Osteosarcoma

By

Osama ElzaafaranyAssistant lecturer of clinical oncology

Medical Research InstituteAlexandria University

May 2015

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.

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 %.

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

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 earlytwenties, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.

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.

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.ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

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.

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 ClinOncol, 2005) identified a favorable outcome for extr-aosseousosteosarcoma treated with surgery and conventional osteosarcoma therapy.

Molecular biology

Morphological Cytogenetics:

High-grade tumors were seen to be hyperdiploïdwhereas 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.

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.

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.

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.

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%.

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.

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:

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.

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.

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.

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.

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.

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.

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.

The American Joint Committee on Cancer (AJCC) staging system for malignant bone tumors

Tumor sizeTumor grade Stage

< 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 CancerStaging Manual. 7th ed. New York, NY: Springer, 2010, pp 28190.Skip metastases: discontinuous tumors in the primary bone site.

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).

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.

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.

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.

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 localisedosteosarcoma.

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.

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.

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.

RADIATION TECHNIQUESSimulation 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.

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.