wall,
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
Diagnostic Work-Up EWS

 History and physical

examination
 Laboratory tests:  Radiologic tests
 CBC, liver/kidney function  Plain films of primary site
tests, LDH, ESR  CT/MRI of primary site
 Urinalysis  CXR/CT of chest
 Whole body bone scan
 Pathology  PET scan (in future)
 Bone marrow aspirate and
biopsy  Pre-therapy evaluation also
 Biopsy (open preferred) includes echocardiogram/EKG
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
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
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
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
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
Bone tumors:
“Compare & Contrast”
Soft Tissue
Sarcomas
Rhabdomyosarcoma
MOST COMMON
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
 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
 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
 Clinical Presentation
 Detected by mass appearance or
functional disturbance
 ‘systemic’ symptoms are Rare
 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
 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
 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
 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
 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;
From ABP
Certifying Exam Content Outline
 Know that the presenting symptom of
osteosarcoma is usually bone pain or swelling
Credits
 Anne Warwick MD MPH