Osteosarcoma

• These are spindle cell neoplasms that produce Osteoid
• It is the second most common primary malignancy of bone behind multiple myeloma.

OSTEOSARCOMA CLASSIFICATION
• High grade Intramedullary Osteosarcoma
• Low Grade “ “
• Telengiectatic Osteosarcoma
• Surface Osteosarcoma
1. Paraosteal
2. Periosteal
3. High Grade Surface Osteosarcoma
• Osteosarcoma of the Jaw
• Multicentric osteosarcoma
• Secondary osteosarcoma
• Irradiation induced Osteosarcoma
• Dedifferentiated Chondrosarcoma
• Osteosarcoma derived from benign precursors

Osteosarcoma may be also classified based on prognostic importance

Low Grade
• Parosteal
• Low-grade central
Intermediate Grade
• Periosteal
High Grade
• Conventional
• Telangiectatic
• Small cell
• Postradiation
• Pagetoid
• High-grade surface


Aetiology:
‣ Genetic abnormalities: p53 suppressor genes, Rb gene, F33 isoform, ErbB-2 (Her – 2neu), transforming growth factor beta, isoform 3 expression
‣ Associations: Retinoblastoma (Rb gene), Rothmund-Thomson syndrome, and Li-Fraumeni syndrome (p53 gene)
‣ Li-Fraumeni syndrome: sarcomas in young patients and pre-menopausal breast cancer in the mothers of the young patients
‣ Rothmund Thomson syndrome: rare genodermatosis that features a progressive, early-onset poikiloderma, a high incidence of juvenile cataracts, stunted growth, and a wide range of skeletal abnormalities.

‣ Osteosarcoma is the most common type of bone sarcoma(The most common primary bone malignancy is multiple myeloma, and the most common malignancy affecting bone is metastatic carcinoma)
‣ Bimodal peak age incidence
‣ Majority occur within the second decade (~60%)
‣ Second peak age >55; often secondary osteosarcomas
‣ Incidence: 0.3 per 100,000 per year

Local Growth:
 Osteosarcomas usually arise within the metaphyseal region of long bones.
 They may be located within the bone or on the surface of the bone.
 If untreated, osteosarcomas will continue to grow, with local destruction of bone and extension outside the bone into the surrounding soft tissues.
 The physis and articular cartilage may act as a relative barrier to tumor extension, but epiphyseal or intra-articular extension is still seen frequently.
Metastases
 Osteosarcomas, as with all sarcomas, usually metastasize hematogenously.
 Lymph node metastases are not common and usually present only very late in the course of metastatic disease.
 15% to 20% of patients present with metastases at time of diagnosis.
 Most common site of metastasis: lungs
 Second most common: bone
 Skip lesions: distinct smaller areas apart from primary tumor within same bone
 Prognosis: same as or worse than distant metastases (lung or bone)


a) Classic Osteosarcoma (High Grade Intramedullary osteosarcoma)

 Most common in second or third decade.
 Fifty percent of lesions seen about the knee joint.
 Histological cell types are osteoblastic, chondroblastic, fibroblastic and small cell
 Arises from the medullary canal
 MC location: distal femur > proximal tibia >proximal humerus
 Can occur in any bone

CF:
 Pain before a tumour mass is noticeable.
 Pain is due to microinfarctions occurring in the bone.
 Night pain is an important symptom but is seen in only 25% of patients.
 Pain gradually worsening, though may be intermittent or increase with activity
 Pain is usually present for weeks to months, not acutely
 Dilated veins over swelling.
 Fusiform swelling, fixed to bone, firm and immobile
 Tenderness is usually present to palpation, with range of motion, and with weight bearing
 About 10- 20% patients have pulmonary metastasis at presentation
 Metastasize in 80% patients treated by surgery alone

Investigations:
• X-ray:
 Permeated lytic destruction of metaphyseal bone
 “Codman’s reactive triangle”
 Sunburst pattern or hair on end appearance.
 Areas of bone formation maybe present
 Occasionally the lesion is pure sclerotic or lytic.
 There is usually some cortical destruction with extension of a soft tissue mass
 Associated higher-level lesion in the femur- “skip” lesion

MRI: identifies
 Extent of soft tissue involvement
 Intramedullary spread
 Neurovascular involvement
At least one sequence of entire bone (preferably coronal T1 images) to rule out skip lesion in same bone (metastasis) is essential

Whole-body bone scan: Uptake on scan of primary lesion is almost always present, but scan is to rule out other sites of disease.
 May detect other sites of disease
 May also show skip lesion in same bone

• Biopsy:
Periphery of the tumour is the best tissue for a biopsy because
• It is easy to reach.
• Soft enough for a diagnostic frozen section, and
• Representative of the most aggressive portion.

CT chest to detect any pulmonary metastasis

Pathology:
 Osteosarcoma produces high-grade spindle cell sarcomatous stroma with malignant osteoblasts that produce malignant osteoid or bone.
 Tumor cells are typically anaplastic (less differentiated), may show marked atypia and pleomorphic (widely variable) nuclei, and may show many and/or bizarre mitoses.
 There may be areas of osteoblastic (osseous), fibroblastic (fibrous), or chondroblastic (cartilage) appearance, but if there is the presence of malignant osteoid (wavy, lace-like, uncalcified bone matrix produced by malignant osteoblasts), the diagnosis of osteosarcoma is made regardless of the associated areas.

Grading:
 Helps to assess prognosis
 Low grade tumours do not require chemotherapy and are less likely to develop metastasis
 Most osteosarcomas are high-grade tumors( mostly IIB Enneking)


• Poor prognostic factors in osteosarcoma are:-
a. Metastases to lung, bone and lymph nodes
b. Expression of P glycoprotein in the cells
c. High Alkaline phosphatase
d. High Lactate dehydrogenase
e. Vascular Invasion
f. Large tumour size
g. No alteration in DNA ploidy after chemotherapy
h. Absence of anti heat shock protein 90 antibody after chemotherapy

Treatment:
Neoadjuvant chemotherapy, Surgery
In extremity osteosarcoma, limb-sparing surgery, with wide resection of the tumour, is the standard approach.
Chemo for osteosarcoma: Methotrexate, Adriamycin, cisplatin, and ifosfomide. Neoadjuvant chemotherapy is delivered for 8- 12 weeks followed by resection of the tumour. Maintenance chemotherapy is given for 6- 12 months.

Neoadjuvant chemotherapy:
 Neoadjuvant chemotherapy may shrink the primary tumor and sterilize microscopic tumor foci in the reactive zone around it, facilitating resection and increasing the chance for limb-sparing surgery.
 Neoadjuvant chemotherapy also allows time for surgical planning, the fabrication of a custom tumor prosthesis, or the procurement of allograft tissue for implantation.
 Finally, neoadjuvant chemotherapy induces necrosis in the primary tumor, and the amount of this necrosis serves as an extremely important prognostic indicator for long-term survival
 Thallium 201 is used to assess tumour response after chemotherapy
Side effects of these medications can be severe, and toxicities can occur.
These include mucositis, cardiomyopathy (doxorubicin), alopecia, myelosuppression, nausea/vomiting, and relative immunocompromise, sepsis, and rarely even death.

Medications used during chemotherapy treatment to minimize side effects
 Granulocyte colony-stimulating factor (G-CSF;):Improves neutropenia by stimulating neutrophil production by marrow, decreases infections and febrile neutropenias
 Erythropoietin stimulates red blood cell production.
 Dexrazoxane protects against cardiomyopathy of doxorubicin.
 Leucovorin rescues normal cells from effects of high-dose methotrexate and decreases myelosuppression and mucositis

Limb sparing Surgery

Limb-sparing surgery is indicated for patients in whom wide margins can be obtained without sacrificing so much tissue that the remaining limb is nonfunctional.
 Usually, the determining factor is the ability to spare major nerves. Major vessels need to be preserved or reconstructed.

Role of radiation therapy:
 Mainly for palliation
 may be the safest oncologic treatment following initial resection with positive margins(margins containing malignant cells)

b) HAEMORRHAGIC or Telengiectatic Osteosarcoma
 High-grade, purely lytic tumour, incidence of pathologic fracture is high.
 0.4% to 12% of all osteosarcomas
 Histology: Bag of blood with few cellular elements, cellular elements have highly malignant appearance
 X ray: Permeative or ballooned out appearance resembling aneurysmal bone cyst with little bone production
 A pathologic fracture may necessitate amputation rather than limb salvage.
 Impending lesions should be either immobilized to prevent pathological fracture or treated with early surgery.
 Treatment is by multi agent chemotherapy and surgery

c) PARAOSTEAL OSTEOSARCOMA
 More common in females, slightly older age group(2nd and 3rd decades)
 Most common surface osteosarcoma. Other surface osteosarcomas include periosteal osteosarcoma and high grade surface osteosarcoma
 5% of osteosarcomas
 MC sites: distal femur>proximal humerus
 Patients usually complain of a painless mass, dull aching type of pain may also be a presenting complaint
 Slow growing low-grade tumour usually appearing in posterior aspect (surface) of the distal femur (over the external aspect of bone)

X-rays reveal dense mineral deposits within the tumour
• DD on X-ray: Myositis ossificans. The ossification in myositis ossificans is more mature at the periphery of the lesion, whereas the center of a periosteal osteosarcoma is more heavily ossified and lobulated.
• Differentiated from osteochondroma that it lacks the corticomedullary trabecular continuity
• ‘Cleavage plane’ or a radiolucent line between tumour and cortex
• Has a ‘stuck on’ appearance. It may wrap around cortex, with invasion into bone later

Histology:
• The osseous trabeculae are regularly arranged. Between the normal trabeculae are atypical spindle cells. Cartilage is frequently present and is arranged as a cap over the lesion
• In around 1/6th of the lesions that appear in X-rays as Paraosteal osteosarcoma there is a high grade element. In this circumstance the lesion is termed a “Dedifferentiated Osteosarcoma”, for which the prognosis is worse.

Treatment:
• It does not respond well to either chemotherapy or radiation therapy.
• Wide surgical resection is the treatment of choice.
• Dedifferentiated form: responds to multiagent chemotherapy.

d) PERIOSTEAL OSTEOSARCOMA
 More common in females in the second decade of life.
 1-2% of all osteosarcomas
 Common in the diaphysis of femur and tibia(anterior surface)
 X rays:
 Radiographically, a fusiform mass with lucency and ossification
 A sunburst appearance is seen resting on a saucerised cortical depression.
 Cortical depression can mimic a periosteal chondroma, but periosteal osteosarcoma is associated with a larger size (>4 cm) and irregular margins
 Histologically the lesion is more chondroblastic.
 Wide surgical resection is the modality of choice. This is combined with chemotherapy.
 The prognosis is intermediate between High grade intramedullary osteosarcoma and paraosteal osteosarcoma

e) SECONDARY OSTEOSARCOMA
 May arise in Paget’s disease, osteoblastoma, fibrous dysplasia, benign giant cell tumour, osteochondroma, Melorheostosis, osteogenesis imperfecta, bone infarction, and chronic osteomyelitis.
 Most common of the “secondary osteosarcomas”-Pagetic osteosarcoma
 The most frequent location for pagetic osteosarcoma is the humerus, followed next by the pelvis and femur.
 Several thousand-fold increased risk of osteosarcoma in patients with Paget's disease compared to the general population
 Occur in an older population (55 to 85 years old)
 Increasingly painful mass is most common presentation.
 Occur in Flat bones, unlike conventional osteosarcoma due to frequent involvement of pelvis and scapula with Paget's disease
 X-rays: reveal destructive mass, usually with soft tissue extension in bone with Paget's disease.
 The prognosis for patients with pagetic osteosarcoma is extremely poor.
 Occur in 5% of patients with polyostotic Paget’s disease

f) LOWGRADE INTRAMEDULLARY OSTEOSARCOMA
 1 to 2% of all osteosarcomas
 Older, typically third decade
 Radiographically, sclerotic density in metaphyseal bone.
 Often confused with fibrous dysplasia or by progression or recurrence after treatment for suspected benign disease
 Prognosis is similar to paraosteal sarcoma
 Wide resection is the treatment of choice.

g) IRRADIATION INDUCED OSTEOSARCOMA
• Usually with >4000 cGy radiation dosage
• Usually appears after 3- 15 years from the time of radiation insult.
• Common in flat bones like scapula, pelvis and rib

h) MULTICENTRIC OSTEOSARCOMA
a. Synchronous–occurring in childhood and adolescents and
b. Metachronous – occurring in adults.
Prognosis is poor for both types.
i) Soft -Tissue Osteosarcoma (extra osseous osteosarcoma)
• Can occur in muscle tissue (4% of all osteosarcomas)
• Tumour is usually seen in large muscle groups of the pelvis, thigh areas or the shoulder.
• DD: Myositis ossificans.
Myositis ossificans has a zonal pattern of ossification (Ackermann zone phenomenon) with the mature dense ossification concentrating at the periphery of the lesion.
Treatment: Wide resection, +/- adjuvant chemotherapy and radiotherapy

j) HIGH GRADE SURFACE OSTEOSARCOMA
 Up to 1% of osteosarcomas
 Located on surface of bone
 Otherwise identical to conventional osteosarcoma in histology, treatment, and prognosis

k) SMALL CELL OSTEOSARCOMA
 Rare; about 1% to 4% of all osteosarcomas
 Controversy: Are these “atypical Ewing sarcoma”?
 Age, location, and radiographic picture similar to conventional osteosarcoma
 Typically has a destructive, permeative pattern, sometimes extends into diaphysis
 Histology: there is often difficulty in distinguishing this tumor from Ewing sarcoma and other small round cell tumors if no osteoid is seen on biopsy.
 Usually has areas of osteoblastic activity, which helps distinguish it from Ewing sarcoma