Bone and Soft

Tissue Sarcomas
PIEAS Lecture
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 2
nd
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
2
nd
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 2
nd
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
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
Complications / Late effects
EWS
Radiation
Second malignant neoplasms
Relatively high rate, especially bone tumors
Bone growth arrest

Chemotherapy
Anthracycline-induced cardiomyopathy
Veno-occlusive disease of the liver
Infertility
Second malignant neoplasms
Bone tumors:
Compare & Contrast
Epidemiology
Osteosarcoma
#1 bone tumor
2
nd
decade of life
Rare under 10 yr
M:F 1.5:1
15% more common in
African-Americans
than in Caucasians
Ewing Sarcoma
#2 bone tumor
2
nd
decade of life
Not rare under 10 yr
M:F ~1.4:1
Rare in African-
Americans, other
ethnic groups
Presentation
Osteosarcoma
Pain
Often mass
Duration of symptoms
3 months
Ewing Sarcoma
Pain
Often mass/swelling
Duration of symptoms
9 months
Systemic symptoms
Fever, weight loss
Associations / Risk Factors
Osteosarcoma
Lots
Radiation
Hereditary
retinoblastoma
Li-Fraumeni
Rothmund-Thomson

Cytogenetics
None characteristic
Ewing Sarcoma
None established





Cytogenetics
t(11;22)
Location of disease
Osteosarcoma
Majority occur in the
distal femur, proximal
tibia and proximal
humerus



Mostly metaphyseal

Most mets to lungs
Ewing Sarcoma
Fairly even split between
the extremities and the
axial skeleton
Axial occur in pelvis,
chest wall, spine, head
and neck

Classically diaphyseal

Mets to lungs, bone, bone
marrow
Radiology
Osteosarcoma
starburst

Usually blastic,
often lytic with
cortical destruction
Soft tissue
calicification
Ewing Sarcoma
onion skin

Permeative,
destructive,
cortical erosion
Soft tissue mass may
be difficult to see
without MRI
Treatment
Osteosarcoma
Local control
Surgery
NO radiation


Systemic control
Chemotherapy
Ewing Sarcoma
Local control
Surgery
and/or radiation


Systemic control
Chemotherapy
Outcomes
Osteosarcoma
Local disease only
55-65% overall
80-85% if > 90%
necrosis

Metastatic disease
20% if to lungs
<10% if to bones
Ewing Sarcoma
Local disease only
60-75% overall



Metastatic disease
40% if only to lungs
<20% if elsewhere
Late effects
Osteosarcoma
Chemotherapy
related

Surgery related
Ewing Sarcoma
Chemotherapy
related

Surgery related

Radiation related
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
Clinical Presentation
Detected by mass appearance or
functional disturbance
35% Head/neck (orbit & parameninges)
with proptosis, opthalmoplegia (orbital)
and nasal/sinus S/S, ICP (parameningeal)
22% GU (bladder or prostate)
with S/S of hematuria, obstruction,
pelvic or testicular mass, constipation
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, contd
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, contd
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;
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