Bone Cancer ONCOLOGY BONE CANCER IN THE ONCOLOGY

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
Osteoblastic Fibroblastic
Chondroblastic
Telangiectatic
Small Cell

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

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 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

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

Complications / Late effects of Therapy OS
 Surgical
Functional outcomes of limb salvage vs.
amputation under study
 Chemotherapy
Anthracycline induced cardiomyopathy
 may arise 15+ years after therapy
Cis-platinum induced ototoxicity and renal
toxicity
Ifosfamide induced renal tubular dysfunction

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
Neuroblastoma
PNET/Ewing Sarcoma
Small Cell Osteosarcoma
Ewing
Tumor without
differentiation
PNET
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:
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

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

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
 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
 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 Cancer ONCOLOGY BONE CANCER IN THE ONCOLOGY

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