For educational purposes only

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