This PPT presentation talks about osteosarcoma from the clinical point of view, summarizing the recent guidelines in diagnosis and treatment of osteosarcoma.

1. Osteosarcoma
By
Osama Elzaafarany
Assistant lecturer of clinical oncology
Medical Research Institute
Alexandria University
May 2015

2. Epidemiolog
 Primary bone tumors are rare, accounting for <0.2% of
malignant tumors registered in the EUROCARE
database; (Stiller CA, et al, results from the EUROCARE study. Eur J Cancer 2001; 37: 760–
766).
 Osteosarcoma is the most frequent primary cancer of
bone (incidence ~ 0.2/100 000 per year).
 The incidence is higher in adolescents (0.8–1.1/100 000
per year at age 15 –19 ), where it accounts for >10% of
all solid cancers.
 The male : female ratio is 1.4 : 1.

3.  In children and adolescents, > 50% of these tumors arise
from the long bones around the knee. Osteosarcoma can
rarely be observed in soft tissue or visceral organs.
 There appears to be no difference in presenting symptoms,
tumor location, and outcome for younger patients (<12
years) compared with adolescents.
 the 5-year survival rate increased from 40% at 1975 to 76%
at 2010 in children younger than 15 years, and from 56% to
approximately 66% over the same time in adolescents aged
15-19 years.
 5-ys OS in metas disease is about 20 %.

4. Risk factors for the occurrence of
osteosarcoma include:
 Previous radiation therapy.
 Paget disease of bone.
 Germline abnormalities; such as Li–Fraumeni syndrome,
Werner syndrome, Rothmund–Thomson syndrome, Bloom
syndrome, and hereditary retinoblastoma

5. Li–Fraumeni syndrome: Inherited mutation in TP53 gene.
Affected family members at increased risk for bone
tumors, breast cancer, leukemia, brain tumors, and
sarcomas.
Werner syndrome: Impaired DNA helicase; exonuclease
activity. Patients develop signs of aging in their early
twenties, including graying of hair and hardening of skin.
Other aging problems such as cataracts, skin ulcers, and
atherosclerosis develop later.

6. Rothmund–Thomson syndrome: also called poikiloderma
congenitale. Autosomal recessive condition; impaired DNA
helicase activity. Associated with skin findings (atrophy,
telangiectasias, pigmentation), sparse hair, cataracts, small
stature, and skeletal abnormalities. Increased incidence of
osteosarcoma at a younger age.
Bloom syndrome: rare inherited disorder; impaired DNA
helicase activity, characterized by short stature and sun
sensitive skin changes. Often presents with a long, narrow
face, small lower jaw, large nose, and prominent ears.

7. Pathology
The WHO histologic classification:
Central (Medullary) Tumors:
 Conventional central osteosarc. (most com. ).
 Telangiectatic osteosarcomas.
 Intraosseous well-differentiated (low-grade) osteosarcomas.
 Small cell osteosarcomas.
Surface (Peripheral) Tumors:
 Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas.
 Periosteal osteosarcoma: Low-grade to intermediate-grade osteosarcomas.
 Highgrade surface osteosarcomas.
characterized by the direct
formation of bone or osteoid
tissue by the tumor cells.
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8.  Conventional central osteosarcoma is
The most common pathologic subtype
which is characterized by areas of
necrosis, atypical mitoses, and malignant
osteoid tissue and/or cartilage.
 The other subtypes are much less
common, each occurring at a frequency
of less than 5%.
 Telangiectatic osteosarcoma may be
confused radiographically with an
aneurysmal bone cyst or giant cell tumor,
this variant should be approached as a
conventional osteosarcoma.

9.  Malignant fibrous histiocytoma:
 (MFH) of bone is treated according to osteosarcoma treatment
protocols.
 MFH should be distinguished from angiomatoid fibrous
histiocytoma, a low-grade tumor that is usually noninvasive,
small, and associated with an excellent outcome with surgery
alone.
 One study suggests similar event-free survival rates for MFH
and osteosarcoma.
 Extra-osseous osteosarcoma:
 Is a malignant mesenchymal neoplasm without direct
attachment to the skeletal system.
 Previously, treatment for extraosseous osteosarcoma followed
soft tissue sarcoma guidelines, although a retrospective analysis
of the German Cooperative Osteosarcoma Study (J Cancer Res Clin
Oncol, 2005) identified a favorable outcome for extr-aosseous
osteosarcoma treated with surgery and conventional
osteosarcoma therapy.

11. Molecular biology
Morphological Cytogenetics:
 High-grade tumors were seen to be hyperdiploïd
whereas low-grade tumors were seen to be diploid.
 It was reported that patients whose tumors showed a
non diploid DNA content had a longer event-free
survival after surgical resection and chemotherapy
than did those with diploid tumors.
 The most commonly identified numeric chromosomal
abnormalities were gain of chromosome 1 and loss of
chromosomes 9, 10, 13 and 17.

12. Molecular Cytogenetics:
 Many studies were using comparative genomic
hybridization (CGH) technique showed DNA
sequence copy number increases on certain regions,
the most important regions are 8q, 1q and 17p.
 Patients with copy number increases at 8 q have a
shorter survival.
 Ring chromosomes frequently observed in
paraosteal osteosarcomas.

13. Involved Genes and Proteins:
 Alterations in the RB gene pathway : present in approximately 60
-70 % of osteosarcomas, and recently LOH at the RB locus has
been proposed as a poor prognostic factor
 Alterations in the P53 pathway : p53 gene is located on
chromosome 17p13, abnormalities of p53 were identified in 50
% of cases.
 The MDM2 gene located on chromosome 12q13 encodes a
protein that negatively modulates p53 function by binding the
p53 protein. MDM2 is amplified in 5-10 % of osteosarcomas.
 DCC gene (deleted in colon cancer); tumor suppressor gen, seen
in Paget’s disease where osteosarcoma risk is increased.

14. Prognostic Factors
 Pre-treatment factors:
 Primary tumor site.
 Size of the primary tumor.
 Clinically detectable metastatic disease.
 Post-treatment: (pre-operative chemotherapy)
 Surgical resectability.
 Degree of tumor necrosis.

15. Primary tumor site
 Osteosarcoma usually arises in the metaphysis of a long bone, most
commonly around the knee.
 Involvement of the axial skeleton and craniofacial bones is
primarily observed in adults.
 Among extremity tumors, distal sites have a more favorable
prognosis than do proximal sites.
 Axial skeleton primary tumors are associated with the greatest risk
of progression and death, primarily related to the inability to
achieve a complete surgical resection.
 Pelvic osteosarcomas make up 7% - 9% of all osteosarcomas;
survival rates for patients with pelvic primary tumors are 20% to
47%.

16. craniofacial (Head & Neck) osteosarcoma:
 Mandibular tumors have a significantly better prognosis than
extra-gnathic tumors.
 Complete resection of the primary tumor with negative
margins is essential for cure.
 Characterized by higher incidence of lower grade types, less
metastasis, but inferior necrosis after CTx compared to
extremities Osteosarcoma.

17.  20% of patients will have detectable metastases at diagnosis,
with the lung being the most common site (85% - 90%).
 The prognosis for patients with metastatic disease is
determined by the site(s), the number of metastases, and the
surgical resectability of the metastatic disease.
 Patients with skip metastases (at least two discontinuous
lesions in the same bone) have been reported to have inferior
prognoses.
Presence of Metas. disease:

18. Tumor resectability:
 Resectability of the tumor is a critical prognostic feature because
osteosarcoma is relatively resistant to radiation therapy.
 Complete resection of the primary tumor and any skip lesions with
adequate margins is generally considered essential for cure.
Necrosis following induction or neoadjuvant chemotherapy:
 Patients with at least 90% necrosis in the primary tumor after
induction chemotherapy have a better prognosis than those with
less necrosis.
 Imaging modalities such as dynamic magnetic resonance imaging
or positron emission tomography scanning are under investigation
as noninvasive methods to assess response.

19. Additional prognostic factors
 Possible prognostic factors identified for patients with conventional
localized high-grade osteosarcoma include: the age of the patient;
(older patients appear to have a poorer outcome), LDH level,
alkaline phosphatase level, and histologic subtype.
 Increased body mass index at initial presentation is associated with
worse overall survival.
 Osteosarcoma arising in a radiation field, share the same prognosis
as patients with de novo osteosarcoma if they are treated
aggressively.

20. Prognostic factors under investigation:
 HER2/cerbB2 expression: data are conflicting
concerning the prognostic significance.
 Tumor cell ploidy.
 Loss of heterozygosity of the RB gene.
 Loss of heterozygosity of the p53 locus.
 Increased expression of p-glycoprotein: earlier studies
suggested that overexpression of p-glycoprotein
predicted for poor outcome.

21. Clinical presentation:
 The presence of persistent non-mechanical pain in any bone
lasting more than a few weeks should cause concern and lead to
further immediate investigation.
 Swelling will only be present if the tumour has progressed
through the cortex and distended the periosteum.
 The most likely diagnosis of a suspected bone tumor is
related to age:
 Before 5 years of age, a destructive bone lesion is most
commonly metastatic neuroblastoma or eosinophilic
granuloma.
 > 5 years, it is often a primary bone sarcoma.
 > 40 years of age, it tends to be metastasis or myeloma.

22. Diagnosis:
 Conventional radiographs in two planes should always be the
first investigation.
 the next imaging step is magnetic resonance imaging (MRI) of
the whole compartment with adjacent joints, which is the best
modality for local staging of extremity and pelvic tumors.
 The biopsy of a suspected primary malignant bone tumor
should be carried out at the reference centre by the surgeon
who is to carry out the definitive tumor resection or a
radiologist member of the team.
 Others: for staging; Bone scan (for Intra-medullary skip
metastases), CXR and CT chest and ? Whole body MRI, ?
PET/CT.

25. The principles of the biopsy:
 There should be minimal contamination of normal tissues.
 In many situations, core-needle biopsies (taken under imaging
guidance) are an appropriate alternative to open biopsy.
 Adequate sampling of representative areas for histology must be
assured.
 Samples should always be sent for microbiological culture in all cases
entailing a potential differential diagnosis.
 Samples must be interpreted by an experienced pathologist with the
collaboration of a radiologist.
 The request form should contain sufficient details for the pathologist
including: the site of the tumor, the patient’s age, and the radiological
imaging.

26. Principles of open biopsy:
 Use a longitudinal incision.
 Make X-rays of the biopsy location and sometimes undertake
a frozen section in case more material is required
 Biopsy tract must be considered to be contaminated with
tumor and must be removed together with the resection
specimen to avoid local recurrences.
 Biopsy tracts should be clearly marked by means of a small
incision or ink tattoo.

27. The American Joint Committee on Cancer (AJCC) staging
system for malignant bone tumors
Tumor sizeTumor gradeStage
< 8 cmLowI A
> 8 cmLowI B
< 8 cmHighII A
> 8 cmHighII B
skip metastasesIII
distant metastasesIV
Reprinted with permission from AJCC: Bone. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer
Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 28190.
Skip metastases: discontinuous tumors in the primary bone site.

28. Treatment
General principles: (based on ESMO-guidelines)
 Curative treatment of high-grade osteosarcoma consists of
chemotherapy and surgery.
 Multimodal treatment of high-grade localised osteosarcoma
increases DFS from only 10-20% to >60% when compared to
surgery alone.
 Low-grade central and parosteal osteosarcoma are malignancies
with a lower metastatic potential, which are treated by surgery
alone.
 Periosteal osteosarcomas; no benefit for chemotherapy was shown
in two retrospective analyses; (Cesari M, et al. Cancer 2011).

29.  Pathological fracture does not necessarily require amputation, but it is
contra-indicated to do internal fixation.
 The goal of surgery is to safely remove the tumor and yet preserve as
much function as possible, striving to obtain adequate surgical margins.
 Narrower margins are associated with an increased risk of local
recurrence. adequate margin is thought to be 5-7 cm from the edge of an
abnormality depicted on magnetic resonance imaging (MRI) or bone
scanning.
 More than 80% of patients with extremity osteosarcoma can be treated
by a limb-sparing procedure and do not require amputation. There is no
difference in OS between patients initially treated with amputation and
those treated with a limb-sparing procedure
 Retrospective analyses have shown that delay (≥ 21 days) in resumption
of chemotherapy after definitive surgery is associated with increased risk
of tumor recurrence and death.

30. limb-salvage reconstruction:
 Autologous bone grafts : vascularized or non-vascularized. Rejection does
not occur with these grafts, and the rate of infection is low.
 Allografts : graft healing and infection can be problematic, particularly
during chemotherapy. Immunologic rejection can also occur.
 Prosthetic joint reconstruction : can be solitary or expandable, though it is
usually expensive. The longevity of such implants is a major concern in
young children.
 Rotationplasty : is particularly suitable for patients with distal femur and
proximal tibia tumors, particularly large tumors in which a high
amputation is the only alternative. Lesions located in other areas of the
femur or tibia may also be amenable to this treatment approach. Patients
who are very young or athletic may benefit greatly from this procedure
from a functional standpoint, and this procedure may also serve to
minimize the number of future surgeries needed.

31. Intraoperative photograph of a Van Ness
rotationplasty procedure; Osteosynthesis of the
tibia to the residual femur is being performed
the new "knee" of the operative side (left) is purposely
reconstructed distal to the normal right knee.
This is in anticipation of the future growth potential of
the un-operated limb.

32.  Most current protocols include a period of preoperative
chemotherapy, to facilitate local surgical treatment and allow
the assessment of tumor response, although this has not been
proven to entail a survival benefit over postoperative
chemotherapy alone.
 Treatment is commonly given over periods of 6–10 months.
 Doxorubicin, cisplatin, high-dose methotrexate, ifosfamide,
and etoposide have anti-tumour activity in osteosarcoma.
 Immune modulation has been attempted with some agents,
e.g. interferon and muramyl tripeptide.
 Muramyl tripeptide added to postoperative chemotherapy
was associated with OS benefit, and was approved in Europe for
patients <30 years of age with completely resected localised
osteosarcoma.

33. A meta-analysis, published by Anninga JK at the Eur J
Cancer 2011 of the protocols for the treatment of
osteosarcoma concluded that:
 Regimens containing 3 active chemotherapy agents were
superior to regimens containing 2 active agents.
 Regimens with 4 active agents were not superior to regimens
with 3 active agents.
 It also suggested that 3 drug regimens that did not include
high-dose methotrexate were inferior to 3 drug Regimens that
did include high-dose methotrexate.

34.  In general, there is no indication for radiation therapy, but there
are anatomical locations in which the possibility of complete
surgical resection is limited.
 Older patients (>40 years) may require tailored regimens,
especially as far as high-dose methotrexate is concerned.
Doxorubicin and cisplatin are the most active drugs, with the
cumulative dose of anthracycline being a critical factor.
 Primary metastatic osteosarcoma patients are treated with a
curative intent, as about 40% of patients with complete surgical
resection of metas. disease become a long term-survivors.

35.  Intensity modulated photon radiation therapy (IMRT) is
increasingly being employed for treatment of challenging
bone sarcomas of the axial skeleton because of the higher
conformality of dose and sparing of selected normal tissues
from the high-dose region.
 Sarcomas of the skull base and cervical spine were among the
first tumors to be treated with proton-beam radiotherapy.
 The role of second-line chemotherapy for recurrent
osteosarcoma is much less well defined than that of surgery
and there is no accepted standard regimen; active agents:
ifosfamide ± etoposide ± carboplatin, and other active drugs:
gemcitabine and docetaxel; sorafenib.

36. RADIATION TECHNIQUES
Simulation and field design
 Spare 1.5–2 cm strip of skin in extremity RTx, if possible, to
prevent edema.
 Include entire surgical bed + scar + 2 cm margin, if possible.
 Bolus scar for first 50 Gy.
 CT/MRI data for RTx planning.
 Try to exclude skin over anterior tibia, if possible, due to poor
vascularity.
 Physical therapy instituted as early as possible during treatment
to improve functional outcome.
Dose limitations
 > 20 Gy can prematurely close epiphysis.
 > 40 Gy will ablate bone marrow.
 > 50 Gy to bone cortex significantly increases risk of fracture.

40. FOLLOW-UP
 Intensive physical rehabilitation very important,
especially for pediatric cases.
 Regular H&P with functional assessment, CBC, chest
imaging, and local imaging:
 Every 3 months for 2 years.
 Every 4 months for third year.
 Every 6 months for years 4 and 5.
 Then annually.