Principles and diagnosis

• Nomenclature:
• Primary bone tumours are one of three types:

• Benign
1. Malignant
2. Lesions that simulate bone tumours (tumour mimics)

• This is not a classification however. Historically, tumours are classified (as opposed to staged) according to the predominant tissue type expressed within the lesion.

• Although a useful tool, there are drawbacks:
• The most predominant tissue type is not necessarily the tissue of origin.
• No pathological or clinical correlation between the conditions in any one category.
• Often no relationship between the benign and malignant conditions with similar tissue types.
• Some tumours named as a single entity (e.g. osteosarcoma have several subtypes with very different behaviour).

• Staging:

Why?

1. To understand how far the tumour has spread.

2. To assess how aggressively it will behave in its current location.

• It is only through assessing these parameters that the resection type can be planned to balance the needs of an adequate resection against curative surgery.

How

• Staging systems are based on:
• Histological grade (G)
• Site (T)
• Metastases (M)

• Enneking staging system was tested retrospectively on 397 cases of bone and soft tissue tumours.
• Shown that prognosis varied with the stage.

NB. Applies to lesions of connective tissue, not primary lesions of round cell origin (e.g. leukaemia’s, lymphomas, myeloma or Ewing’s).

Tumour grade

• This is the assessment of the aggressiveness of the tumour:
• G0 Histologically benign (well differentiated and low cell to matrix ratio).
• G1 Low grade malignant (few mitoses, moderate differentiation and local spread only). Have low risk of metastases.
• G2 High grade malignancy (frequent mitoses, poorly differentiated). High risk of metastases.
• Aggressive or high grade tumours have several histological features:
• Cellular atypia
• Frequent mitoses (Indicates highly active)
• Extensive necrosis
• Significantly vascular
• Small amounts of immature matrix

Tumour site

• T0 Intracapsular
• T1 Intracompartmental (e.g. cortical bone, joint capsule or fascia)
• T2 Extracompartmental (spreads beyond “fascial” plane without longitudinal containment). Bone and periosteum are separate compartments.

Tumour work-up

• The goals of the tumour work-up are to identify the type and extent (staging) of the tumour, specifically its tissue of origin remembering that the most common bone tumours are metastases.

1. History and clinical examination (age, sex, site and past history especially malignancy).

• Thyroid
• Breasts
• Chest
• Liver
• Kidney
• Rectal (prostate and rectal tumours)

2. Bloods:

• FBC

Underlying Hb

Leukaemic cells, etc.

• ESR (often elevated)
• Biochemistry

• Baseline liver and renal function before potent cytotoxic therapy

• Screen for metastases: Ca²⁺, PO4, liver enzymes and alkaline phosphatase

• Acid phosphatase (prostate and increased with metastatic deposits)
• Thyroid function tests
• PSA
• Serum protein electrophoresis (myeloma)

3. Urinalysis
4. Urine Bence–Jones (myeloma)
5. CXR
6. Abdominal ultrasound
7. Bone scan (PET–CT scan) ® other sites
8. MRI ® soft tissue extent and association with nerves and vessels
9. CT of lesion and chest (® staging)
10. Angiography ® tumour blood supply and relationship to major vessels
11. Biopsy

Bone tumour diagnosis

• Before the biopsy is taken it is often possible to either identify or at least reduce the differential diagnosis of a bone tumour through assessing:
• Radiographic features
• Patient’s age and history
• Location of the tumour

Plain radiography

• These will almost always be the first examination to be performed. The plain X-ray can reveal characteristic features diagnostic of particular tumour types. Evaluation depends on assessing the effect of the lesion on the bone and the response of the bone to the lesion.
• Multiple lesions will be more likely to be metastases.
• Slow growing lesions will allow the bone to react to the formation of the lesion and a narrow zone of transition will occur.
• Rapidly growing lesions will have a permeative appearance with a wide zone of transition.
• Codman's triangle: forms when a subperiosteal lesion elevates the periosteum only allowing bone formation at the margin.
• Sunray spiculation: caused by attempts at bone formation by the periosteum overlying the lesion.
• Cartilage tumours will also have speckled calcification within the tumour.
• Endosteal scalloping: cortical resorption caused by aggressive medullary lesions. Less aggressive lesions cause bony expansion.

• Phemister’s law = the most common site of infection & tumours is the fastest growing site of the long bone.

Figure 1. Tumour location made simple

• Juxta-cortical lesions:
• Parosteal osteosarcoma – no space between lesion and cortex.
• Myositis ossificans – space between lesion and cortex.
• Osteocartilagenous exostoses (cartilage capped) – shares cortex with bone (medullary continuity).

• Principles:

1. Should know probable diagnosis and stage of tumour before biopsy as it is the last step in the staging of the patient.
2. Performed by or in conjunction with the surgeon who will perform the definitive surgery (? biopsy ® frozen section ® definitive surgery during the same anaesthetic for presumed metastases).
3. Biopsy tract orientation and location is critical – will need to be resected in the definitive surgery if lesion is malignant.
4. Meticulous haemostasis to avoid tracking haematomas.
5. Send samples for microbiological analysis.

• Aim for excisional biopsy when possible for benign lesions.
• Needle biopsy or Incisional biopsy preferable in potentially malignant lesions.
• After consultation with the pathologist, radiologist and definitively managing surgeon.

1. Longitudinal incision.
2. Sharp dissection should proceed directly to the tumour, through muscle not between muscle planes.
3. Uninvolved anatomic compartments should not be exposed.
4. Avoid all major neurovascular structures to prevent contamination.
5. Excise block of reactive tissue, pseudo capsule, capsule, and block of tumour ® formalin with or without frozen section.
6. Windows in bone should be as small as possible and oval to avoid stress risers and pathological fracture.
7. Release tourniquet prior to closure ® haemostasis.
8. Close with a subcuticular stitch.
9. Drains should come out through the wound.
10. If proceed following biopsy ® new instruments and drapes to stop seeding.

Needle biopsy (preferred for potentially malignant lesions)

1. As for open biopsy.
2. Place the biopsy tract where it can be excised.
3. Fine needle biopsy (popular in Scandinavia):

• Relies on cytological interpretation by an experienced pathologist.
• Accuracy = 65–95% (determined by the adequacy of the collected tissue sample).
• Does not allow for immunohistochemical analysis.

4. Core needle biopsy:

• Uses trocar cannula system (e.g. Jamshidi), with an outer sleeve which closes over the trocar, capturing the sample of tissue.
• Provides more tissue than fine needle and allows for immunohistochemical analysis.
• Accuracy = 75–95%.

5. Disadvantage of needle biopsy = tissue obtained may be from necrotic portion of tumour and therefore not suitable for diagnosis, or tissue may be reactive in nature and not representative of actual tumour. Frozen section may thus be beneficial.

Frozen section

1. Able to determine if specimen is adequate or representative.
2. Can decide if lesion is inflammatory and needs culturing.
3. Can determine if there is need to perform further investigations/tests.
4. Immediate diagnosis possible – can proceed to definitive surgery.

Limb salvage

• Criteria for limb salvage:

          -Local control of the lesion must be at least equal to amputation.
          -The saved limb must be functional.

• Types of osseous resection:

          -Intercalary (between joints).
          -Intra-articular (one side of joint).
          -Extra-articular (both sides of the joint).

• Various methods of salvage, e.g, endoprosthesis, allograft, composite, arthrodesis (allograft).
• Relative contraindications:

         -Pathological fractures.
         -Skeletal immaturity.
         -Must be in an anatomical location which favours reconstruction and allows wide surgical margins.
         -The presence of distal metastasis is not a contraindication.

Surgical margins (Musculoskeletal Tumour Society)

1. Intra-lesional:

• Through the tumour.
• Leaves macroscopic tumour.
• Not therapeutic.

2. Marginal:

• Through pseudo-capsule of tumour/reactive zone (contains inflammatory cells, oedema, fibrous tissue, satellites of tumour cells).
• Controls non-invasive benign tumours.
• Recurrence of malignant tumours = 25–50%.

3. Wide:

• Around reactive zone, leaving a cuff of normal tissue.
• Skip lesions left.
• Recurrence of malignant tumours = <10%.

4. Radical:

• Removal of entire compartment or compartments.
• Distant metastases left.

5. Amputation:

• Should be thought of as a form of reconstruction in which surgical control of the tumour precludes useful function.
• Indications for amputation now include:
• Tumour resection is impossible due to neurovascular invasion.
• Tumour excision requires excessive muscle excision.
• Significant contamination following a pathological fracture.

• Can be administered as neo-adjuvant (induction) and adjuvant (postoperative).

Neo-adjuvant chemotherapy

• = Staging ® Chemotherapy ® Restaging ® Surgery ® Tumour kill rate ® Further treatment (change chemo or introduce radiotherapy as indicated).
• Enables action of agents against tumour to commence immediately.
• Efficacy of chemotherapeutic agents evident at the time of tumour resection.
• Reduces the mass and vascularity of the tumour prior to definitive surgery.
• Enables time for operative planning (manufacture of custom implants).
• Ideally >90% kill rate and if <90% then change agents.
• No increased survival evident with different agents in those who do not respond to the initial treatment (? just identifies those patients with a good prognosis).
• Commence adjuvant treatment once the wound has healed.
• May persist for 2 months to 2 years depending on the response.
• Localised disease = 60–70% long-term disease-free survival.
• May lead to:

        -Stunting of growth (may catch up later).
        -Osteoporosis.
        -AVN.
        -Cisplatinum ® nephrotoxicity and hearing loss.
        -Adriamycin ® cardiotoxicity.
        -Vincristine ® neurotoxicity.
        -Chemotherapeutic induced malignancy usually blood forming, e.g. leukaemias but also may ® cancer of bladder or skin (particularly associated with cyclophosphamide).

Methotrexate

• Binds to dihydrofolate reductase and therefore blocks purine synthesis.
• Citravorum factor “rescue” replenishes the folate pool.
• Potentiates the effects of radiotherapy.

Adriamycin

• Cytotoxic antibiotic.
• Also potentiates radiotherapy.

• Preoperative radiotherapy may reduce size of the tumour, decrease chance of seeding at the time of resection or if seeding then decrease chance of viability of the shed cells.

Effect of radiation

• Direct = absorption by complex molecules causes rupture of chemical bonds with damaging effects.
• Indirect = by ionisation and formation of highly reactive intracellular free radicals ® DNA changes ® stop cell reproduction and slow cell turnover ® loss of specific cell function.
• The effect on cancer cells not due to more rapid growth of cells but the capacity for recovery and repair of normal tissues compared with the poor capacity of cancer tissues.
• Destruction of small blood vessels on which growth of a tumour depends also contributes to the effect and induction of an inflammatory response may ® destruction of cells weakened by radiation.
• Increased sensitivity of cells in the presence of oxygen up to a critical level but above this level (about that of normal atmospheric pressure) sensitivity does not increase appreciably (hypoxic tissue has decreased radio sensitivity).
• Radiosensitivity of a tissue is directly proportional to its mitotic activity and inversely proportional to the degree of differentiation of its cells.

Adverse effects

• Joint ® stiffness and loss of function (treatment = physiotherapy).
• Subcutaneous fibrosis.
• Children ® premature fusion of growth plates.
• Radiation-induced sarcoma.
• Enteritis, diarrhoea, obstruction and bleeding.
• Cystitis and hepatitis.
• Scoliosis may develop therefore include both sides of vertebrae.
• Muscle atrophy and fibrosis.
• Erythema of skin and hyperpigmentation.
• Hair loss and skin flaking.
• Lymphoedema ® need to screen a strip of skin ® lymphatic drainage.

Definitions

• Rad (radiation absorbed dose) is a measure of the energy imparted to the matter by ionising radiation per unit mass (1 rad = 100 erg/g (0.01j/kg).
• Grays (Gr) = 1 joule of energy absorbed by a mass of 1 kg (equivalent to 100 rad).