Department of Radiation Oncology SAMC and PGI Indore

1. BONE TUMORS
(OSTEOSARCOMA)
Dr Manika Batra
Resident
Radiation Oncology

2. General Classification of bone tumors
Histological type Benign Malignant
Hematopoietic – 41.4%
(most common)
Myeloma
Lymphoma
Chondrogenic – 20.9% Osteochodroma Chondrosarcoma
Chondroma
Chondroblastoma
Chondromyxoid fibroma

3. Histological type Benign Malignant
Osteogenic 19.3% Osteoma Osteosarcoma
Osteoid osteoma
osteoblastoma
Unknown origin 9.8% Giant cell tumor Ewing tumour
Malignant giant cell tumor
Admantinoma

4. Histological type Benign Malignant
Histiocytic origin Fibrous histiocytoma MFH
Fibrogenic Fibroma Fibrosarcoma
Desmoplastic fibroma
Notochordal Chordoma
Vascular Hemangioma Hemangioendothelioma
Hemangiopericytoma
Lipogenic Lipoma Liposarcoma
Neurogenic Neurilemmoma

5. Important Facts
• Most common benign tumor – Osteochondroma,
Osteoid Osteoma
• Most common Skeletal malignancy – Metastasis
• Most common bone tumor in Pediatric age group
and adolescence – Osteosarcoma and Ewing’s
sarcoma
• Most common tumors arising from bone marrow
elements – Ewing’s sarcoma and non-Hodgkin’s
lymphoma.

6. Musculoskeletal Tumor Society
Classification (MSTS)
A
B
T1
T2

8. Osteosarcoma
• Tumor is characterised by production of osteoid by
malignant mesenchymal cells.
• Most common primary malignant bone tumor (35%).
• Most common radiation induced sarcoma.
• 10%-20% present with metastatic disease at diagnosis.
Spreads hematogenously, with lung being the most
common metastatic site.
• 5 year survival rate is 5% - 23%

9. • Bimodal distribution as a function of age : Primary
high grade osteosarcoma – 10–20 years, Parosteal
osteosarcoma – 3rd and 4th decade, Secondary
osteosarcoma in older population associated with
other conditions (Paget Disease, fibrous dysplasia)
that arise in an older population (age >65 years).
• more common in boys (> girls) (with the exception
that parosteal osteosarcoma is more common in
females)
• more common in blacks (> whites).

10. • Sites:
Metaphysis: 90%
Diaphysis: 8-10%
Epiphysis: 1%
• Occurrence:
Long Bones: 70%-80%
Distal Femur (40%)
Proximal Tibia (20%)
Proximal Humerus (15%)
Axial Skeleton
Pelvis
Jaw

11. Tumor is located at the typical metaphyseal site
A. Tumor is largely restricted to bone
B. Tumor is accompanied by massive soft tissue extension.

12. skip metastasis located in the upper half of the femur. The
primary tumor was located in the lower metaphysis of the same
bone

13. • The exact cause of osteosarcoma is unknown
Risk factors –
• Rapid bone growth
• Environmental
• Genetic
• Pre-existing benign /malignant lesions
Etiology

14. • Rapid bone growth
- increased incidence during the adolescent
growth spurt
- location in the metaphyseal area adjacent to
the growth plate of long bones
• Genetic
Li-Fraumeni syndrome (p53 mutation)
Rothmund-Thomson syndrome
Mutation of the RB gene (retinoblastoma)

15. • Environmental
Radiation – localised radiation >2000 cGy
latent period - 4 to 40 years
Chemicals – methylcholanthrene
acetylaminofluorene
beryllium compounds
Virus - RNA : mouse sarcoma virus
DNA : polyoma ,SV 40 virus

16. • Pre-existing benign /malignant lesions
– Paget disease
– fibrous dysplasia
– enchondromatosis
– hereditary multiple exostoses
– chondrosarcoma

17. – Intramedullary (80%) : typically presents within areas
of rapidly proliferating skeletal bone.
– Juxtacortical/Surface (7-10%) : arise adjacent to the
outer surface of cortical bone.
– Intracortical (2%)
Sub-types

18. • Intramedullary
– conventional
a. Osteoblastic
b. Chondroblastic
c. Fibroblastic
d. Small-cell
e. Epithelioid
– Telangiectatic
– Well-differentiated
• Juxtacortical Osteosarcoma
– Parosteal
– Periosteal
– High Grade Surface
• Intracortical

19. www.eyst.org
Intramedullary Osteosarcoma
• Rare
• Low grade

20. www.eyst.org
Conventional Osteosarcoma
• High grade
• Common type of
Osteosarcoma
• Common radiographic
appearance is aggressive
lesion producing osteoid
matrix. Periosteal reaction
may take the form of
“codmans triangle” or
“sunbrust” or “hair on end”
appearence

21. www.eyst.org
Small Cell Osteosarcoma
• Rare
• High grade
• Uniform small size tumor
cells.
• Diffuse pattern of growth.
• Resemble Ewing sarcoma or
Lymphoma

22. Telangiectatic
• Blood filled cystic space and radiologically
appears as pure lytic lesion.
• Pathological fractures.
• Grossly the lesion simulate aneurysmal bone
cyst.
• Detection of malignant stroma in the septa
that separate the blood cysts.

24. Well differentiated intramedullary
• This tumor is microscopically bland - underdiagnosed as a
benign lesion.
• In contrast to fibrous dysplasia:
– this tumor shows radiographic evidence of cortical
destruction.
– Microscopically, atypia is minimal but still present.
– Invasive growth pattern.

25. Juxtacortical osteosarcoma
Osteosarcoma of upper femur: minimal
involvement of the cortex
Osteosarcoma with large
extracortical component

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Parosteal Osteosarcoma
• Low grade malignancy
• Rare
• Arises on surface of bone
and invades medullary
cavity only at later stages.
• Peculiar tendency to occur
as a lobulated mass on the
posterior aspect of femur
• Occur in slightly older age
group

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Periosteal Osteosarcoma
• Intermediate grade
• Grows on surface of long
bones
• Commonly on upper tibial
shaft and femur.

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High grade surface Osteosarcoma
• High grade
• Least Common
• Radiographs show invasive lesions with ill defined borders

29. • Very rare
• High grade
• confined to the
cortex
• Sites : Diaphysis of
femur or tibia
Intracortical Osteosarcoma

30. www.eyst.org
Secondary Osteosarcoma
• These occur at the site of another disease process
• E.g. Pagets disease, previous radiation treatment, fibrous
dysplasia, bone infarcts, osteochondromas, chronic
osteomyelitis, dedifferentiated chondrosarcomas,
melorhestosis and osteogenesis imperfecta.
• Older patients
• Prognosis poor
• Long history of dull aching pain and recent lytic destruction

31. Osteosarcoma of jaw :
• Slightly older population is affected (average age, 34
years)
• Most lesions show a prominent chondroblastic
component.
• Most common sites of involvement: body of the
mandible and alveolar ridge of the maxilla.
Osteosarcoma in Paget’s disease :
• Polyostotic type
• Pelvis, humerus, femur, tibia and skull.
• Large number of osteoclasts alternating with atypical
osteoblast.

32. • Synchronous Osteosarcoma:
Lesions that affect multiple bones
discovered within 6 months of each other.
• Metachronous Osteosarcoma:
Lesions involving multiple bones
discovered more than 6 months apart.
Multicentricity

33. Clinical Features
• Presenting complaints :
- pain (night pain)
-sometimes only tiredness & limp
-palpable, painless mass
-skin conditions to be examined
carefully
• History of trauma sometimes draws attention.

34. Associated Features
• Effusion and swelling of nearby joints
• Fever
• Pallor and cachexia
• Regional lymph nodes
• Symptoms associated with pulmonary metastasis
• Pathological fracture: unusual presentation

36. Laboratory Studies
• Full blood count, ESR, CRP.
• LDH (elevated level is associated with poor prognosis)
• ALP (highly osteogenic)
• Platelet count
• Electrolyte levels
• Liver function tests
• Renal function tests
• Urinalysis
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Radiological Investigations
• Plain radiographs
• CT scan
• Bone scan
• MRI
• Chest radiographs and CT for staging

38. Plain X-ray (Most valuable)
• Lesions are usually permeative
• Associated with destruction of the cancellous and
cortical elements of the bone
• Ossification within the soft tissue component, if tumor
has broken through cortex
• Intra medullary extension may be present
• Borders are ill defined
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39. • Codman’s triangle

40. • Sunray or hair-on end appearance : Extension of the tumor
through the periosteum

41. Pathological fracture

42. CT scan
• Approximately 10% to 20% of
patients present with
radiographically detectable
metastases at diagnosis mostly in
the lungs.
• Conventional radiographs of the
chest show metastatic nodules 10
mm or greater in diameter.
• Pulmonary metastases 3 to 7 mm
or greater in diameter are
identified with CT.
• Spiral CT is superior to
conventional CT for this purpose.

43. MRI
• Excellent for describing lesions in the marrow cavity
• Helpful to determine the level of resection
• Useful for screening skip lesions of 2mm or more
• Can detect medullary invasion in case of juxtacortical
tumors
• Can detect epiphyseal involvement and penetration of
cartilage.
• MRI demonstrates relationship of the extra-
compartmental tumor to fascial planes and
neurovascular structures.

44. 44

45. Angiogram
• Determine vascularity of the tumor
• Detect vascular displacement
• Relationship of vessels to the tumor
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46. Bone scan
• Bone scan with technetium 99m
shows a marked increase in the
uptake of radionuclide in tumor.
• Increased uptake is due to active
formation of new tumor and host
bone as well as the vascularity of the
lesion.
• Used to look for bony metastases in
the involved bone (skip
metastases)and at other skeletal
sites.
• Detect local recurrence of tumor
• Mineralized metastases are more
likely to be detected by bone scans
than are non-mineralized ones at
extra-pulmonary sites.
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47. Biopsy
• to confirm the diagnosis.
• Types :
– Fine needle aspiration
– Core needle biopsy
– Open incisional biopsy
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48. Lace-like osteoid deposition is characteristic

49. Histochemistry, IHC & molecular genetics
• Strong alkaline phosphatase activity.
• Vimentin, S-100, keratin and EMA.
• Osteonectin, osteocalcin, osteopontin.

50. Prognostic Factors
• Extent of the disease
– Patients with pulmonary, non-pulmonary ( like bone) or skip
metastasis have poor prognosis
• Grade of the tumor
– High grade tumor have poor prognosis
• Size of the primary lesion
– Large size tumors have worse prognosis then small size
tumors
• Skeletal location
– proximal tumors do worse than distal tumors.
• Secondary osteosarcoma
• Proximity to neurovascular structures
• Elevated LDH and Alkaline phosphatase
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Poor prognosis

51. Management
Radiological staging
Biopsy to confirm diagnosis
Preoperative chemotherapy x 6weeks
Repeat radiological staging (access chemotherapy response, plan surgical
treatment)
Surgical resection with wide margin (3-4 weeks after chemotherapy)
Reconstruction
Adjuvant chemotherapy based on pre-operative response (2 weeks after
surgery) x 32weeks
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52. • Low grade osteosarcoma - treated by surgery alone.
• Pulmonary metastatic disease - treated as for non-metastatic
disease. If possible, resection of nodules after completion of
chemotherapy.

53. Chemotherapy
• Chemotherapy has excellent role in terminating these
lesions.
• Historical data suggests that survival rate with ablative
surgery alone is <20%.
• When combined with chemotherapy it is almost 65%.
• Multidrug chemotherapy found to be more effective than
single agent (39% vs 68%)
• Chemotherapy given in two modalities :
– Neoadjuvant chemotherapy
– Adjuvant chemotherapy

54. • Commonly used drugs :
– Doxorubicin - 60-75 mg/m² (cardiotoxic)
– Cisplatin - 50-100 mg /m² (nephrotoxic)
– Vincristine - 1.5 mg /m²,weekly (peripheral neuropathy)
– Methotrexate - 500-1000 mg/m² (megaloblastic anaemia,
pancytopenia)
– Cyclophosphamide and Ifosfamide - 1-1.5 g/m²
(haemorrhagic cystitis)
– Dacarbazine - 250mg/m² (flu like syndrome)
– Dactinomycin - erythema, myelosuppresion

55. • First line therapy
– Cisplatin, Doxorubicin
– MAP (HD-Mtx, Doxorubicin, Cisplatin)
– HD-Mtx, Doxorubicin, Cisplatin, Ifosfamide
– Cisplatin, Ifosfamide, Epirubicin
• Second line therapy
– Docetaxel, Gemcitabine
– Cyclophosphamide, Etoposide
– Cyclophosphamide, Topotecan
– Gemcitabine
– Ifosfamide, Etoposide
– Ifosfamide, Etoposide, Carboplatin
– HD-Mtx, Ifosfamide, Etoposide
– 153 Sm-EDTMP for disease beyond second line therapy
– Sorafenib

56. • High dose methotrexate (HDMTX) with leucovorin
regresses pulmonary metastasis.
• Efficacy of HDMTX mostly depends on dosage (minimum
of 8-12g/m2 is required to get tumoricidal effect).
• Chemotherapeutic agents under clinical trials are
– High dose Ifosfomide
– Muramyl tripeptide phosphatidylethanolamine (MTP-
PE)

57. Neoadjuvant Chemotherapy
• Advantages
– Regression of primary tumor, making limb salvage surgery easier.
– Effectively treat micro-metastases at earliest possible.
– Avoid tumor progression, which may occur due to any delay in surgery.
– Determination of pathologic response : Percent of necrosis after
neoadjuvant chemotherapy is a prognostic factor (> 90% necrosis has
significant survival advantage).
• Disadvantages
– May increase peri-operative complications (delayed wound healing,
infection)
– nausea, vomiting and other toxicities may cause delay in surgery.
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58. Intra-Arterial Chemotherapy
• Highly cytotoxic
• Cisplatin – most successful agent
• Requirements :
– pretreatment angiography
– catheter placement

59. Restaging after Neoadjuvant
Chemotherapy
• Clinical : Pain
ALP
Tumor size
• Radiographic response : increased ossification, marked
thickening and new bone formation of periosteum and
tumor border and decreased soft tissue mass.
• Angiographic : vascularity
• Bone Scintigraphy : in activity
• PET Scan : SUV < 2 : good response
SUV > 5 : poor response

60. Histologic Grading for Neoadjuvant
Chemotherapy Response
Salzer-Kuntschik Picci Huvos
I No viable
tumor cells
Total response No viable
tumor
IV No histologic evidence of
viable tumor
II Single viable
tumor cells or
cluster <0.5 cm
Good response 90%–99%
tumor necrosis
III Only scattered foci of viable
tumor cells
III Viable tumor
<10%
Fair response 60%–89%
tumor necrosis
II Areas of necrosis due to
chemotherapy with areas of
viable tumor
IV Viable tumor
10%–50%
Poor response <60% tumor
necrosis
I Little or no chemotherapy
effect
V Viable tumor
>50%
VI No effect of
chemotherapy

61. Memorial Sloan-Kettering Cancer Centre T10 regimen is
frequently used for non-protocol patients : high-dose
methotrexate, doxorubicin, bleomycin, cyclophosphamide and
actinomycin D.

62. Surgery
• Goal of the surgery: Remove the tumor en-bloc and achieve
adequate negative margins.
• Small Tumors : can be removed adequately by resection with or
without reconstruction.
• Large Tumors : may mean loss of ipsilateral lower extremity and
compromising bowel and bladder function.

63. Principles of Surgery
• Choice between limb salvage surgery and amputation must
be made on the basis of the expectations and desires of the
individual patient and the family.
• Points to be stressed
– survival after the procedure
– short and long term morbidity
– function of salvaged limb compared to prosthetics
– psychosocial consequences

64. Options for Surgery
• Non Functioning Limb : Amputation
• Limb sparing procedure (preferred)
• Reconstruction Options :
– Autologous Bone Grafts
– Allografts
– Endoprosthesis
• Less commonly :
– Rotationplasty
– Arthrodesis

65. Limb Salvage Surgery
• Removal of tumor and reconstruction of the limb with an
acceptable oncologic, functional and cosmetic results.
• Goal is to safely and completely remove the tumor while
preserving vascular and nerve supply to the extremity.
• Historically - amputation.
• Over the past few years - limb-sparing procedures have become
the standard, mainly due to advances in chemotherapy and
sophisticated imaging techniques
• Limb salvage procedures now can provide rates of local control
and long-term survival equal to amputation.

66. • Guidelines :
– No major neurovascular involvement
– Wide resection of affected bone with a normal muscle cuff all
around
– En-bloc removal of all biopsy sites and contaminated tissue
– Resection of bone 3-4 cm beyond abnormal uptake
– Resection of adjoining joint and capsule
– Adequate motor reconstruction
– Adequate soft tissue coverage.

67. • Contraindications
– Displaced pathological fracture
– Inappropriate biopsy site
– Infection
– Skeletal immaturity
– Major neurovascular involvement
– Extensive muscle involvement
Predicted leg-length discrepancy should not be greater than 6-
8cm.

68. Amputation
• Amputation involves removal of the limb with a safe margin
between the end of the retained portion and the tumor.
• Indications :
– Grossly displaced pathologic fracture
– Encasement of neurovascular bundle
– Tumor that enlarges during pre-operative chemotherapy and
is adjacent to neurovascular bundle
– Palliative measure in metastatic disease
– If the tumor has caused massive necrosis, fungation,
infection, or vascular compromise.
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69. Surgical Margins

70. • The skeletal defect must be reconstructed by :
– Endoprosthesis (most common) – replacing the removed bone
with a metal implant
– Allograft (cadaveric) bone
– Vascularized bone acquired from the patient
– Allograft-prosthetic composite constructions
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A B

71. Rotationplasty
• Most commonly used for osteosarcoma of distal femur in skeletally
immature patients
• Neurovascular structures and distal aspect of limb (leg) are retained
and re-attached to the proximal portion after the tumor has been
removed.
• Principle is to excise the diseased part of the limb and then join the
ramainning parts together but in so doing, rotating them through
180 degrees.
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• Main vessels are divided and re-
anastamosed but sciatic nerve is
retained in anastamosed segments
• Here the ankle becomes knee and the
foot becomes a useful attachment for
a below knee prosthesis

72. • Pelvic tumors require hemipelvectomy for en bloc resection.
Adjuvant radiation has been used to improve outcomes in
patients with incomplete resections.
• Spinal tumors are difficult to resect with negative margins.
Typically, an en bloc resection with vertebrectomy is performed,
combined with mechanical stabilization. Postoperative radiation
therapy used when negative margins cannot be obtained,
particularly when there is microscopic dural involvement.

73. Radiation Therapy
• Role is limited in treatment of osteosarcoma : relatively radio-
resistant tumor.
• Indications :
– Patients who refuses surgery
– Those with positive margins after resection.
– Those with sites not amenable to resection and
reconstruction (skull, vertebra, ilium, sacrum).
– Palliate symptomatic metastasis and local recurrence
– Bilateral lung irradiation in pulmonary metastasis.

74. 1. Modern external beam radiotherapy
– 3-D treatment planning with aid of presurgical and
postsurgical imaging.
– Typically, 2cm margin for axial tumors, which can be
extended to 4 to 5cm for extremity tumors.
– These margins can be restricted at natural tissue and fascial
boundaries.
– Chemotherapy should not be interrupted to deliver local
radiation therapy.
– Radiation can be given concurrently but is usually delivered
after chemotherapy due to increased acute toxicity with
concurrent administration.

75. Dose
• 60Gy at 2Gy/# for microscopically involved margins
• 66Gy for macroscopic residual disease
• 70Gy for inoperable tumors.
A non-irradiated strip of limb – length should be maintained
and wherever possible, overlie lymphatic drainage pathways
located medially in extremity (or atleast restricted to
maximum dose to less than 40Gy).

76. 2. Extracorporeal and definitive IORT :
– Extracorporal technique includes en-bloc resection of the
tumor and surrounding soft tissues, irradiation of the
specimen (30Gy) and re-implantation with aid of prosthesis.
– Associated with low rate of recurrence (<5%) but higher rate
of complications.
3. Particle therapy :
– Neutrons
– Protons

77. • Neutrons :
– Higher relative biologic effectiveness and o2
enhancement ratio.
– Complications: severe fibrosis, scarring of soft tissues
and adjacent organs.
• Protons :
– Largest study was done by Massachusettes general
hospital: 15 patients with osteosarcoma of base of
skull or vertebra - 5 year local control was reported to
be 59%
– Advantage: physical property of Bragg peak.

78. 4. Whole lung irradiation :
– 3 arm EORTC/SIOP study compared chemotherapy and
whole lung irradiation or combination of both which
showed same disease free survival and overall survival in
both arms.
– WLI following completion of chemotherapy/
metastatectomy (NCCN guidelines)
• 15Gy (1.5Gy/#) for patients < 14 years
• 18Gy for patients > 14 years

79. 5. Radionuclide therapy :
– Rhenium, strontium, samarium
– used for palliation of extensive bone metastases.
– Major toxicity : decreased platelet and white blood cell
counts, transient hypocalcemia.
– Radium-223 dichloride is bone seeking radiopharmaceutical
,under investigation for treatment of metastatic or recurrent
osteosarcoma. This agent is approved in US for treating bone
metastasis associated with castration resistant prostate
cancer.

80. Extracorporeal Irradiation (ECI)
• en-bloc removal of tumor bearing bone segment, removal of tumor
from bone, irradiation and re-implantation back in body.
• Advantages :
– Avoidance of radiation injury to un-irradiated bone, muscles,
joint, and other healthy tissues of body.
– Delivery of very high doses of radiation to tumor bearing bone
by ECI, which is otherwise not possible in the intact bone.
– Provides an anatomically size-matched graft for biological
reconstruction.
– Cost effective as compared to the prosthetic devices.
– Psychological advantage as patients feel that their own bone is
being used as prosthesis.

81. Davidson et al (2005)
• Reported a series of 50 patients with malignant bone tumor
mainly ESFT (21 patients) and OS (16 patients) using en bloc
resection and ECI (50Gy).
• Mean time of ECI process was 35min.
• With a mean follow-up of 38 months (range 12-92), 84%
patients were alive without any disease and only 8% developed
LR.

82. Poffyn et al (2011)
• Retrospective analysis of 107 patients with 108 malignant or
locally aggressive bone tumors treated by ECI with 300Gy,
and re-implantation of the bone as autograft.
• At 5 year follow-up, there was no LR and 64% of patients had
well healed graft. The 0% LR rate could be due to relatively
very high dose of ECI (300Gy) used in their study.

83. Side Effects
• Acute effects :
– skin reaction
– Mild fatigue
– Anorexia
– altered sleep & rest cycle
• Late effects :
– lymphatic & vascular obstruction
– Osteo-necrosis
– Joint stiffness
– Radiation induced sarcomas