OSTEOGENIC SARCOMA

Osteosarcoma is a malignant mesenchymal tumor in which neoplastic cells produce bone matrix.

It is the most common primary malignant tumor of bone excluding those of hemopoietic origin.

It is the second most common primary malignancy of bone behind multiple myelomaOsteosarcoma (osteogenic sarcoma) is the most common malignant bone tumor in children and adolescents

INCIDENCEOsteosarcoma accounts for approximately 20% of primary malignancies of bone.The incidence is approximately 1 to 3 per 1 million per year.

The incidence is slightly higher in males (with the exception that parosteal osteosarcoma is more common in females).

Primary high-grade osteosarcoma occurs most commonly in the second decade of life. Parosteal osteosarcoma has a peak incidence in the third and fourth decades, and secondary osteosarcomas are more common in older individuals.

No bone is immune to develop osteosarcoma, commonly develops at sites of rapid bone growth where mitotic activity is high.

The most common sites involved are distal femur, proximal tibia, proximal humerus.More than 50% lesions occurs around knee

Secondary osteosarcomas are equally distributed in all bones

Most common site involved in a bone is Metaphysis 91% diaphysis <9% Epiphyseal involvement is extremely rare

ETIOLOGYNo specific etiologic cause developing osteosarcoma is not established till now.

But some genetic abnormalities are associated with increased incidence of these tumors Hereditary Retinoblastoma (1000 times), Li-fraumeni syndrome (p53 mutation), Rothmund-Thomson syndrome.According to loss of heterozygocity, chromosome arms 3q, 13q, 17p and 18q are most commonly Involved.

Secondary osteosarcomas are commonly associated with Pagets disease Irradiation Fibrous dysplasia

The incidence of osteosarcoma in Paget disease is approximately 1% and may be higher (5% to 10%) and the pelvis is the most common location.

Radiation-induced osteosarcoma occurs in approximately 1% of patients who have been treated with greater than 2500 cGy and can occur in unusual locations, such as the skull, spine, clavicle, ribs, scapula, and pelvis. osteosarcoma is the most common radiation-induced sarcoma.

Other conditions that have been reported to be associated with secondary osteosarcomas include bone infarcts, osteochondromas, chronic osteomyelitis, dedifferentiated chondrosarcomas, melorheostosis, and osteogenesis imperfecta.

Osteosarcomas classified according toSite of origin in bone Intra medullary Intra cortical Surface or Juxtra corticalDegree of differentiation: High or Low gradeMulticentricityHistological variant Osteoblastic Chondroblastic Fibroblastic Telangectatic Small cell Primary or Secondary Classic osteosarcoma is a primary Intramedullary solitary high grade osteoblastic variant arising from metaphysis of long bones

Classification of Osteosarcoma

PATHOGENESIS

The tumor ordinarily begins developing in the medullary cavity of a long bone near the metaphysis,

Then, they penetrated and extended through the cortex to raising the periosteum

In more advanced cases the periosteal barrier may be broken, and a soft tissue tumor mass may be seen invading the adjacent muscle tissue

The articular hyaline cartilage serves as barrier to prevent the extension of the neoplasm into the joint

The tumor may enter the joint, however, by extending along ligamentous and capsular structures Toward the diaphyseal end, the advancing tumor presents as a conical plug that marks the limit of growth of the lesion lengthwise along the shaft.

Skip metastases may occur.

CLINICAL FEATURES Progressive pain is the first and most common presenting symptom.

Pain initially may improve with conservative measures and activity modifications.Night pain may be an important clue to the true diagnosis; however, only about 25% of patients experience this phenomenon.Some times patient presents with a lump

Pathological fracture is very unusual presentation

DIAGNOSIS

Plain radiograph is sufficient to diagnose osteosarcoma most of the times.

But CT, MRI, Bone scan, CT Chest are useful in staging of the tumor and planning of treatment.

Apart from routine blood investigations Serum alkaline phosphatase, LDH are valuable and indicates poor prognosis.

Although the lesion can be either predominantly blastic or predominantly lytic, more commonly areas of bone production and bone destruction are present. The lesion usually is quite permeative, and the borders are ill defined. Tumor pierces the cortex, and extend into adjucent soft-tissue.

X-rayOsteosarcoma predominantly osteoblastic lesion at metaphyseal region of long bone.

Periosteal reaction may take the form of “Codman's triangle,” or it may have a “sunburst” or “hair on end” appearance

Pathological fracture may be seen.

MRI

Occult skip metastases of 2 mm or more in long bones are well seen on MRI.

MRI is also useful in evaluating the adjacent joint for tumor spread.

MRI demonstrates the degree of soft tissue extension and the relationship of the extracompartmental tumor to fascial planes and neurovascular structures.

The best feature of MRI is its ability to precisely evaluate the extent of tumor in the medullary cavity.

Pulmonary metastases 3 to 7 mm or greater in diameter are identified with CT.

Spiral CT is superior to conventional CT for this purpose.

CT Scan

Approximately 10% to 20% of patients with osteosarcoma present with radiographically detectable metastases at diagnosis. Most of these are in the lungs.

Conventional radiographs of the chest show metastatic nodules 10 mm or greater in diameter.

Bone scan with technetium 99m shows a marked increase in the uptake of the radionuclide in the primary tumor. The increased uptake is due to active formation of new tumor and host bone as well as the vascularity of the lesion.

Radionuclide bone scintigraphy is used to look for bony metastases in the involved bone (skip metastases)and at other skeletal sites.

Mineralized metastases are more likely to be detected by bone scans than are nonmineralized ones at extrapulmonary sites.

BONE SCAN

HISTOPATHOLOGY

Principal and essential histological feature of osteosarcoma is that malignant spindle cells directly produce tumor osteoid.

The spindle cell component is high grade with hypercellularity, abundant mitotic figures, and marked nuclear pleomorphism.

The tumor cells must be directly adjacent to osteoid with no intervening normal osteoblasts lining the osteoid.

Besides osteoblastic components,there may be other components like cartilage, fibrous tissue, vascular spaces and sheets of small round cells.

Depending on predominant cell type osteosarcoma classified into histilogical subtypes as Osteoblastic Chondroblastic Fibroblastic Telangiectatic Small cell variant Osteosarcoma may have large areas with little or no bone formation, but if any neoplastic bone is present, it is called osteosarcoma and treated as such. In an adolescent, the diagnosis of chondrosarcoma should be viewed with suspicion. Examination of the entire specimen of a “chondrosarcoma” in an adolescent will reveal neoplastic bone formation, indicating that it is in fact chondroblastic osteosarcoma.

Stage grade Site Metastasis

1 A LOW INTRACOMPARTEMENTAL

No , Mo

1 B LOW EXTRACOMPARTEMENTAL

No , Mo

2 A HIGH INTRACOMPARTEMENTAL

No , Mo

2 B HIGH EXTRACOMPARTEMENTAL

No , Mo

3 ANY ANY REGIONAL OR DISTANT METS

ENNEKING STAGING:

The factors which influence prognosis other than staging system are

Location of the tumor Proximity to neurovascular structures Race (blacks > whites ) Secondary > Primary Elevated LDH and Alkaline phosphatase Presence of skip lesions

Most of the osteosarcomas presents with stage llB or more at rhe time of diagnosis.

TREATMENT

Treatment options for osteosarcoma are Surgery Chemotherapy Radiotherapy in some cases

Historical data suggests that survival rate with ablative surgery alone is <20%. when combined with chemotherapy it is almost 65%.

First step is always to identify whether the patient benefit from chemotherapy or not.NEOADJUVANT

ADJUVANTCHEMOTHERAPY SURGERY CHEMOTHERAPY

CHEMOTHERAPY

Most important factor that determines prognosis is metastasis in lungs it is almost 20% at the time of diagnosis Chemotherapy has excellent role in terminating these lesions.

The survival rate with chemotherapy alone is very disappointing <25%

Chemotherapy applied in two modalities Neoadjuvant chemotherapy Adjuvant chemotherapy

Preoperative chemotherapy causes regression of the primary tumor, making a limb salvage operation easier.

Neoadjuvant chemotherapy usually can be started immediately to prevent tumor progression, which may occur during any delay before surgeryThis allows time to plan the operation properly, including the possible manufacturing of a custom implant.

NEOADJUVANT CHEMOTHERAPY

Allows an assessment of the effectiveness of this chemotherapy when resected tumor is analyzed (where there is > 90% necrosis there is significant survival advantage)

CHEMOTHERAPUTIC AGENTSMETHOTREXATE

High dose methotrexate (HDMTX) with leucovorin regresses pulmonary mets.

Improves survival when used along with excision of tumor.

Efficacy of HDMTX mostly depends on dosage minimum of 8-12g/m2 is required to get tumoricidal effect.

DOXORUBICIN and CISPLATIN are also found to be effective

Multidrug chemotherapy found to be more effective than single agent (39% vs 68% )

Chemotherapeutic agents under clinical trials are High dose Ifosfomide Muramyl tripeptide phosphoethanolamine

Surgical Management

The aim of tumor surgery is to achieve wide margins whenever possible.

The decision about surgery depends on Diagnosis Site of the tumor Extent of the tumor Response to chemotherapy Age of the patient and some times financial status of the patient.

Main hazard of narrow margins of excision is local recurrence, which requires further surgery even amputation.

Rotationplasty

The principle of rotationplasty is to excise the diseased part of the limb and then join the ramaining parts together but in so doing, rotating them through 180 degrees Most commonly performed for the tumors of distal femur

The main vessels are divided and reanastamosed but sciatic nerve is retained in anastamosed segments.

Here the ankle now becomes knee and the foot becomes a useful attachment for a below knee prosthesis

Advantages

Patient will have functioning limb for which below knee prosthesis can be kept.

No complications like phantom limb.

Arthrodesis

In this method diseased bone is resected and gap is filled with allograft or vascularized fibula and joint Is fused by means of intramedullasy nail across the joint.

The advantage is cheap and simple surgery and useful in manual workers who do not have to kneel.

Complications are delayed union, fracture

Patient may experience problem in activities where sitting is required like, public transport in bus,train and plane etc…

Periosteal Osteosarcoma

It is an intermediate-grade malignancy that arises on the surface of the bone

The most common locations are the diaphyses of the femur and tibia, and common in a age group of around 30-5oyrs.

It presents with swelling and local pain.

Histological examination of periosteal osteosarcoma shows strands of osteoid-producing spindle cells radiating between lobules of cartilage.

Treatment is same as classic osteosarcoma.

Parosteal OsteosarcomaIt is a rare, low-grade malignancy, arising on the surface of the bone and invades the medullary cavity only at a late stage.

Usually situated metaphysis of long bones especially over the posterior aspect of femur.

It common in young adults, presents with enlarging mass.

X-ray shows bony mass on the surface of the bone, usually thin gap remain between cortex and tumor.cortex is not eroded

Differential diagnosis is Myositis ossificans Osteochondroma

In myositis ossificans mature bone is at the periphery of the lesion, whereas in parosteal osteosarcoma centre of the lesion is more heavily matured.

Parosteal osteosarcoma can be easily differentiated from an osteochondroma by showing medullary cavity containing marrow in continuity with the medullary canal of the involved bone.

CT and MRI helpful in differentiating parosteal osteosarcoma from these lesions

Microscopically, parosteal osteosarcoma consists of slightly atypical spindle cells producing slightly irregular osseous trabeculae.

Treatment is wide excision without adjuvant therapy is sufficient with recurrence rate below 10%.

Telangiectatic osteosarcoma is a highly malignant variant of osteosarcoma .

It is twice as common in males than in females and common in 20-30 age group.

It is characterized by a high degree of vascularity and large cystic spaces filled with blood.

It is an osteolytic destructive lesion with an almost complete absence of sclerotic changes; a soft-tissue mass may also be present

Telangiectatic osteosarcoma

Differential diagnosis is cystic bone lesions like simple bone cyst, aneurysmal bone cyst

Histologically, it is composed of loculated blood-filled spaces, partially lined by malignant cells producing sparse osteoid tissue.

Treatment is same as classic osteosarcoma

It is rare variant of osteosarcoma which is a high-grade lesion that consists of small blue cells that may resemble Ewing sarcoma or lymphoma.

Distal femur, proximal humerus are sites of prediliction.

Cytogenetic and immunohistochemistry studies sometimes are needed to differentiate these lesions

Small cell osteosarcoma

Secondary osteosarcomas are commonly associated with Pagets disease Irradiation Fibrous dysplasia

Common in elderly people after age 60

Secondary osteosarcomas

MALIGNANT BONE TUMORS

Dr.Laxmikanth.SP.G(M.S.Ortho)Gandhi Medical College

EWING SARCOMA

Ewing's sarcoma of bone is a highly malignant, small, round cell tumor of neuroectodermal origin

It is the second most common primary malignant bone tumor in children.

Fourth most common malignant bone tumor in all ages.

Incidence

Male > Female,

No case noticed in black people

The incidence is less than 1 per 1 million per year,

It can arise in any bone of the body, but more than 60% of the lesions occur in the pelvic girdle and long bones especially at diaphyseal region

It is very rarely found in individuals younger than 5 years or older than 30 years.

It is common in the first and second decades of life; more than 90% of patients are younger than 30 years of age.

ETIOLOGY AND PATHOGENESIS

The reciprocal translocation of t(11;22)(q24;q12) is present in more than 90% of cases.

ESW/FLI-1 produced by this translocations which transforms fibroblasts to malignant cells.

Other translocations, including t(21;22)(q22;q12) and t(7;22)(p22;q12), also have been identified. These tumors have a cell surface glycoprotein called p30/32 MIC2, which is a product of the MIC2 gene located on the short arms of the X and Y chromosomes.

CLINICAL FEATURES

PAIN and SWELLING are the most common symptoms.

Patients also may have fever, erythema, suggesting osteomyelitis.

When involving spine neurological symptoms noted in 50-60% of cases.

When a rib is involved - pleural effusion.

Rectal and urinary complaints may result when the neoplasm is located in an innominate bone and impinges on pelvic organs or involves the sacral nerve roots.

Pathological fractures reported in 5-15% of cases.

Weight loss, anorexia present in advance cases.

In tumor arising from pelvis and axial skeleton diagnosis delayed because of late presentation.

Plain radiograph is sufficient to diagnose ewing sarcoma in most cases.

But CT, MRI, Bone scan, CT Chest are useful in staging of the tumor and planning of treatment.

Routine blood investigations are non specific but anemia, leukocytosis, elevated LDH is present which indicates poor prognosis.

DIAGNOSIS

Ewing's sarcoma usually originates in the intramedullary cavity and commonly involves an extensive portion (even the entire bone) of a long bone

Lytic destruction in a mottled or moth-eaten pattern is the most common radiographic appearance. The margins are indistinct.

Cortical destruction with periosteal elevation and multiple layers of subperiosteal new bone gives the classical onion skin appearance.�

Codmans triangle and sun ray appearance may be seen but not specific.

X-RAY

In subperiosteal Ewing's sarcoma saucer-shaped destruction of the cortex is a fairly characteristic feature.

In spine destructive lesions producing no matrix are seen.

But extensive tumor involvement can cause vertebra plana, absence of pedicle are seen.

In other axial disease locations radiographic changes are non specific

The radiographic findings of ewing sarcoma resembles histiocytosis, lymphoma, osteosarcoma, metastatic neuroblastoma, Wilms' tumor, leukemia, and osteomyelitis.

CT and MRI

MRI is useful to evaluate the extent of the soft-tissue extension which often is very large. CT scan of the chest is useful in detecting lung metastases.

A bone scan should be performed because bone is the second most common site of metastases after lungs.

Bone marrow aspirate is useful in Ewing sarcoma to rule out diffuse systemic disease.

HISTOLOGY

The tumor is characteristically gray or white and has a semiliquid consistency that suggests purulence, mimic osteomyelitis

Microscopically, it is a cellular sheetlike proliferation of small round cells without matrix production.

The cells have indistinct cytoplasmic borders with round or oval nuclei. It may be difficult to differentiate Ewing's sarcoma from other round cell tumors such as lymphoma, embryonal rhabdomyosarcoma, metastatic neuroblastoma, and small cell osteosarcoma by light microscopy alone.

Ewing sarcomas usually are periodic acid–Schiff positive reticulin negative. diastase digestible

Immunohistochemical and molecular genetic methods to differentiate Ewing's sarcoma from other small round cell tumors

Strong expression of the cell-surface glycoprotein p30/32MIC2 (CD99) is characteristic of Ewing’s sarcoma.

Diffuse membrane staining in a “chain-mail pattern” is present in 95%–100% of Ewing’s sarcoma  

Monoclonal antibodies used to stain this antigen are O13, 12E7, and HBA71 

The most definitive test for Ewing's sarcoma is demonstration of the chromosomal translocation t(11;22) by karyotyping or reverse transcriptase–polymerase chain reaction (RT-PCR).

Ewing’s sarcoma is immunoreactive for vimentin 

Small round cell tumors of bone

Prognostic factors

Size of the primary lesion (>8cm or 200ml)

Location

Fever, anemia, and elevation of laboratory values.Older age at presentation (with a cutoff around 12 to 15 years old) and male gender Histological response to neoadjuvant chemotherapy

TreatmentNonmetastatic Ewing's Sarcoma

Chemotherapy

Original IESS regimen (VAC): vincristine, actinomycin D, cyclophosphamide

VAC + ADR - vincristine, actinomycin D, cyclophosphamide + adriamycin

Standard 5-drug U.S. regimen (VCD + IE): vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide and etoposide x48 weeks

Clinical response to preoperative chemotherapy is indicated by a decrease in tumor size, drop in LDH level, and tumor necrosis in the resected specimen.

Addition of ifosfamide and etoposide in non-metastatic pts results in improved survival.

The total duration of therapy is approximately 48 weeks.

Four to six cycles of chemotherapy are given before local control

Postoperatively, additional cycles of the same treatment are given after assessing clinical response

Recent data suggests that chemotherapy administered every 2 weeks instead of every 3 weeks leads to better outcomes without any more toxicity in patients with localized Ewing's sarcoma.

Complications: Secondary malignancies cardiotoxicity infertility hemorrhagic cystitis lung fibrosis bone marrow suppression aloepacia

Radiation therapy effectively controls local disease, especially when combined with chemotherapy.

The usual dose is 40 to 60 Gy to the affected tissues.

Useful in cases where surgical resection is difficult and cases where doubtful surgical margins

Complications

Radiatiotherapy

The local recurrence

Pathologic fracture

Secondary malignancies

Growth disturbances

Surgical Management

Resection of primary tumor with wide margins is the essential part of treatment.

Negative margins are defined as bony margins of at least 2- to 5-cms.

In soft tissue, at least 5 mm in fat or muscle is required, with 2 mm through fascial planes, with the margin being through noninflammatory tissue

The decision about surgery depends on

Site of the tumor Extent of the tumor Response to chemotherapy and some times financial status of the patient.

Main hazard of narrow margins of excision is local recurrence, which requires further surgery even amputation.

Surgical options available are Limb salvage Amputation/disarticulation

Limb salvage vs amputationDepends on preservation of sufficient structures that are useful for limb survival after tumor resection.

Limb cant be salvaged after resection of main nerve

If blood vessels needs need resection and can easily replaced,is not absolute contraindication to limb salvage

The presence of pathological fracture is not contraindcation providing a good response to neoadjuvant chemotherapy.

Assessing outcome of limb salvage by clinician derived (MSTS Score) Patient derived (TESS Score)

The higher up the limb, the more likely it is the limb salvage will be beneficial to the patient.

Types of limb salvage

AutograftsAllograftsEndoprosthetic replacement

AutograftsVascularisedNon Vascularised

Ideal vascularised graft is one which has a well documented blood supply,and reasonably strong.

Extracorporeal irradiation and reimplantation in which tumor bone resected sterilized by irradiation and reimplanted at the defect, which accomidates perfectly.

This technique useful in sites such as pelvis and ankle

An essential pre requisite is that bone should initially not be damaged by tumor

AllograftsAn allograft is a dead piece of bone harvested from a bone donor. Complications Delayed or non union (35%) Infection (18% ) Delayed fracture (25% )Best results can be achieved by combining allograft with vascularised autograft.

An allograft –prosthesis combinations are used to replace osteoarticular junction by replacing joint with prosthesis and bone by allograft. Main indication for an allograft-prosthesis composite is an inadequate length of remaining host bone to secure the stem of an endoprosthesis.

Endoprosthetic replacement

Endoprosthetics are are used to fill bone gaps and reconstruct the joint surfaces after tumor excision.

Titanium is optimum metal to use, being light and strong, although expensive.

High density polyethelene is traditional bearing surface used at hip and knee

Complications: Infection wear breakage loosening

INFECTION

-MC org. to cause acute infection STAPH AUREUS & STERPTOCOCCI

Immediate drainage and iv antibiotics Most acute turn into chronic - present with pain and increasing stiffness around a previously good functioning prosthesis

-ANY PATIENT WITH PAIN & RADIOLOGICAL LOOSENING SHOULD BE SUSPECTED OF HAVING INFECTION UNTIL PROVED OTHERWISE.

Risk of infection is realted to site ( tibia and pelvis more risk), local radiotherapy ( more risk) , repeat operations ( increase by 2% per operation on an existing prosthesis)

-Removal of prosthesis and all infected material , filling the resulting cavity with antibiotic spacer ( often gentamycin and vancomycin) and reimplantation once all signs of infection have resolved.

- this is effective in 80% cases but in some controlled only by amputation.

Metastatic Ewing's Sarcoma

These patients will have a significantly worse prognosis, with expected survival rates of approximately 25% at 5 years

Isolated pulmonary metastases fare better than those with metastases elsewhere

Adding ifosfamide and etoposide to standard therapy did not improve the outcome in patients with metastases at diagnosis.

 Nearly 25% of Ewing’s sarcoma patients present with clinically detectable metastases in the lung and/or in bone and/or in bone marrow at the of diagnosis

Bilateral pulmonary irradiation at a dose of 14–20 Gy improve the outcome of patients with pulmonary disease 

Future Trends

Targeted therapy against EWS-FLI fusion protein or its products may inhibit growth of Ewing's sarcoma cells. 

Efficient delivery of EWS-FLI antisense oligonucleotide to malignant cells remains a barrier to therapeutic application of these agents.

IGF-1R is found on the surface of most Ewing's sarcoma cells and is necessary for the transforming ability of EWS-FLI fusion proteins. 

Targeted therapy against IGF-1/ IGF-1R may be a very effective strategy in future.

Cell surface transmembrane protein CD99 encoded by the MIC2gene is consistently expressed in Ewing's sarcoma cell lines.

Anti-CD99 antibodies can be tried in treating ewing sarcoma.

But, clinical trials using anti-CD99 antibodies have not yet been attempted because of high levels of CD99 expression in hematopoietic cell line, pancreas, and gonads.

Rapamycin, is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap-dependent translation.

Inhibition of mTOR signaling potentially inhibits cell cycle regulators as well as transcription factors such as c-Myc.

mTOR inhibitor causes inhibition of Ewing's sarcoma cells in vitro,

suggesting a possible therapeutic role in Ewing's sarcoma

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