This document provides an outline and overview of osteosarcoma, including its epidemiology, pathology, clinical presentation, investigations, treatment, and prognosis. It begins with an introduction to osteosarcoma and outlines its surgical importance. Key points include that osteosarcoma most commonly affects the long bones of teenagers and young adults, neoadjuvant chemotherapy and limb salvage surgery have improved outcomes, and prognosis depends on several risk factors like tumor size and response to pre-op chemotherapy.

1. Pathology and
management of
Osteosarcoma
Dr Okonkwo chukwuebuka Augustine

2. Outline
• Introduction
• Statement of surgical importance
• Anatomy of long bones
• Pathology
1. Epidemiology
2. Aetiology
3. Risk factors
4. Genetic predisposition
5. Pathological types
6. Pathogenesis
7. Staging
• Clinical presentation
1. History
2. Physical examination
• Investigations
• Treatment

3. Outline contd
• NCCN guidelines
• Future considerations
• Complications
• Prognosis
• Prevention
• Conclusion
• References

4. Introduction
• Osteosarcoma/osteogenic sarcoma is a malignant
tumor of the bone
• Usually common in fast growing bones - first and 2nd
decades of life
• Histological Hallmark is the production of malignant
osteoid
• Pain is commonest presenting feature as
• Neoadjuvant chemotherapy has improved the long
term survival
• Limb salvage is currently advocated

5. Statement of surgical importance
• Highly malignant tumor
• > 20% at Presentation already have pulmonary
metastasis
• chemotherapy has improved prognosis
• Limb salvage including metastatectomy is now the
standard of care as against amputation

6. Long bone Anatomy

7. Epidemiology
• 80.1% of all primary malignant bone tumors, M:F - 1.35:1
(Lasebikan et al, 2014)
• Peaks in the 2nd decade, (13-16 years of age)
• Prevalence: 2.13% of all childhood malignancies with a male
preponderance (A.Mohammed and Halima Aliyu,2009)
• 3.1/million in the USA
• More in blacks, 5.2/million as against 4.6/million (Michael
Gibson et al,)
• Affects appendicular skeleton ( Distal femur, proximal tibia,
proximal humerus)
• Jaws , axial skeleton

8. Contd

9. Aetiology
• Exact aetiology - unknown
• Predispositions
1. Age, sex, race
2. Bone dysplasia, Paget's disease of bone,
enchondromatosis, hereditary multiple exostosis
3. Mutations in germline - Retinoblastoma Gene, p53
gene- Li Fraumeni syndrome
4. Autosomal recessive association -Rothmund
Thomson's syndrome
5. Exposure to radiation

10. Pathological types
• Primary
1. Intramedullary
• -Conventional/ classic variant
• -Telangiectatic
• -Low grade intramedullary
• -small cell
• 2 Surface Types
• -Parosteal
• -Periosteal
• -high grade surface

11. Contd
• Secondary : occurs at the site of another disease, > 50
years
1. Paget's disease
2. Previous irradiation
3. Fibrous dysplasia
4. Bone infarcts
5. Osteochondromas
6. Chronic osteomyelitis
7. De-differentiated chondrosarcoma
8. Osteogenesis imperfecta

12. Conventional/classic variant
• Most prevalent,80% of osteosarcomas,
metaphyseal origin
• High grade
• Mixed osteolytic/ blastic lesion.
• Based on predominant EC matrix ,(osteoblastic,
chondroblastic, fibroblastic)

14. Telangiectatic
• <4%
• 25% presents with pathological fracture
• Radiography- osteolytic-eccentric lesion looking like
aneurysmal bone cyst, however on histology septa
has high grade sarcoma cells

16. Low grade intramedullary
• 1-2%, 3rd-4th decades
• Mostly in close proximity to the knee
• Could be lytic, mixed lytic/blastic,or blastic
• Resembles fibrous dysplasia but cortical violation
on ct/MRI gives it out.

18. Small cell type
Rare,1.5%
Similar to classic variant but for the cells which are
round in shape
Positive for CD 99

19. Parosteal
• 1-6%, arises from surface of long bones
• Medullary canal is spared
• Affects more females, slow growing
• Consists of a well differentiated fibrous stroma with
osseous components
• Bony trabeculae has a parallel Orientation and a
• "pulled steel wool pattern " on H and E

21. Periosteal
• 1-2%, juxtacortical, more aggressive,
• Demonstrates the typical sunburst appearance and
codmans triangle
• Matrix is usually cartilaginous with areas of
calcification

22. High grade
• <1%
• Radiographically has partial mineralisation
• Disruption of cortex
• High grade spindle cell with atypia

23. Pathogenesis
• Develops at sites of rapid bone turnover
• TUMOR SUPPRESSOR GENES
• Familial syndromes associated with osteosarcoma
1. Retinoblastoma (RB1 gene, 13q14)
2. Li Fraumeni (p53)
3. Rothmund Thomson
4. Werner
5. Bloom syndromes

25. Contd
• Mutations could be from
• For RB1
1. Loss of heterozygosity
2. Structural rearrangements
3. Point mutations
• Which causes phosphorylation of pRb , transition G1-S is blocked
• For p53
1. Allelic loss
2. Point mutations
3. gene rearrangements
• Causes defective repair and apoptosis

26. Contd

28. Contd
• For REcQ helicases
1. Increased mitiotic recombination
2. Elevated chromosome mis-segregation
3. Hypersensitivity to DNA damaging agents
4. Defect in meiosis
• RANKL - Protein

29. Pathogenesis 2
• PROTO-ONCOGENES
1. MYC
2. FOS
3. GL11
• GROWTH FACTORS AND RECEPTORS
1. FGFR2 (10q11)
2. IGF-1R
3. BMP and BMPR
4. TGF-B
5. VEGF

30. Contd
• FACTORS FOR METASTASIS
1. NF-2 which codes Merlin (mediates contact
inhibition) and Ezrin

31. Contd
• Excessive cell proliferation
• Cellular atypia
• Demand necrosis
• Pain
• Attempt at healing
• Loss of inhibition by EC matrix
• Access to medullary and periosteal vessels
• Distant metastasis

32. Staging
• Enneking staging is the commonest

33. Default extra compartment sites
• Antecubital fossa
• Inguinal region
• Popliteal fossa
• Intra Pelvic space
• Paraspinal space

34. Clinical presentation
• History
• Age, sex,
• Pain usually prevents sleep.
• Swelling- distal femur, prox tibia, prox humerus
• Multiple bone lumps( within 6 months synchronous, 6 months
apart - metachronous)
• Ulcers that may fungate
• Weight loss, fever
• Pathologic fractures
• Hemoptysis/ persistent cough
• Low back pain

36. Examination
• Chronically ill looking
• Painful distress
• Pallor, icterus, febrile
• Lymphadenopathy
• Mass
• Decreased ROM
• Ulcers
• Differential warmth
• Deformities/abnormal movement
• Respiratory signs in late cases (decreased air entry, tachypnea, coarse
crepitation)
• Performance status (Karnorfsky,EcOG)

37. Investigations
• To confirm diagnosis
• To stage disease
• To work up for surgery
• To monitor treatment
• Could be
1. Radiological
2. Tissue diagnosis
3. Laboratory

38. Radiological
• X ray (uses the rule of 2s)
• Shows bone destruction
• Soft tissue extension
• Classical sun burst appearance and Codman
triangle
• Cystic lesion
• Fractures

40. Contd
• CT scan
1. Best modality for excluding distant metastasis
(lungs)
2. Primary tumor site CT can be used to predict the
risk of pathologic fracture
3. Can be used to guide biopsy

42. Contd
• MRI
• Single most important study for accurate clinical
staging using Enneking
• Can help demonstrate skip lesions
• Gives extent of disease and extracompartmental
involvement
• Axial view shows presence of neurovascular
involvement

44. Skip lesions

45. Bone scanning
• Radionuclide bone scanning with technetium-99
(99mTc)-methylene diphosphonate (MDP/MDI) is
important in evaluating for the presence of
metastatic or multifocal disease
• After the bone scan, an image of abnormal areas
should be obtained with computed tomography
(CT) or magnetic resonance imaging (MRI).

48. Laboratory Studies
• Full blood count- Anemia, neutrophilia
• Esr
• SEUCR
• Urinalysis
• Liver function test
• Prognostic markers ALP, LDH

49. Biopsy
• Process of obtaining tissue for histological diagnosis
• Should be preferably performed by the definitive surgeon
• Scar of biospy should be incorporated into the enbloc tissue
to be removed
• Frozen section usually done to be sure of tissue being
sampled
• Drain(vacuum) should pass through short incision
• Open biopsy (preferred to avoid sampling error and to
provide adequate tissue for biologic studies)
• Trephine biopsy or core-needle biopsy (preferred for
vertebral bodies and many pelvic lesions)
• Fine-needle aspiration (FNA; not recommended)

50. Contd
• Craig needle used for bone core needle biopsy

51. Other investigations
• 2D -ECHO
• Multi gated acquisition scanning (MUGA)
• Audiography

52. Treatment
Multidisciplinary
• Algorithm
1. Radiological staging
2. Biopsy
3. Pre - op chemotherapy
4. Repeat radiology (to assess and redefine)
5. Surgical resection
6. Reconstruction
7. Adjuvant care

53. Neoadjuvant Chemotherapy
• Facilitates tumor shrinkage
• Reduces tumor spread at time of surgery
• Takes care of micrometastasis
• Ascertains response
• chemotherapy regimen comprising both a cell
cycle–specific drug and a cell cycle–nonspecific
drug could increase response rates.(Xiao et al)
• Given 3-4 weeks before surgery

55. Contd
• Response to neoadjuvant Chemotherapy Is
ascertained objectively after surgery
• Based on histological disapperance of neoplastic
cells and preservation of stromal and matrix cells
• Huvos classification
1. Poor responders < 95% kill
2. Good responders > 95 % kill

56. Surgery
• Mainstay
• Limb salvage currently advocated when possible
• All clinically detectable tumor, including metastases,
should be excised
• The two primary surgical options are
• tumor excision with limb salvage, and
• amputation.
• Surgical margins in excision should encompass
resection of tumor, pseudocapsule, and a cuff of
normal tissue en bloc
• As many detectable metastatic lesion as is technically
feasible should be excised (5 fold increase in survival)

59. Contd
• When limb-salvage reconstruction is possible, the
following options exist, which must be chosen on the
basis of individual considerations:
• Arthrodesis
• Autologous bone graft
• Allograft
• Allograft prosthesis construct
• Prosthesis
• Rotationplasty

60. Prosthesis/Endoprosthesis
• Used to reconstruct articular joints
• Provides immediate skeletal and joint stability
• Can allow interval lengthening in growing bones
• Life span of about 15 years-mechanical failure

61. Intraoperative photography of
salvage surgery

62. Neurovascular bundle identified
and tagged

63. En Bloc excision
Further sizing of endoprosthesis

64. Implantation

65. Rotationplasty
• An option for a growing child
• Strikes a balance between amputation and salvage
• Deployed in tumors of Distal femur and proximal tibia
• Distal tibia is rotated 180° and fixed to proximal femur
• The ankle joint becomes the knee joint
• Offers mechanical advantage
• Cosmetic appearance maybe a source of worry

70. Other surgical options

71. Post op chemotherapy
• Essentially same as pre op chemotherapy
• Usually commenced 2 weeks after surgery
• Poor responders based on pre op gets salvage
therapeutic regimen
1. Increased dose
2. Increased duration
3. Change of regimen

72. Contd
• For second-line therapy (relapsed/refractory or
metastatic disease)
• Ifosfamide (high dose) ± etoposide
• Regorafenib
• Sorafenib
• Sorafenib ± everolimus
• Cyclophosphamide and topotecan
• Docetaxel and gemcitabine
• Gemcitabine

73. Radiotherapy
• Generally Osteosarcomas are radioresistant

75. Radiotherapy contd

76. National comprehensive cancer
network guidelines NCCN
• Recommends that in all patients with
Osteosarcoma, enrolment into clinical trial should
be done where possible

79. Future direction in care
• Tyrosine kinase inhibitors- shut down signal pathway
that are necessary for tumor survival
• Liposomal muramyl
tripeptidephosphatidylethanolamine (L-MTP-PE) is a
promising drug in clinical trial, stimulates the formation
of tumoricidal macrophages.
• Intra arterial cisplatin
• Intra- arterial embolisation
• Samarium-153 ethylene diamine tetramethylene
phosphonate (SM-EDTMP) for relapsed or refractory
disease beyond second-line therapy

80. Recurrence
• Same frequency for appropriately done limb
salvage and amputation
• Primary site recurrence 4-6%
• 30-40% relapse in 3 years
• Lungs is the commonest site, prognosis is poor
• Re-excision offers better outcome

81. Prognosis
• Depends
• Age at Presentation
• Histologic type
• Tumor biology
• Presence of metastasis at Presentation
• Location of primary tumor
• Size of tumor
• Response to pre-op chemotherapy
• Lymph node involvement
• Elevated ALP, LDH
• Interval before recurrence

82. Tumor markers
• Wingless-Type MMTV Integration Site Family,
Member 6 (WNT6), located in chromosome 2q35,
belongs to the WNT gene family showing diverse
functions on cell fate, proliferation, migration,
polarity, and death (Jiang K. et al, 2018)
• Ancillary assays- LDH, ALP

83. Complications
• From tumor itself
1. Pain, fractures, psychology
• From chemotherapy
1. Hearing loss
2. Cardiac abnormality
3. Mucositis
4. Bone marrow failure
• From surgery
1. Wound infection, breakdown, sepsis
2. Hemorrhage
3. Phantom pain
• From radiotherapy
1. Diarrhoea
2. Radiation necrosis

84. Prevention
• Primary and secondary prevention may not be
maximally feasible
• Early presentation to hospital through health
education may boost secondary and tertiary
prevention

85. Follow up
• No reliable tumor markers
• History, physical sign, blood work and radiology are
used
• Generally, these visits occur every 3 months for the first
2 years; every 4 months for year 4 and every 6 months
for years 4 and 5 and yearly thereafter.
• When patients have been without therapy for 5 or
more years, they are considered long-term survivors.
These individuals should be seen annually

86. Conclusion
• Osteosarcoma is an aggressive malignant tumor of
bone mostly affecting skeletally immature bones
• Care is multidisciplinary
• A combination of chemotherapy and wide excision is
currently favored and has improved survival and quality
of life
• Advances in molecular biology may produce a more
reliable target therapy
• Lack of biomarkers makes follow up and prevention
tasky

87. Thank you
For your Time

88. References
• Meyers PA, Schwartz CL, Krailo M,et al: Osteosarcoma: The
addition ofmuramyl tripeptide to chemotherapy improves
overall survival: A report fromthe Children’s Oncology Group. J
ClinOncol 2008;26:633-638
• Gorlick R, Janeway K, Marina N. Osteosarcoma. Pizzo PA,
Poplack DG, eds. Principles and Practice of Pediatric Oncology.
7th ed. Philadelphia: Wolters Kluwer; 2016. 876-97
• Orthobullets
• Kim SY, Helman LJ. Strategies to Explore New Approaches in
the Investigation and Treatment of Osteosarcoma. Cancer
Treat Res. 2010. 152:517-528. [QxMD MEDLINE Link].