Bone Tumours (2): Radiological Approach, Malignant Bone Tumours

Introduction

Bone tumours can be generally divided into two groups: benign, including tumour-like lesions (see Chapter 40 ), and malignant. The malignant category can be subclassified into primary, secondary and metastatic. In common parlance the terms secondary and metastatic are frequently used interchangeably. In the context of this chapter, however, the term secondary is reserved for those tumours arising from malignant transformation of a pre-existing benign bone condition.

Bone Metastases

Bone metastasis or metastatic disease refers to the spread of a malignant tumour from its primary site to a non-adjacent part of the skeletal system. These lesions are relatively common, frequently found on imaging to be multiple and are the commonest bone malignancy in people over 40 years of age. Approximately 10% of carcinoma metastases present as a solitary bone lesion. A solitary lesion in a middle-aged or elderly patient is, therefore, still more likely to be a metastasis than a primary malignant bone tumour. Post-mortem studies have shown that bone, is the third commonest site, after the lung and liver, of metastatic spread.

Metastases are assumed to arise from venous tumour emboli, from the primary tumour or from prior disease spread to the regional lymph nodes or other metastases (e.g. in the lung). Venous embolisation of malignant cells is multifactorial but particularly related to the vascularity of the primary tumour and/or access to a valveless venous plexus (e.g. the Batson vertebral plexus).

Bone metastasis is a relatively late occurrence in the natural history of malignant disease because the lungs trap most tumour emboli. It is recognised that bone metastases may occur without obvious evidence of pulmonary involvement due to:

• 1.

  Pulmonary lesions that are present but occult

• 2.

  Transpulmonary spread of malignant cells

• 3.

  Paradoxical embolisation via a patent foremen ovale

• 4.

  Retrograde venous embolism with involvement of the vertebral column

Arguably, the prevalence of truly occult bone metastases is less today owing to the superior sensitivity of multidetector computed tomography (CT) of the chest, which is now routinely used in cancer staging as compared with standard radiography or single-slice CT employed in the past.

The most common primary malignancies metastasising to bone are carcinoma of the breast, bronchus, prostate, kidney and thyroid, making up over 80% of all cases of bone metastasis. The overall incidence of bone metastasis during life is uncertain and will depend on the sensitivity of the imaging technique employed. At the time of death the prevalence of metastatic bone disease is approximately 80%–85% for breast and prostate cancer and more variable for lung cancer, with a quoted range of between 40% and 80%, 50%–60% for thyroid cancer and 20%–35% for renal cancer. With modern improved cancer management leading to longer survival times, metastatic bone disease has become a fairly common occurrence in everyday medical practice.

Distribution of Bone Metastases

The commonest sites of metastatic involvement are those containing red bone marrow, which explains why the axial skeleton is affected more commonly than the appendicular skeleton in adults; hence, the predilection for the spine, pelvis, proximal femora and humeri, ribs, sternum and skull ( Fig. 41.1 ). Spinal metastases occur most commonly in the thoracic vertebrae, but carcinomas arising within the pelvis, particularly prostatic carcinoma, show a predilection for the lumbosacral spine.

Diagnosis of Bone Metastases

Clinical

Unexplained back or limb pain in a patient with a history of carcinoma may indicate a skeletal metastasis. Non-mechanical pain (i.e. bone pain at rest) is highly suggestive of tumour, be it primary or metastatic. A metastasis may present with a pathological fracture following minor trauma. Radiographs are necessary to reveal the pre-existing lesion. Elevation of the serum alkaline phosphatase is a non-specific finding and typically is not seen until multiple bone metastases have developed.

Radiological Features

Bone metastases may be lytic (most common) ( Fig. 41.2 ), mixed lytic and sclerotic and predominantly sclerotic ( Fig. 41.3 ). Small lytic lesions confined to the medullary bone can be difficult to identify on radiographs, particularly in complex anatomical areas such as the pelvis and spine or where there is reduced bone density (osteopenia). It is much easier to detect a metastasis as and when there is evidence of cortical destruction. It is for this reason that vertebral metastases are frequently first detected on radiographs as showing destruction of the cortex of a pedicle even though cross-sectional imaging may reveal fairly extensive destruction of the medullary bone in the adjacent vertebral body ( Fig. 41.4 ). As the destructive process increases, a soft-tissue mass may develop. A periosteal reaction may be seen, but this is usually less pronounced than those seen in primary bone malignancies. Exceptions include some prostatic metastases and mucinous adenocarcinoma metastases from the colon. Some carcinomas, such as renal, almost always produce lytic metastases. Others, such as prostate, are most commonly osteoblastic, whereas breast metastases may show a mixed appearance. It should be noted that the osteoblastic reaction reflects the response of the host bone to the metastasis rather than the production of tumour bone, which is a characteristic of osteosarcoma. Cortical-based metastases are less common than medullary and tend to arise along the diaphyses of the long bones from lung, kidney and breast primaries ( Fig. 41.5 ).

The importance of identifying multiple lesions cannot be over­emphasised, as an individual metastasis may be indistinguishable from a primary malignant bone tumour. For this purpose, ^99m Tc-MDP bone scintigraphy is the most cost-effective method, although both whole-body magnetic resonance imaging (MRI) and ¹⁸ F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) are considered more sensitive. A variety of scintigraphic abnormalities are seen, the most common being multiple foci of increased skeletal activity, predominantly in the axial skeleton (see Fig. 41.1 ). Abnormal increased activity relies on an intact local blood supply and increased host bone osteoblastic activity. Metastases that have infarcted or stimulate no host osteoblastic response may appear as photopenic areas or ‘cold spots’, most commonly seen with larger renal metastases. Occasionally a combination of ‘hot’ and ‘cold’ lesions occurs. Diffuse osteoblastic metastatic disease, typically from breast or prostate carcinoma, may result in a ‘superscan’ appearance where there is generalised increase in skeletal activity with diminished renal and soft-tissue activity ( Fig. 41.6 ).

It is important to recognise that in a patient being investigated for suspected metastatic disease, not all foci of abnormally increased activity on bone scintigraphy must necessarily be due to metastases. Foci of activity in the ribs, particularly if contiguous, suggest old fractures; linear foci peripherally in the sacrum suggest insufficiency fractures; and intense expanded foci of activity extending up to a joint margin may indicate Paget disease. Any area of unexplained abnormal uptake should be correlated with further up-to-date imaging. Generally, MRI is used as it is more sensitive than radiography and more specific than scintigraphy. Most metastases are located within the medulla and show reduced signal intensity (SI) on T ₁ weighted sequences, with increased SI on T ₂ weighted or fat-suppressed sequences. The identification of a hyperintense ‘halo’ around a lesion is a feature highly suggestive of a metastasis on fluid-sensitive images.

Whole-body MRI is an MRI technique which uses fast pulse sequences over the entire body to give a survey of the whole body ( Fig. 41.7 ). T ₁ and STIR (short tau inversion recovery) sequences of the entire body are produced. This technique has better sensitivity and specificity than planar bone scintigraphy. The additional use of quantitative diffusion-weighted sequences further improves the detection of metastatic disease and can also be used to quantitatively assess the response of metastatic lesions to treatment.

PET is a nuclear medicine technique where images are produced through the detection of high-energy photon pairs during radioisotope decay. ¹⁸ F-Fluorodeoxyglucose (FDG) is the isotope most commonly used. It is a glucose analogue taken up by tissues with high metabolic activity, such as tumour cells. A major advantage of using ¹⁸ F-FDG-PET is that a standardised uptake value (SUV) of a deposit can be calculated. A threshold value of 2.4 or above is suggestive of a malignant lesion. The benefit of this technique is that it allows an objective measurement of the response of the lesion to treatment. PET has a high sensitivity (of nearly 100%) and a specificity of around 56% for the detection of metastatic disease. When PET is combined with CT or MRI, it gives both functional and anatomical information, which improves the specificity to over 90% ( Fig. 41.8 ).

Prostate.

Prostatic metastases are typically osteoblastic (sclerotic) ( Fig. 41.9 ) or mixed, with purely lytic lesions being very rare. Occasionally, long bone metastases may exhibit a prominent ‘sunburst’ periosteal reaction mimicking an osteosarcoma, a rare disease in this age group in the absence of Paget disease or previous radiotherapy. Disseminated prostatic metastases may produce confluent sclerosis on radiographs, simulating other disorders such as myelofibrosis and Paget disease, although the latter condition can usually be excluded by noting the absence of bony expansion. Assessment of the prostate-specific antigen (PSA) level can be useful in determining the value of performing bone scintigraphy. If the PSA level is below 10 ng/mL the likelihood of positive bone scintigraphy is less than 1%. This increases to approximately 10% if the PSA level is 10 to 50 ng/mL and 50% with a PSA level above 50 ng/mL. Although ^99m Tc-MDP bone scintigraphy may be adequate for the initial identification of prostatic metastases, FDG-PET is preferred after treatment for distinguishing persistent active metastases from healing bone.

Breast.

Most breast bone metastases are lytic (see Fig. 41.2 ), but breast carcinoma is the commonest cause of osteoblastic metastases in women (see Fig. 41.3 ). About 10% of metastases are purely osteoblastic and 10% mixed ( Fig. 41.10 ). Diffuse marrow infiltration may occur and become radiographically visible only when sclerosis develops after therapy. In this situation the sclerosis may be mistaken for disease progression rather than a response to treatment. Breast metastases have a predilection for the spine, pelvis and ribs. Patients may present with acute-onset vertebral collapse at one or more levels and positive neurology. In this clinical situation the differential diagnosis would include benign causes such as osteoporotic collapse and malignant causes such as metastases from other primaries, lymphoma and myeloma. Further investigation with MRI and/or diffusion-weighted and/or chemical shift imaging would be mandatory. Features suggestive of malignant collapse include vertebral body expansion, posterior bowing of the vertebral body, and a lack of a fluid-filled cleft. Restricted diffusion on diffusion-weighted sequences and a less than 20% signal dropout on chemical shift imaging are advanced MRI techniques which are also considered helpful adjuncts ( Fig. 41.11 ). Bone scintigraphy is usually sufficient to confirm/exclude bone metastases when clinical or laboratory parameters are suspicious; after treatment, however, follow-up studies may show increased activity due to the ‘flare phenomenon’ secondary to the normal healing response of bone. Again, in this context FDG-PET may be preferred, with increasing activity indicating a lack of response to treatment.

Lung.

Lung metastasis to bone is common. Most lesions spread to the axial skeleton and are typically lytic. Metastases to the hands and feet (acrometastases), although rare, originate from a lung primary in approximately half of the cases ( Fig. 41.12 ). Bronchogenic carcinoma is the commonest source of cortical-based metastases, with large lesions showing the ‘cookie-bite’ appearance (see Fig. 41.5 ). This is also the commonest disorder associated with hypertrophic osteoarthropathy, formerly known as hypertrophic pulmonary osteoarthropathy. A single- or multiple-layer periosteal reaction along the distal long bones, including the hands and feet, characterises this condition. Bone scintigraphy will reveal symmetrically increased linear activity along the long bones, known as the ‘double stripe’ or ‘parallel tract’ sign.

Kidney.

Renal carcinoma is the commonest primary malignancy associated with solitary bone metastases. Solitary or multiple lesions are invariably lytic and may be expansile (blowout) and trabeculated. So-called expansile metastases may also be typically seen in thyroid metastases ( Fig. 41.13 ) and less commonly in breast and lung. A similar radiographic appearance may be seen with plasmacytoma and, if subarticular, also in a younger age group as giant cell tumour of bone. Renal metastases tend to be hypervascular, exhibiting multiple serpiginous signal voids within and around the periphery of the lesion on MRI ( Fig. 41.14 ).

Melanoma.

After extension to locoregional lymph nodes, malignant melanoma can spread to almost any part of the body, including the axial skeleton. It is important to appreciate that melanoma metastases may be clinically silent and that there can be a long latent period between treatment of the primary lesion and development of the metastases. Most bone metastases from melanoma are lytic. Melanin is paramagnetic and, depending on the concentration, the metastases may show mild hyperintensity on T ₁ weighted MR images ( Fig. 41.15 ).

Primary Malignant Neoplasms of Bone

Primary malignant tumours of the skeleton are fairly rare. Metastatic bone and benign bone tumours along with non-neoplastic lesions of bone far outnumber the incidence of primary bone malignancies. They account for only 0.2% of all neoplasms in the United Kingdom and the United States, with an annual incidence of new diagnoses of approximately 1/100,000 population. However, in the paediatric population the incidence of primary malignant bone tumours is approximately 5% of all malignancies. Major advances in the past 40 years in chemotherapy and limb-salvage surgery have vastly improved the outcome, such that in specialist centres the 5-year survival for appendicular osteosarcoma now exceeds 60%. The classification of these tumours, as described by the , is based on their histopathological characteristics. Although the tumours themselves have remained unchanged over the years, the nomenclature has metamorphosed as successive generations of pathologists have attempted to refine and reclassify them.

The staging of primary bone tumours includes the degree of histological differentiation along with the local and distant spread of the tumour in order to estimate the patient's prognosis. The tumour/nodes/metastasis (TNM) classification is not widely used for primary bone sarcoma because lymph node metastatic disease is a rare finding. Commonly used staging systems include the Enneking and the American Joint Committee on Cancer (AJCC) systems. The Enneking classification system ( Table 41.2 ) is based on the tumour grade, the site of the tumour and presence or absence of metastatic spread. The AJCC system ( Table 41.3 ) is based on tumour grade, size, presence of metastasis and site of metastasis. Despite such systems, their usefulness lies mainly in the detailed description of the primary tumour itself.

The radiological assessment of bone tumours requires consideration of some basic clinical details, as it has considerable influence on the differential diagnosis. Important clinical information includes the following:

• 1.

  Age. Many primary bone tumours demonstrate a peak incidence at certain ages. In the first 2 years of life neuroblastoma metastases are the most common bone tumours. In the first and second decades it is osteosarcoma and Ewing sarcoma. In the third and fourth decades it is giant cell tumour, lymphoma and parosteal osteosarcoma. After 40 years of age it is metastasis, myeloma and chondrosarcoma ( Table 41.4 ).

  TABLE 41.4

  Malignant Primary Bone Tumours and the Decades in Which They Occur Most Frequently

  Open full size image

  GCT , giant cell tumour.

• 2.

  Ethnicity. Ewing sarcoma is more commonly seen in Caucasians and is rare in Afro-Caribbeans. Osseous tuberculosis, though not a tumour, can mimic a tumour and is commonly seen in the Indian subcontinent.

• 3.

  Family history. Certain hereditary bone disorders predispose to malignancy. These include hereditary multiple exostosis (HME) and the Ollier and Maffucci syndromes. Certain syndromes, including Rothmund -Thomson syndrome and congenital retinoblastoma, are associated with a higher incidence of osteosarcomas.

• 4.

  Past medical history. A history of previous malignancy or radiotherapy is important, as recurrence or radiation-induced malignancy is possible. A history of pre-existing bone disease is important, as certain lesions can undergo malignant transformation (e.g. Paget disease of bone).

Despite the advances in CT and MRI over the last 30 years, plain radiography remains the most useful technique to determine the differential diagnosis of a bone lesion. Several important radiographic factors must be taken into account when a suspected bone tumour is being evaluated:

• 1.

  Which bone is involved? Many bone lesions have a predilection for certain bones. For example, cartilage lesions are common in the hands and feet. Adamantinoma and osteofibrous dysplasia (OFD) involve the diaphysis of the tibia and are rare elsewhere. Chordomas are commonly seen in the sacrum and clivus.

• 2.

  Where in the bone is the lesion? Osteosarcomas can occur anywhere in the bone, but conventional osteosarcoma tends to affect the metaphysis or metadiaphysis. Parosteal and periosteal osteosarcomas affect the outer and deeper layers of periosteum, respectively, and arise on the surface of the bone. Ewing sarcoma tends to be an intra-medullary lesion in the diaphysis. Malignant epiphyseal lesions include malignant giant cell tumours and clear cell chondrosarcomas.

• 3.

  Pattern of destruction. An aggressive pattern of destruction suggests a malignant process. It includes a wide zone of transition from normal to abnormal bone. Moth-eaten and permeative reactions reflect the aggressiveness of these lesions.

• 4.

  Pattern of periosteal reaction. A lamellated periosteal reaction looks like an onion skin and is commonly seen in Ewing sarcoma ( Fig. 41.16 ). A Codman triangle ( Fig. 41.17 ) and spiculated (hair-on-end) ( Fig. 41.18 ) periosteal reaction are signs of a rapidly evolving process and are commonly seen in Ewing and conventional osteosarcoma.

  
  
  

• 5.

  Pattern of matrix mineralisation. Matrix mineralisation does not help to distinguish benign from malignant disorders but can be an indicator of the underlying histopathological origin, be it osteoid (i.e. bone-forming) or chondroid (i.e. cartilage-forming).

• 6.

  Multiplicity. The presence of multiple osseous lesions will influence the differential diagnosis, making metastatic lesions more likely than a primary lesion.