Radiological and pathological diagnosis of paediatric bone tumours and tumour-like lesions

Pathology (February 2008) 40(2), pp. 196–216

DIAGNOSTIC TUMOURAL HISTOPATHOLOGY

Radiological and pathological diagnosis of paediatric bone tumours and tumour-like lesions M. VLYCHOU

AND

N. A. ATHANASOU

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Nuffield Department of Pathology, Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Oxford, United Kingdom

Summary Primary bone tumours are rare but account for a significant proportion of cancers occurring in childhood and adolescence. Malignant bone tumours need to be distinguished not only from their benign counterparts but also from tumour-like lesions, many of which are developmental or reactive in nature and are found commonly in the paediatric population. Taking note of the age of the patient and the site of the lesion within bone (aided by several imaging techniques including plain radiographs, ultrasound, computed tomography, bone scintigraphy and magnetic resonance imaging) is essential for pathological diagnosis. Immunohistochemistry, cytogenetics, molecular analysis and other techniques are now powerful diagnostic tools in bone pathology. This review aims to provide an approach to the radiological and pathological diagnosis of paediatric bone tumours. It also provides a brief overview of some of the more common bone tumours and tumour-like lesions, both benign and malignant, which occur in childhood and adolescence. Key words: Paediatric, bone tumour, histopathology, radiology, review. Received 18 October, accepted 30 October 2007

is evidenced by the type of connective tissue matrix which is formed by the neoplastic cells found within the tumour (e.g., where tumour cells produce osteoid/bone, the tumour is categorised as an osteoblastic bone-forming neoplasm; cytological and other features are then used to determine whether the tumour is benign or malignant). Not all tumours can be categorised as benign or malignant; some neoplasms are of intermediate malignancy, behaving as locally aggressive but non-metastatic tumours. In addition to true bone neoplasms, there is a large category of tumour-like lesions of bone, many of which occur commonly in the paediatric age group (Table 2). These lesions need to be considered in the differential diagnosis of a paediatric bone tumour, and are generally developmental or reactive and not neoplastic in nature (e.g., fibrous dysplasia, avulsive cortical irregularity), although some are often categorised as neoplasms (e.g., non-ossifying fibroma). The diagnostic evaluation of a bone tumour demands close co-operation between the surgeon, radiologist, pathologist and oncologist, all of whom should be experienced in the assessment of musculoskeletal tumours. Any tumour diagnostic protocol for evaluation of bone tumours needs to take into account the clinical and radiological features of the tumour as well as its pathological features (Table 3).

INTRODUCTION Musculoskeletal disease constitutes about 10% of problems in childhood. These include primary neoplastic and nonneoplastic lesions of bone as well as lesions arising secondary to a generalised or localised developmental, inflammatory, metabolic or neuromuscular disorder. Although neoplasms of bone are uncommon, they need to be considered in the differential diagnosis of any bone lesion. Benign bone tumours occur much more commonly than malignant bone tumours. In adults, primary bone sarcomas are rare, constituting less than 1% of all malignancies; however, in the paediatric population bone sarcomas are relatively more common, representing 6% of all malignancies.1,2 Bone sarcomas need to be distinguished not only from primary benign bone tumours but also tumour-like conditions that occur as a result of abnormalities in development of the growth plate or other bone structures. Many different types of tumour have been described in bone.3,4 These lesions vary widely in their clinical behaviour and pathological appearance. Primary bone tumours are classified morphologically according to the pathway of differentiation exhibited by the neoplastic cells (Table 1); this

CLINICAL ASSESSMENT OF BONE TUMOURS Most children and adolescents with a bone neoplasm present with non-specific symptoms of pain, swelling and limitation of movement.5,6 These complaints are difficult to distinguish from those due to other bone lesions, particularly trauma and infection. Pain associated with bone tumours is often continuous and dull; it is usually severe at rest and characteristically worse at night. A soft tissue mass and raised local temperature, as well as rapid growth, may indicate a malignant tumour. The age of the patient is extremely important to note as many types of tumour tend to arise within a certain age range. Also important is the site of the lesion as some bone tumours tend to arise predominantly in certain bones of the skeleton (Table 4). Radiological investigations (see below) are used to determine the precise location of the tumour within the involved bone; this needs to be noted as it provides essential diagnostic information (Table 5). A number of laboratory investigations, often taken at the time of initial clinical assessment, can be useful in determining the nature of a bone tumour.6,7 The white cell count

Print ISSN 0031-3025/Online ISSN 1465-3931 # 2008 Royal College of Pathologists of Australasia DOI: 10.1080/00313020701813784

DIAGNOSIS OF PAEDIATRIC BONE TUMOURS AND LESIONS

TABLE 1

Classification of primary bone tumours

1. Bone forming tumours Benign Osteoma, osteoid osteoma,* osteoblastoma* Malignant Osteosarcoma: intramedullary* (conventional; telangiectatic; small cell; well differentiated); surface (parosteal; periosteal; high grade surface) 2. Cartilage forming tumours Benign Enchondroma;* osteochondroma;* periosteal chondroma; chondroblastoma;* chondromyxoid fibroma* Malignant Chondrosarcoma: conventional; juxtacortical; mesenchymal;* dedifferentiated; clear cell

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3. Giant cell tumours of bone Giant cell tumour of bone; giant cell reparative granuloma (GCRG) of jaw*; GCRG small bones* 4. Round cell tumours Ewing’s sarcoma/primitive neuroectodermal tumour of bone;* lymphoma; leukaemia;* mastocytosis 5. Vascular tumours Benign Haemangioma; lymphangioma; glomus tumour; angiomatosis;* Gorham-Stout disease* Malignant Haemangiopericytoma; haemangioendothelioma; angiosarcoma 6. Fibrous/fibrohistiocytic tumours Benign Non-ossifying fibroma;* desmoplastic fibroma;* myofibromatosis;* benign fibrous histiocytoma Malignant Fibrosarcoma/malignant fibrous histiocytoma 7. Other primary tumours Chordoma Adamantinoma of long bone

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TABLE 3 Protocol for bone tumour diagnosis 1. Clinical history . Age . Pain; swelling . Past history; family history 2. Clinical examination . Site (bone affected) . Size of swelling; tenderness 3. Radiological imaging . Intraosseous location of lesion (e.g., epiphyseal, metaphyseal, diaphyseal; intramedullary, cortical, surface) . Extent; consistency; borders; matrix composition; bone reaction 4. Biochemistry/haematology . Haemoglobin/white cell count/erythrocyte sedimentation rate . Electrophoresis (plasma/urine) . Calcium/phosphate/alkaline phosphatase 5. Histopathology . Routine stains: H&E, reticulin; periodic acid-Schiff + diastase . Immunohistochemistry i. Leukocyte markers: CD45 (leukocyte common antigen); CD68 (macrophage/osteoclast); HLA-DR (osteoclast negative); B/T cell marker, e.g., CD20, CD3; Langerhans cell markers e.g., CD1a, S-100 ii. Epithelial markers: epithelial membrane antigen; cytokeratin iii. Ewing’s markers: CD99; FLI-1; WT1 iv. Other: Cartilage cell, S-100; vascular endothelial cell, CD31, CD34, factor VIII; lymphatic endothelial cell, LYVE-1, podoplanin; neuroblastoma, NB84a, synaptophysin, chromogranin 6. Other investigations . Cytogenetics, e.g., t(11:22) for Ewing’s sarcoma . Molecular biology, e.g., p53, RBI abnormalities . Electron microscopy . Flow cytometry

*Paediatric.

RADIOLOGICAL ASSESSMENT OF BONE TUMOURS TABLE 2

Tumour-like lesions of bone

Simple bone cyst* Aneurysmal bone cyst* Fibrous dysplasia* Fibrocartilaginous dysplasia* Osteofibrous dysplasia* Langerhans cell histiocytosis* Mesenchymal hamartoma of chest wall* Avulsive cortical irregularity and other avulsive injuries (periosteal desmoid)* Myositis ossificans* Surface reactive lesions of bone (e.g., BPOP, subungual exostosis) Hyperparathyroidism (‘brown’ tumour) Bone infection* Bone trauma* *Paediatric. BPOP, bizarre parosteal osteochondromatous proliferation.

and erythrocyte sedimentation rate (ESR), are often raised in the context of an infection, but may also be elevated in some paediatric bone tumours, such as Ewing’s sarcoma, leukaemia, lymphoma and Langerhans cell histiocytosis. The plasma alkaline phosphatase level is variable in growing children; it is elevated in about 50% of patients with osteosarcoma but may also be raised in other destructive primary or secondary malignant bone tumours.

Radiological imaging of bone tumours is essential for accurate diagnosis.4,5,8 Imaging techniques are employed to identify the nature of the tumour and to determine its extent. In addition to conventional plain radiographs, the diagnostic assessment of primary and secondary bone tumours may require ultrasound, bone scintigraphy, computed tomography (CT) and magnetic resonance imaging (MRI).7–9 The role of imaging is not only limited to diagnosis; it is also important in disease staging and follow up and provides guidance for interventional procedures, such as a CT guided biopsy.9,10 Good conventional plain radiographs remain the mainstay for the initial evaluation of a primary bone tumour.4,5,8 Plain radiographs provide information on the anatomical site of the lesion within bone, the nature of the host bone in which the tumour has arisen, the presence of any mineralised matrix, which may represent areas of calcification or ossification within the tumour, the nature of the interface between the tumour and the surrounding host bone, as well as the reaction of the host bone to the presence of the tumour. The anatomical site of the lesion within bone is a major factor in determining the differential diagnosis8 (Table 5). Possibly on account of its proximity to the physis, the metaphysis of long bones is a common location for development of a number of primary bone tumours and tumour-like lesions in the paediatric age group.5,7,8 A few primary bone tumours also arise in the

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TABLE 4 Skeletal location of some paediatric bone tumours and tumourlike lesions Small tubular bones

Enchondroma Periosteal chondroma Osteoid osteoma Osteoblastoma Giant cell reparative granuloma

Long tubular bones

Most primary benign and malignant bone tumours and tumour-like lesions Metastasis (e.g., neuroblastoma)

Ribs/sternum

Benign/malignant cartilage tumours Fibrous dysplasia Mesenchymal hamartoma of chest wall Eosinophilic granuloma Metastasis

Spine

Aneurysmal bone cyst Osteoblastoma Osteoid osteoma Haemangioma Metastasis

Skull/facial bones

Pelvis

Fibrous dysplasia ‘Fibro-osseous lesions’ of jaw Osteoma Giant cell reparative granuloma Haemangioma Eosinophilic granuloma Osteosarcoma Mesenchymal chondrosarcoma Metastasis Osteochondroma Chondrosarcoma Ewing’s sarcoma Metastasis

Pathology (2008), 40(2), February

TABLE 5 Intraosseous location of some paediatric bone tumours Long bones Epiphyseal (+ metaphyseal)

Metaphyseal (+ diaphyseal)

Diaphyseal (+ metaphyseal)

Spine Vertebral body

Chondroblastoma Giant cell tumour of bone Desmoid tumour Clear cell chondrosarcoma Aneurysmal bone cyst Simple bone cyst Fibrous dysplasia Osteochondroma Chondromyxoid fibroma Enchondroma Non-ossifying fibroma Haemangioma Fibrosarcoma/MFH Osteosarcoma Lymphoma Osteoid osteoma Ewing’s sarcoma Adamantinoma Metastasis Myeloma Giant cell tumour of bone Metastasis Osteoid osteoma Osteoblastoma Aneurysmal bone cyst Metastasis

Vertebral arch

MFH, malignant fibrous histiocytoma.

TABLE 6 Radiological features of benign and malignant bone tumours

epiphysis and diaphysis. Whether the bone lesion is predominantly or exclusively periosteal/subperiosteal, intracortical or intramedullary should also be noted on plain radiographs and other imaging as this site determinant also provides a major clue to diagnosis. Many benign tumours enlarge slowly and are welldefined; a sclerotic rim is often present around a slowgrowing lesion whereas a non-sclerotic margin is usually found around a more rapidly growing lytic lesion9,10 (Table 6). Tumours that exhibit rapid growth may contain areas where the margin is ill-defined; this can be seen in some benign as well as malignant lesions.8–10 Rapidly growing malignant lesions are evidenced by destruction of the host bone. The character of this bone destruction should be noted.6,8 One or more large areas of ‘moth-eaten’ bone destruction or multiple small areas of ‘permeative’ bone destruction are indicative of a malignant bone tumour; in contrast ‘geographic’ osteolysis and a wellcircumscribed margin point to a benign or less aggressive tumour. The relationship of the tumour to the bone cortex should also be noted. Slow-growing tumours result in cortical expansion, whereas more rapidly growing tumours cause thinning of the bone cortex. Frankly infiltrative lesions show clear evidence of cortical bone destruction.8,9 Another feature of a bone tumour that can be noted on plain radiographs is the presence of matrix mineralisation within the lesion; evidence of calcification or ossification may indicate whether the tumour is of bone or cartilage differentiation.6,8 The nature of the periosteal reaction associated with a growing bone tumour should be noted.

Feature

Benign

Malignant

Periosteal reaction Margin of lesion/zone of transition Trabeculation Cortical destruction Pattern of osteolysis

Variable Well defined + sclerotic

Common Poorly defined

May be present Rare Geographic, expansile

Soft tissue involvement Size

May be absent or present Variable, often limited

Unusual Unusual Moth-eaten, permeative Common Usually extensive

Slow-growing lesions typically produce a solid periosteal reaction, resulting in thickening of the bone cortex due to the presence of multiple layers of newly formed bone on the outer surface of the cortex. A single lamellar reaction, often in the form of a solitary radio-dense line above the cortical surface, is typically found in rapidly growing benign lesions such as infection or eosinophilic granuloma but may also be seen with malignant bone tumours.6,8,9 Rapid tumour growth typically results in multiple sheets of woven bone being laid down. This may result in concentric phases of periosteal new bone formation, producing an ‘onion skin’ appearance; this is typically seen in Ewing’s sarcoma (Fig. 1) but may be noted in other malignant bone tumours and in some benign conditions, such as osteomyelitis, stress fracture and eosinophilic granuloma.8 Rapid tumour growth may also lead to bone being laid down at right angles to the periosteum, producing a spiculated ‘sunburst’ appearance. Thin filiform spicules of reactive bone are seen more commonly in malignant tumours, whereas short thick spicules occur more commonly in benign lesions.8,9

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FIG. 1 Periosteal reaction. Extensive lytic lesion located in the diaphysis with moth-eaten osseous destruction and multilayered periosteal response. The underlying lesion is a Ewing’s sarcoma. FIG. 2 Fluid-fluid level. Axial STIR MRI shows a lesion with eccentric location and fluid-fluid levels with different signal intensity. The appearance is characteristic of an aneurysmal bone cyst. FIG. 3 Transverse US scan measuring the cartilage cap of an osteochondroma. FIG. 4 Bone scintigraphy. Radionuclide bone scan shows an extensive site of involvement in the left distal femur of a young patient without evidence of other skip lesions. FIG. 5 Osteoid osteoma. Radiograph of the lower limb demonstrates an extensive osteoblastic pattern in the middle third of the tibia. FIG. 6 Osteoid osteoma. CT of the same lesion as Fig. 5 demonstrates the classic nidus of the osteoid osteoma with the sclerotic centre surrounded by reactive bone formation. FIG. 7 Toxic osteoblastoma. Woven bone trabeculae, lined by plump osteoblasts, are separated by a wellvascularised fibrous stroma (H&E, low power). FIG. 8 Osteosarcoma. Anteroposterior radiograph shows a destructive lesion in the distal femur and a soft tissue mass and periosteal response that has the pattern of a Codman’s triangle. FIG. 9 Osteosarcoma. Axial CT scan at the level of the lesion demonstrates a periosteal response of sunburst type that is characteristic of an osteosarcoma. FIG. 10 Osteosarcoma. Coronal T1-weighted MR image shows a lesion in the distal third of the femur with low sign intensity accompanied by a soft tissue mass.

Elevation of the periosteum may also result in the formation of a Codman’s triangle which radiographically outlines the elevated periosteum, the underlying cortex and the growing tumour mass. A drawback of conventional radiography is its inability to detect early bone changes; 30–40% bone destruction needs to have occurred prior to detectable alterations in

bone architecture on plain radiographs. In this regard, computed tomography (CT) is more sensitive as it has greater tissue contrast resolution and displays crosssectional anatomy and spatial resolution of the tumour more clearly and effectively than plain radiographs.9,11 CT provides the most accurate means of evaluating the intraosseous and extraosseous extent of a bone lesion; it

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FIG. 11 Osteosarcoma. Tumour cells with large, atypical, hyperchromatic nuclei exhibit osteoid formation (H&E, low power). FIG. 12 Digital chondroma. There is abundant cartilage matrix containing cartilage cells, one of which is binucleated (H&E, high power). FIG. 13 Osteochondroma. Lateral radiograph of the femur shows a typical pedunculated type of osteochondroma arising near and directed away from the distal growth plate of the femur. FIG. 14 Osteochondroma. There is a fibrous perichondrium beneath which there is a cartilage cap showing extensive degenerative change and underlying woven bone formed by endochondral ossification (H&E, low power). FIG. 15 Hereditary multiple exostoses. Anteroposterior radiograph of the pelvis shows multiple osteochondromas mainly affecting the proximal femora. FIG. 16 Hereditary multiple exostoses. Anteroposterior radiograph of the right knee shows numerous sessile and pedunculated osteochondromas. FIG. 17 Chondroblastoma. Anteroposterior radiograph of the proximal tibia demonstrates a lytic lesion with sclerotic margin located in the proximal epiphysis.

shows the presence and configuration of mineralisation within the lesion and demonstrates associated cortical and periosteal changes. Cortical penetration and soft tissue extension are usually well shown. Soft tissue thickening around the cortex may indicate the presence of tumour but may also represent oedematous reactive tissue.8,10,11 MRI is undoubtedly superior for the detection of abnormalities of bone marrow, but CT is often necessary for the assessment of the tissue matrix of a lesion and differentiation of a malignant from a benign periosteal reaction. CT enables a

more precise assessment of bone destruction and fracture risk.9–11 CT also demonstrates the relationship of the tumour to major vessels, particularly when the vessels are surrounded by fat.11 Contrast enhancement and three-dimensional reconstruction may aid in the characterisation of a bone tumour by CT.9,10 The availability of multidetector CT scanners (MDCT) has facilitated data acquisition and enabled the creation of 3D reconstructive images such as multiplanar (MPR) reconstruction and volume rendering (VR)

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DIAGNOSIS OF PAEDIATRIC BONE TUMOURS AND LESIONS

FIG. 18 Chondroblastoma. There is lace-like calcification of the cartilage matrix around which there are chondroblasts and scattered osteoclast-like giant cells (H&E, high power). FIG. 19 Mesenchymal chondrosarcoma. There are numerous round or spindle-shaped mesenchymal cells surrounding an island of cartilage formation (H&E, high power). FIG. 20 Ewing’s sarcoma. Anteroposterior X-ray of the left femur in a child with a lytic lesion in the diaphysis that exhibits permeative bone destruction associated with an aggressive periosteal reaction. FIG. 21 Ewing’s sarcoma. Coronal STIR MRI of the same patient shows an extensive, high signal intensity intraosseous lesion that affects the entire femoral diaphysis with a proximal soft tissue component of mixed signal intensity. FIG. 22 Ewing’s sarcoma. The tumour is composed of a solid proliferation of small round tumour cells (H&E, high power). FIG. 23 Lymphoma. There is proliferation of lymphoid cells with hyperchromatic nuclei (H&E, high power). FIG. 24 Gorham-Stout disease. There are large vascular spaces and there is a proliferation of small blood vessels present (H&E, low power). FIG. 25 Non-ossifying fibroma. Anteroposterior and lateral radiographs of the lower leg show a radiolucent cortical lesion with elliptical shape and thin marginal sclerosis near the distal growth plate of the tibia. FIG. 26 Non-ossifying fibroma. There are numerous fibroblasts and macrophages lying in a storiform pattern. There are scattered giant cells (H&E, low power). FIG. 27 Simple bone cyst. The cyst wall is composed of cellular and collagenous fibrous tissue (H&E, low power). FIG. 28 Aneurysmal bone cyst. Anteroposterior radiograph shows a large, expansile, multiloculated lytic lesion in the distal fibula.

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FIG. 29 Aneurysmal bone cyst. Sagittal STIR MRI of the distal femur demonstrates a multiloculated lesion with multiple fluid-fluid levels. FIG. 30 Aneurysmal bone cyst. There are blood filled cystic spaces; the cyst wall contains macrophages and osteoclast-like giant cells (H&E, low power). FIG. 31 Fibrous dysplasia. Coronal STIR MRI shows a lesion with relatively mixed high signal in the diaphysis of the femur. FIG. 32 Fibrous dysplasia. There is abundant cellular fibrous tissue amongst which there are scattered irregular woven bone trabeculae (H&E, low power). FIG. 33 Fibrocartilaginous dysplasia. The lesion contains cartilage which undergoes growth plate-like organisation to form woven bone trabeculae (H&E, low power). FIG. 34 Osteofibrous dysplasia. Radiograph of the lower leg shows a mixed cortical lesion in the mid-segment of the tibia with lobulated sclerotic margin. FIG. 35 Mesenchymal hamartoma of chest wall. There is a proliferation of mesenchymal cells and focal areas of matrix formation (H&E, low power). FIG. 36 Langerhans cell histocytosis. There is a scattered infiltrate of macrophages, giant cells, polymorphs, including eosinophils, and Langerhans cells (H&E, high power). FIG. 37 Metastatic neuroblastoma. There is a proliferation of tumour cells with scanty cytoplasm and hyperchromatic small round nuclei (H&E, high power).

imaging.12 MDCT angiography is considered superior to MR angiography due to its better spatial resolution as it permits simultaneous visualisation of vessels, tumour, bone and other anatomical structures in a single scan.9,12 Where post-operative imaging is required and metal hardware or other implant components are present, CT is indicated for the evaluation of a potential recurrence, as the bone marrow at the site of hardware is often obscured; volume rendered 3D CT images virtually eliminate streak artefact associated with hardware. CT is used to guide percutaneous needle biopsies of musculoskeletal lesions for histological diagnosis.12,13 CT guided biopsies in the paediatric population generally require sedation or general anaesthesia; they are performed under sterile conditions and the needle pathway is carefully

selected in order to avoid vital structures or intercompartmental contamination or tumour seeding. It has recently been reported that in a series of 127 image-guided biopsies in 111 children, the diagnostic success in primary malignant musculoskeletal tumours was 92%.13 MRI is now routinely employed in the investigation of bone tumours.9–11,14–16 It is particularly patient friendly in the paediatric context as it avoids radiation exposure. The multiplanar imaging capabilities of MRI accurately define the origin, extent and margins of a bone lesion.14 MRI provides excellent soft tissue contrast and detects marrow oedema around the lesion. Bone marrow oedema is noted around benign tumours (e.g., chondroblastoma, osteoid osteoma, eosinophilic granuloma) and reactive lesions (e.g., infection); it can also commonly be seen in malignant

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DIAGNOSIS OF PAEDIATRIC BONE TUMOURS AND LESIONS

conditions such as Ewing’s sarcoma, osteosarcoma, and metastasis.11,14 MRI can demonstrate occult fracture, cortical breakthrough and the presence of a soft tissue mass. It also detects a fluid signal in a simple bone cyst and fluid-fluid levels within some lesions (e.g., aneurysmal bone cyst).11,15 Fluid-fluid levels may occur in both benign malignant and malignant lesions (Fig. 2); it has been reported that the extent of fluid-fluid levels within a solitary bone lesion appears to be inversely related to the degree of malignancy.15 Areas of haemosiderin deposition and punctate foci of low signal, indicating calcification or ossification, may be noted in chondroid tumours.14,16 Haemangiomas, particularly of the spine, show high signal intensity on T1-weighted MRI images, corresponding to areas of high fat content, and high signal intensity on T2-weighted images, corresponding to the increased vascularity of these lesions.14 Multiplanar imaging in coronal, axial and sagittal planes throughout a bone lesion is particularly useful in evaluating the morphology of a tumour and its relation to adjacent structures.14,16 As a general rule, short axis images indicate whether there is cortical destruction and/or displacement or invasion of the neurovascular bundle, and long axis images allow the evaluation of the extent of the lesion and its spatial relationship to the nearest joint. MRI scans can cover large areas of an extremity, a feature which is useful in excluding the possibility of skip or multiple lesions.16,17 A whole-body MRI scan is indicated in cases where metastatic disease is suspected. Whole-body MRI using a short tau inversion recovery (STIR) sequence is an effective radiation free method for examination of children with suspected multifocal bone lesions.17,18 MRI demonstrates more lesions than conventional 99m Tc-methylene diphosphonate scintigraphy and MRI is the screening method of choice for investigation of metastatic and skip lesions in osteosarcoma, Ewing’s sarcoma/primitive neuroectodermal tumour (PNET) and Langerhans cell histiocytosis in children.17 MRI is the recommended imaging modality in follow-up studies in order to exclude local recurrence19 and specific sequences that reduce artefacts from metalwork can be performed where post-operative studies are required. Gadolinium is not routinely indicated in evaluating osseous lesions as almost any bone lesion with a vascular supply will enhance.14,19 Gadolinium enhancement, however, can be useful in follow-up studies to determine whether there is residual or recurrent tumour. Dynamic studies may identify a lesion, as the tumour will enhance early, unlike fibrous scar tissue which tends to enhance more slowly. Ultrasound (US) is an imaging modality with a wide application spectrum in the paediatric population due to its lack of ionising radiation.16,20 A US scan is well tolerated by a child and can be quickly and easily performed. US can be used for the detection and characterisation of a soft tissue mass adjacent to a bone; based on colour and power Doppler findings, it also gives information on whether a lesion is cystic or solid and gives an idea of the extent of its vascularity.20 When a bone lesion is purely osseous, the role of US is relatively limited, although US can detect periosteal reaction. Percutaneous US-guided biopsies can be performed with local anaesthetic.15,20 US follow-up scans are particularly useful in the assessment of osteo-

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chondromas, when measurement of the dimensions of a growing cartilage cap may be required (Fig. 3); it is also useful in assessing the soft tissue component of a malignant bone tumour. Bone scintigraphy is a well-recognised modality that can add information for staging and treatment planning of primary bone tumours. Its role in the evaluation of a primary paediatric bone tumour is limited.6–9 Osteoblastic activity associated with bone-forming tumours, particularly osteosarcoma, and reactive bone formation associated with other sarcomas can be imaged on bone scanning (Fig. 4). The whole body screening of bone scintigraphy provides a cost-effective method of screening for metastatic spread or multifocal bone pathology, and bone scanning has a role in the follow-up of patients with osteosarcoma.17,18 Bone seeking radiotracers include 99m Tc methylene diphosphonate (MDP) and 18F fluoride, which can be imaged by positron emission tomography (PET).21 High 99mTc MDP uptake in soft tissue sarcomas is uncommon except in osteosarcoma metastases. The intensity of osteoblastic activity within a Ewing’s sarcoma is variable but is generally less than in an osteosarcoma. High affinity for Thallium-201 (201Tl) has been observed in various bone and soft tissue sarcomas. PET is a relatively new imaging modality that enables the evaluation of tissue metabolism and physiology in vivo with positron-emitting radionuclides.21,22 [18F] 2-deoxy2fluoro-d-glucose (FDG) is the metabolic tracer that is most widely used in clinical PET oncology. On PET imaging a high uptake of FDG can be seen in several tumours, including those of musculoskeletal origin. PETCT offers an important advantage over PET alone because correlative CT images provide a means of accurately identifying the location of increased FDG activity; in many cases this allows the differentiation of normal from pathological structures and distinction between different pathological processes.21,22 A few studies have evaluated the role of FDG-PET and PET-CT in the management of musculoskeletal tumours and found that the sensitivity and specificity of combined PET/CT is 100% and 93.3%, respectively, for the detection of metastatic disease.22 PET-CT would appear to provide a useful imaging modality for the detection and follow up of primary osseous tumours, although it is less sensitive in the detection of metastatic pulmonary disease.

BONE BIOPSY AND PATHOLOGICAL ASSESSMENT OF BONE TUMOURS Adequate tissue can be obtained through needle biopsies for bone tumour diagnosis but this is not always possible in the paediatric context and an open biopsy is often necessary.23 Fine-needle aspiration biopsy (FNAB) can be used to provide a cytological diagnosis but the small sample size of an FNAB limits the amount of diagnostic information obtained by this technique.24–26 False positive and false negative rates range from 1–5% and 2–15%, respectively. This technique can be useful in providing confirmatory morphological evidence of the benign or malignant nature of a tumour, particularly if it presents with characteristic clinical and radiological features; this information may be all that is required to initiate treatment in some circumstances.

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Core needle biopsy using a 14 gauge or 18 gauge needle or biopsy gun provides much more biopsy tissue for histological analysis, permitting assessment of not only the cytological features but also the tissue architecture of the tumour. As with FNAB, needle track seeding occurs rarely.23,27,28 This technique also permits analysis of imprint preparations and frozen sections for diagnosis; these investigations are useful in determining whether glycogen or alkaline phosphatase is present in tumour cells in the case of Ewing’s sarcoma or osteosarcoma, respectively. A needle biopsy is not always tolerated by younger paediatric patients. In many cases, an open biopsy is preferable as it allows a frozen section of the biopsied tissue to be carried out, thus ensuring that adequate tissue is available for diagnosis and that this tissue is representative of the lesion. Using a disposable microtome blade, 5 mm thick sections of tissue containing a small amount of bone can be cut. Diagnostic possibilities are suggested at the time of frozen section and, on this basis, appropriate investigations can be carried out on the remaining tissue. For example, the tumour may be processed for cytogenetic studies and flow cytometry or frozen in liquid nitrogen for molecular analysis. The pathologist’s approach to the evaluation of a bone tumour involves not only assessment of the cell and tissue morphology of the biopsied tumour but also correlation of the morphological features with the clinical and radiological findings. It is first important that the pathologist is confident that the biopsy tissue is adequate for assessment and that it is likely to be representative of the lesion. The morphological features of the lesion will dictate the use of other investigations including histochemical or other special stains, immunohistochemistry, cytogenetics and molecular analysis (Table 3). Immunophenotypical markers are useful in identifying or confirming the nature of cells in a bone tumour or in tumour-like lesions.3,4 For example, in the diagnosis of a malignant round cell tumour, expression of leukocyte common antigen (CD45) indicates that tumour cells are of haematopoietic origin. If a lymphoma is suspected, B and T cell markers, such as CD19/CD20 and CD3, respectively, are useful; Langerhans cells in Langerhans cell histiocytosis can be identified using antibodies directed against S-100, and CD1a. Other useful markers include factor 8 related antigen, CD31, and CD34, which are expressed by endothelial cells in vascular tumours. Expression of CD99 is also useful in confirming the diagnosis of Ewing’s sarcoma, although it should be appreciated that this antigen can be expressed in other round cell tumours such as in lymphoblastic lymphoma, small cell osteosarcoma and mesenchymal chondrosarcoma.29,30 NB84a, synaptophysin and chromogranin are useful in the identification of neuroblastoma.31 Decalcification, even in relatively strong acid solutions, does not abrogate the immunohistochemical detection of the above and many other antigens employed in bone tumour diagnosis.32 Immunohistochemistry for the expression of FLI-1, a nuclear protein that is involved in cell proliferation and tumorigenesis, is useful in the analysis of round cell tumours, providing an alternative to cytogenetic and molecular genetic analysis of Ewing’s sarcoma (see below). FLI-1 is normally expressed by endothelial cells and haematopoietic cells, including T lymphocytes. Immuno-

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histochemistry for the carboxy-terminus of FLI-1 protein provides a highly sensitive (71%) and specific (92%) test for Ewing’s sarcoma.33 FLI-1 expression may also be noted in lymphoblastic lymphoma and endothelial cells of vascular neoplasms. WT1, a proliferation marker, which represents a nuclear transcription factor, is also useful in the diagnosis of small round cell tumours.34 WT1 is found in Wilms’ tumour and lymphoblastic lymphoma and is occasionally expressed in neuroblastoma and lymphoma but not in Ewing’s sarcoma. Mutations in the p53 gene result in the accumulation of p53 protein in the nucleus. p53 expression may be elevated in some malignant tumours of bone.35–37 However, the expression in bone tumours of p53 and other proliferation markers, such as proliferating cell nuclear antigen and Ki-67, has not proved to be generally useful in bone tumour diagnosis or in determining prognostic behaviour. Cytogenetic and molecular analysis of tumour cells is proving increasingly useful in bone tumour diagnosis. It is particularly useful in the diagnosis of Ewing’s sarcoma, which is associated with characteristic reciprocal translocations that involve the EWS gene on chromosome band 22 q12 and genes from different members of the ETS family of transcription factors.38,39 Increased transcription activation by EWS may provide Ewing’s sarcoma cells with a means of avoiding programmed cell death by down-regulating the putative tumour suppressor transforming growth factor-b type II or by inactivating INK4, a locus that encodes the cell cycle inhibitor CDKM2A. The most common of these translocations is t(11; 22) (q24; q12), which is present in nearly 85% of cases of Ewing’s sarcoma; this results in a tumorigenic fusion protein composed of the 50 - end of the EWS gene and 30 - end of the ETS family gene FLI-1: This EWS-FLI-1 fusion product has been reported in other malignant round cell tumours including neuroblastoma and mesenchymal chondrosarcoma.29,40–42 The second most common translocation is t(21; 22) (q24; q12), which involves the same segment as the EWS gene combined with the 30 - end of the ETS family gene ERG. The EWS gene may combine with other ETS family genes in other translocations including t(7; 22), t(17; 22), and t(2; 22). Molecular studies are useful in identifying loss or mutation in tumour suppresser genes, such as p53 and the retinoblastoma gene, both of which are associated with the pathogenesis of osteosarcoma.35,36,43,44 The loss of both functional alleles by either deletion or mutation results in unrestrained cell growth.45,46 p53 mutations often result in intracellular accumulation of abnormal proteins that can be detected by immunohistochemistry. Cytogenetic analysis of osteosarcomas frequently shows karyotypic abnormalities in these tumours; these include gain of regions of chromosome 1, and loss of regions of chromosomes 6, 9, 10, 13 and 17.47 Another possible mechanism of tumourigenesis in osteosarcoma is the activation of an oncogene, a gene that promotes tumour cell proliferation. Mutations in the H-ras and SAS genes are known to enhance cell transformation and to increase tumorigenicity of osteosarcoma cells; amplification of c-myc and c-fos has been noted in human osteosarcomas48 and c-fos plays a role in bone and cartilage cell differentiation. Amplification of the N-myc gene in neuroblastoma is associated with a poor prognosis.49 Multidrug resistant genes have also been identified, and identification of their expression may prove

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useful in the future in determining the response of sarcomas to therapy.50 Although flow cytometry does not accurately distinguish between benign and malignant bone tumours of bone, it can provide supportive evidence that may favour the diagnosis of a benign or malignant tumour; it can also provide prognostic information and a guide to the response to therapy.51 Flow cytometry provides a measurement of a number of features including cell size, viability, cell cycle time and DNA ploidy as well as other cytological parameters. With regard to DNA ploidy, tumours are generally divided into diploid and aneuploid. DNA aneuploidy indicates an abnormal amount of DNA in a tumour cell population relative to normal (diploid) cells. DNA aneuploidy has been documented in benign bone tumours and does not equate with malignancy. However, aneuploidy is more prevalent in high grade malignant tumours and is an independent risk factor for predicting metastasis. Electron microscopy can also be useful in establishing the pathological diagnosis of some bone tumours;52 it can be employed to identify Birbeck granules in Langerhans cell histiocytosis or cytoplasmic glycogen in Ewing’s sarcoma.

PRIMARY BONE TUMOURS In the paediatric population, benign and malignant bone tumours occur more commonly in adolescents than in children. An analysis of a large series of primary tumours and tumour-like lesions of bone found that 42% of all bone tumours arose in the first and second decade;5 9% occurred in the first decade and 33% in the second decade. It should be noted that many more benign bone tumours and tumour-like lesions are diagnosed than appear in recorded series as many of these lesions are asymptomatic or documented as incidental radiological findings. Almost all primary bone tumours that can occur in adults have been reported to arise in the paediatric population.5,53 The most common primary malignant bone tumours that arise in children are osteosarcoma and Ewing’s sarcoma. The most common benign bone tumours arising in children are osteochondroma, enchondroma, osteoid osteoma, osteoblastoma, chondroblastoma, chondromyxoid fibroma, and haemangioma. The most common tumour-like bone lesions arising in children are metaphyseal fibrous defect/non-ossifying fibroma, eosinophilic granuloma, simple bone cyst, aneurysmal bone cyst and fibrous dysplasia. Primary bone tumours in infants are very rare.5,53,54 Ewing’s sarcoma is rarely encountered before the age of 5 years but is probably the most common primary malignant tumour of bone that occurs in the first year of life; osteosarcoma, chondrosarcoma and other tumours have also rarely been reported. Benign lesions that may arise in infants include diffuse haemangiomatosis, congenital multiple fibromatosis, hamartoma (mesenchymoma) of the chest wall, osteochondromatosis, enchondroma, enchondromatosis, and simple bone cyst; other primary benign tumours have also rarely been reported. The differential diagnosis of multiple neonatal and infantile bone tumours includes Langerhans cell histiocytosis (LCH) osteomyelitis and metastasis. In general, LCH presents as a

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generalised disease with extensive systemic involvement and does not occur as a monostotic disease in infancy. Osteomyelitis in the first year of life usually presents as a multifocal process in a metaphyseal location and is often associated with articular involvement and signs and symptoms of generalised sepsis; the erythrocyte sedimentation rate (ESR) and white cell count are often elevated. This review, derived from a number of general and specific publications on bone tumour pathology,3–5,53–57 focuses on diagnostic aspects of the most common benign and malignant bone tumours and tumour-like lesions that arise in the paediatric population.

BONE-FORMING TUMOURS Benign Of the benign bone-forming tumours, osteoid osteoma and osteoblastoma occur most commonly in the paediatric population. Osteoma rarely occurs in children. Osteoid osteoma This is a relatively common benign boneforming tumour which has characteristic clinical, radiological and pathological features.57–59 It rarely occurs in very young children and in most cases arises in the second decade. It is twice as common in males than females. Typically, the patient complains of severe bone pain that is worse at night and often relieved by salicylates. The tumour arises most commonly in the shaft of long and short tubular bones. The femur and tibia are most commonly involved but it may also arise in the posterior elements of the vertebra. Radiologically, it is characterised by intense osteosclerotic thickening of the cortex in which a radiolucent nidus may be noted (Fig. 5); this is best shown by CT (Fig. 6). Grossly, the lesion is small (520 mm) and well-vascularised. Histologically, it shows disorganised osteoid and woven bone formation; bone trabeculae are covered by plump osteoblasts and are separated by a vascular stroma. There may be scattered osteoclasts. Cartilage is not present. Complete removal of the nidus is required for relief of symptoms. Malignant change has not been reported in osteoid osteomas. Osteoblastoma This is an uncommon benign boneforming tumour that has similar age and sex distribution as osteoid osteoma, arising more commonly in children and adolescents.57,59,60 It occurs most commonly in the vertebral column where it usually involves posterior elements, particularly the vertebral arch. It may also occur in long and short tubular bones. Radiologically, the bone lesion is well-defined and mainly radiolucent; small radiopaque areas within the lesion may be noted; sclerosis around the lesion is not typically seen. Histologically, the lesion exhibits disorganised osteoid and woven bone formation with prominent osteoblastic activity. In both osteoid osteoma and osteblastoma, a relatively well-defined row of plump osteoblasts covers newly formed osteoid and woven bone. Cartilage is not typically found in osteoblastomas. There are scattered osteoclasts and secondary aneurysmal bone cyst formation may occur. A very rare subtype of osteoblastoma, ‘toxic’ osteoblastoma has only been reported to arise in children less than 5 years of age61 (Fig. 7). This lesion is characterised by marked

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inflammatory periostitis of the involved bone and other skeletal sites, as well as systemic symptoms including fever, anorexia and weight loss, all of which resolve upon excision of the lesion. An osteoblastoma which exhibits local invasion and tends to recur but does not metastasise is often termed an aggressive osteoblastoma.62 This lesion is often large and grossly and radiologically well-defined. It arises in an older age group than typical osteoblastoma. This lesion characteristically has large epithelioid osteoblasts that line the surface of sheets of osteoid or thickened bone trabeculae. It has been shown that atypical osteoblastomas, like osteosarcomas, commonly express p53.63 This tumour is difficult to differentiate histologically (and radiologically) from lowgrade osteosarcoma and requires careful follow up. Malignant Osteosarcoma This is a malignant osteoid/bone-forming tumour which is characterised by the presence of malignant tumour cells producing osteoid or bone.64,65 Osteosarcoma is the most common primary malignant bone tumour in children. It occurs more commonly in males than females. Approximately 10% of osteosarcomas arise in children in the first decade of life but most cases occur in the second decade. Osteosarcomas may arise following radiation or rarely develop secondary to other benign conditions. Multifocal osteosarcoma can arise in children.66,67 An osteosarcoma usually develops in the metaphysis of a long bone, most commonly in the distal femur or proximal tibia, but any bone may be affected. Radiologically the tumour shows a variable degree of osteolysis and sclerosis.17 There may be a prominent periosteal reaction (Fig. 8). The tumour is usually centred on the metaphysis and contains focal areas of mineralisation (Fig. 9). Expansion of the tumour leads to cortical infiltration and invasion of surrounding soft tissues (Fig. 10). Histologically, the usual picture is one of numerous tumour cells with large pleomorphic, hyperchromatic nuclei; these cells form osteoid or woven bone and are alkaline phosphatase positive (Fig. 11). An osteosarcoma may be described as osteoblastic, chondroblastic or fibroblastic depending on the predominant tissue element which is formed within the tumour. Within an osteosarcoma there may be elements that resemble chondrosarcoma, fibrosarcoma or malignant fibrous histiocytoma. Immunohistochemistry shows that the tumour cells express vimentin: they may also rarely express smooth muscle markers (actin, desmin) and epithelial antigens.3,4,56 These tumours may also uncommonly express CD99 and exhibit expression of p53 and various non-collagen proteins. As noted earlier, these tumours exhibit a wide range of karyotypic abnormalities and are associated with abnormalities of the Rb and p53 genes, as well as abnormal expression of a number of oncogenes, including c-fos, c-myc and H-ras.47 Tumour necrosis of 90% or more following chemotherapy is associated with a favourable prognosis. A number of histological subtypes of osteosarcoma have been described, including giant cell-rich osteosarcoma, where there are numerous osteoclast-giant cells, and telangiectatic osteosarcoma, which contains numerous blood-filled cystic spaces, and small cell osteosarcoma,

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which contains numerous Ewing-type round cells.68,69 Small cell osteosarcoma usually arises in the first or second decade of life and is a rare aggressive variant of osteosarcoma that needs to be distinguished from Ewing’s sarcoma; the tumour cells in this type of osteosarcoma have been shown to express CD99 but do not exhibit a t(11; 22) translocation.70 In this tumour, however, tumour cells are alkaline phosphatase-positive and exhibit evidence of osteoid formation. Low grade intramedullary osteosarcoma This is a rare type of well-differentiated osteosarcoma, which may rarely arise in late adolescence but is usually a tumour of adult patients.71 It is characterised histologically by the presence of abundant cellular fibrous tissue and relatively wellformed bone trabeculae and areas of osteoid formation by tumour cells. It can histologically resemble fibrous dysplasia but usually shows increased mitotic activity (not a usual feature of fibrous dysplasia) and cytological atypia, as well as radiological and morphological evidence of invasion. Most osteosarcomas arise in the medulla but some arise from the bone surface. These include parosteal osteosarcoma, periosteal osteosarcoma and high-grade surface osteosarcoma. These tumours usually arise in adults and rarely occur in children. In contrast, myositis ossificans, a reactive soft tissue lesion characterised by extensive heterotopic ossification, is relatively common in children and adolescents.

CARTILAGE-FORMING TUMOURS Benign Benign tumours of cartilage are the most common primary bone tumours that arise in the paediatric population. Enchondroma Enchondroma is a benign intramedullary bone tumour which is characterised by the formation of abundant mature hyaline cartilage.3,4,57 Although many enchondromas are discovered in adult life, approximately 25% are seen in children, mostly in the second decade. It is the second most common benign bone tumour in childhood, accounting for 19% of all benign bone tumours and 24% of all those occurring in children or adolescents.5 Most tumours are located in the short tubular bones of the hands and feet but they may rarely arise in long tubular bones, the ribs or spine. The tumours may present with a pathological fracture or as a result of local swelling and pain. Radiologically, the lesion is usually well-defined and lies within the medulla; it may produce thinning and expansion of the surrounding cortex and there may be endosteal scalloping. There may be a variable amount of calcification or ossification within the lesion which is welldefined and generally surrounded by lamellar bone.72 Cartilage cells show no marked nuclear pleomorphism; binucleated cells are not uncommonly seen in paediatric enchondromas, particularly in bones of the extremities (Fig. 12). Cortical penetration does not occur. A periosteal chondroma is a well-defined chondromatous lesion that arises on the bone surface.73 It may arise in the metaphysis of the long bones or in small bones of the hand. Radiologically it produces scalloping (often with

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sclerosis) of the overlying cortex. The absence of medullary involvement can be confirmed either by CT or MRI. Most enchondromas are solitary lesions but occasionally they may develop in several bones. Enchondromatosis (Ollier’s disease, dyschondroplasia) is a rare non-hereditary disorder which results in the formation of growth plate cartilage that does not undergo endochondral ossification;57 this results in the formation of multiple enchondromas as abnormal cartilage tissue persists as a cartilage rest within the affected bones and can result in considerable deformity. Several karyotypic abnormalities have been noted; a deletion of 9p may point to involvement of the CDKN2A tumour suppressor gene; a mutation in the PTH/ PTHrP type I receptor has also been reported in patients with multiple enchondromas.74 Enchondromatosis affects males and females equally. The extent of skeletal involvement is variable and may be confined to a single bone or limb. Most patients present in childhood. Lesions occur most commonly in the small bones of the hands and feet but can arise in almost any bone in the skeleton. The lesions resemble solitary enchondromas but generally contain larger numbers of chondrocytes and exhibit more cellular and nuclear pleomorphism than is seen in a typical solitary enchondroma. There are frequent binucleated cells. When multiple enchondromas are associated with soft tissue or skin haemangiomas, the condition is termed ‘Maffucci’s syndrome’. Most (but not all) enchondromatosis lesions cease to grow once adulthood is reached. The precise incidence of malignant transformation (usually to chondrosarcoma) is difficult to determine but it has been reported in 15–30% of patients with Ollier’s disease and 20–30% with Maffucci’s’ syndrome.4 This malignant change occurs most commonly in adults and in patients with widespread skeletal involvement. Osteochondroma A cartilage-capped bony outgrowth arising from the external surface of a bone,57 this is the most common benign bone tumour of childhood accounting for 40% of all benign tumours and 58% of all bone tumours arising in children or adolescents.5 Most lesions are diagnosed within the first two decades, particularly the second decade. Osteochondromas occur more commonly in males. They may develop in any bone formed by endochondral ossification, arising on the surface of the metaphysis of long tubular bones, especially the distal femur, proximal tibia and humerus. The lesion is found in the metaphysis and grows away from the nearest epiphysis. Radiologically, the lesion may be sessile or pedunculated (Fig. 13). Cortical and cancellous bone of the lesion is continuous with that of the bone in which the lesion develops. The cartilage cap is often lobulated and may contain focal areas of calcification. US and MRI are useful in measuring the thickness of the cartilage cap, which is usually less than 1 cm. Histologically, the lesion is covered by a fibrous perichondrium beneath which there is a cartilage cap containing chondrocytes separated by a cartilage matrix that frequently shows degenerative change (Fig. 14). During growth there may be a physislike arrangement of cartilage cells with endochondral ossification resulting in the formation of woven bone trabeculae at the base of the cartilage cap. Binucleated cartilage cells are not uncommonly seen in the cartilage cap of younger patients. A bursa may form over an osteochon-

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droma in surrounding soft tissue and cartilaginous metaplasia may be noted within the wall of the bursa. An osteochondroma should cease to grow when skeletal maturity is reached. Asymptomatic lesions can be followed radiologically and only symptomatic lesions require excision; osteochondromas may develop in patients who have received radiation treatment for a bone lesion during childhood. Hereditary multiple exostoses Hereditary multiple exostoses (HME; diaphyseal aclasis, multiple osteochondromas) is an autosomal dominant-inherited condition, which is characterised by the formation of multiple osteochondromas in several bones.57 These lesions slowly enlarge causing considerable deformity (Fig. 15). Mutations in the family of EXT tumour suppressor genes associated with this condition, EXT1, EXT2 and EXT3, have been localised to chromosomes 8q24.1, 11p11-p12 and 19p, respectively.75 EXT1 and EXT2 have been associated with most cases of HME. Similar patterns of EXT gene mutation have been noted in some solitary osteochondromas and chondrosarcomas. The lesions show similar radiological and histological features to those of solitary osteochondroma but are often larger and contain more binucleated cartilage cells (Fig. 16). Enlargement of a HME osteochondroma after skeletal maturity is reached may indicate malignant transformation. The exact incidence of malignant change is unknown but this is thought to occur rarely (0.5–3.0% of cases). Trevor’s disease (dysplasia epiphysialis hemimelica) A rare non-hereditary developmental disorder of cartilage growth and endochondral ossification, this predominantly affects the epiphysis of long bones.57,76 This results in formation of an osteochondroma-like cartilaginous lesion adjacent to one or more of the epiphyses of the long bones. Histologically, the lesion resembles an osteochondroma with a broad cartilage cap covered by fibrous tissue. Chondroblastoma (Codman’s tumour) This is a rare benign cartilaginous tumour which arises in the epiphysis and contains immature cartilage cells (chondroblasts) associated with the formation of a mineralised cartilage matrix.57 It usually arises in the second decade of life; 4% of patients are children below the age of 10 years. It most frequently arises in the epiphysis of long tubular bones, including the humerus, femur and tibia, but can also arise in the pelvis and very rarely other bones. Radiologically, the lesion is well-defined and eccentrically located in the epiphysis (Fig. 17). It is essentially radiolucent but may contain small areas of calcification. Histologically, it is composed of a uniform population of small round cells which have a well-defined cell membrane, clear cytoplasm and hyperchromatic round or oval nuclei that frequently contain a longitudinal groove. These cells are associated with the formation of an amorphous cartilage matrix that may exhibit lace-like or chicken wire calcification (Fig. 18). Mitotic figures may be present and there are often osteoclast-giant cells scattered throughout the lesion, particularly around areas of matrix formation. Secondary aneurysmal bone cyst change may occur in these lesions in up to one-third of cases. Spindle cell change may be noted within a chondroblastoma and there may be ossification or

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formation of an osteoid-like as well as a chondroid matrix. Chondroblasts are S-100 positive.77 Chondroblastoma needs to be distinguished from other cartilage-forming tumours including chondromyxoid fibroma and clear cell chondrosarcoma as well as the very large number of giant cell-containing lesions of bone (see below). This lesion is not uncommonly mistaken histologically for an osteosarcoma due the presence of abundant mineralised chondroid or ‘chondrosteoid matrix’; it is important to correlate the histological findings with the clinical and radiological features. Chondromyxoid fibroma This is a rare benign tumour in which there are lobules of chondromyxoid or fibromyxoid matrix containing cells with spindle-shaped or stellate nuclei.57 It accounts for less than 1% of all benign bone tumours. Most chondromyxoid fibromas are detected in the second decade of life but they may also arise in older children. Chondromyxoid fibroma occurs more frequently in males than females. It most often arises in the lower extremity, principally the proximal tibia and bones of the feet. A significant proportion of cases also arise in flat bones, particularly the ilium. The tumour contains numerous spindle-shaped or stellate cells which lie within a myxoid or chondroid matrix. There are often scattered giant cells around lobules of chondromyxoid tissue. Some cells have a vacuolated cytoplasm and show a degree of nuclear pleomorphism, which is degenerative rather than proliferative in nature. Chondomyxoid fibroma has a high recurrence rate after curettage and the best treatment is wide excision. Malignant Chondrosarcoma Uncommon in children and adolescents, accounting for only about 5% of all cases of chondrosarcoma, these tumours are more commonly secondary than primary chondrosarcomas.5 It is important to distinguish a conventional chondrosarcoma from an enchondroma or a chondroblastic osteosarcoma as these tumours are treated very differently. Clinical and radiological features aid in the distinction. Unlike enchondroma, chondrosarcoma generally arises in large bones, including the pelvis and shoulder girdle, as well the metaphysis of long bones.57 It may also arise in the ribs and spine. It very rarely arises in the bones of the extremities. Radiologically, chondrosarcomas contain dense areas of calcification; the tumours are often large and are associated with considerable bone destruction. Chondrosarcoma is characterised histologically by the formation of a cartilage matrix by tumour cells that infiltrate the host bone. Most tumours are well-differentiated and contain abundant cartilage matrix in which there are scattered cartilage cells, some of which are binucleated. Histological evidence of tumour infiltration is required for diagnosis; in chondrosarcoma, the edge of the tumour is not completely surrounded by lamellar bone as in an enchondroma.72 It is important to correlate the clinical and radiological information with the pathological findings. Dedifferentiation of a (low grade) chondrosarcoma can occur rarely. Mesenchymal chondrosarcoma This is a rare variant of chondrosarcoma characterised by the proliferation of

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primitive mesenchymal tumour cells with round, oval or spindle-shaped nuclei, amongst which are scattered islands of cytologically low-grade malignant cartilage57 (Fig. 19). Mesenchymal chondrosarcoma may present at any age but is relatively common in the second decade. Males and females are equally affected. Any bone may be affected but the skull, ribs, vertebrae, pelvis and femur are most often involved. Radiologically, the tumour is a lytic, destructive lesion exhibiting a variable degree of mineralisation. The tumour has a prominent haemangiopericytoma-like vascular component. There may be formation of a matrix component that is partly chondroid, partly osteoid in appearance. This tumour commonly falls into the differential diagnosis of malignant small round cell tumours of bone. Proliferating tumour cells in mesenchymal chondrosarcoma may be CD99-positive and some exhibit the reciprocal t(11; 22) (q24; q12) translocation which is found in Ewing’s sarcoma.70,78 Wide excision is required for cure. Metastasis may develop late and is usually to the lungs and bones. Other variants of chondrosarcoma have been described. These include clear cell chondrosarcoma, which occurs most commonly in young adults. This tumour can arise in the second decade and needs to be distinguished from chondroblastoma, particularly as it can arise in the epiphysis.79 Dedifferentiated chondrosarcoma arises from a low-grade chondrosarcoma and thus occurs more commonly in adults;80 juxtacortical chondrosarcoma is a surface low grade chondrosarcoma that may rarely arise in adolescents.81

GIANT CELL TUMOURS OF BONE There are numerous lesions of bone in which osteoclastlike giant cells form a significant component (Table 7). Correlation of the clinical, radiological and histopathological findings is essential for diagnosis. Giant cell tumour of bone (osteoclastoma) is a relatively common primary tumour of bone, which usually arises in the epiphysis of a long bone in a skeletally mature patient.57 Only rarely does true giant cell tumour arise in patients under the age of 15 years; it occurs more commonly in females than males in this context, probably because females attain skeletal maturity at an earlier age. The age and site restriction of giant cell tumour of bone usually permit distinction from other lesions which contain numerous giant TABLE 7 Giant cell rich tumours of bone Giant cell tumour of bone Giant cell reparative granuloma (jaw/small bones)* Chondroblastoma* Chondromyxoid fibroma* Aneurysmal bone cyst* Simple bone cyst (with fracture)* Langerhans cell histiocytosis* Non-ossifying fibroma* Fibrous dysplasia* Giant cell-rich osteosarcoma* Telangiectatic osteosarcoma* Other bone tumours (e.g., osteoblastoma) associated with excessive bone remodelling activity* Paget’s disease Fracture* Hyperparathyroidism (brown tumour) *Paediatric.

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cells. Many of these giant cell rich lesions of bone, which form a heterogeneous group, arise predominantly in adolescents or children; with the exception of benign chondroblastoma, these tumours do not arise in the epiphysis. Radiologically, giant cell tumour is an eccentric, purely lytic lesion with a well-defined (non-sclerotic) border. Histologically, the osteoclast-like giant cells are numerous and may be huge, containing a very large number of vesicular nuclei; mitotic activity may be seen in the mononuclear component, which includes osteoblastic cells that may exhibit reactive osteoid/bone formation. Malignant change rarely occurs but recurrence is common. The differential diagnosis of giant cell lesions of bone includes giant cell reparative granuloma of the jaw and giant cell reparative granuloma of small bones of the hands and feet, both of which are rare but can occur in children and adolescents.82,83 Histologically, both these lesions exhibit a more focal accumulation of giant cells than giant cell tumour of bone and contain an increased amount of fibrous tissue in which there may be reactive bone formation. Giant cells in both these tumours, however, show similar immunophenotypical characteristics to those of giant cell tumour of bone, being vitronectin receptorpositive and HLA-DR and CD14 negative.84,85

ROUND CELL TUMOURS OF BONE This is a heterogeneous group of malignant tumours of bone characterised morphologically by the presence of numerous small round tumour cells.70,86 Ewing’s sarcoma Ewing’s sarcoma/primitive neuroectodermal tumour (PNET) of bone is a primary malignant tumour of bone which is composed of small round tumour cells of uncertain origin.86,87 Thirty-two per cent of Ewing’s sarcomas develop in children and 58% in adolescence.5 The tumour arises most commonly between the age of 5 and 20 years. It occurs rarely in patients younger than 2 or older than 30 years of age. Ewing’s sarcoma develops most commonly in the diaphysis of long tubular bones and in flat bones, such as the pelvis and clavicle, but any bone may be affected. It occurs more commonly in males than females. Radiologically, the tumour is usually a large intramedullary osteolytic tumour that is predominantly located in the metaphysis and diaphysis where it produces extensive permeative bone destruction.88 There is often periosteal new bone formation, which is classically onion skinning in nature. Cortical destruction and soft tissue extension are common at the time of diagnosis. This can be determined using CT and MRI; Ewing’s sarcomas are commonly low signal on T1-weighted images and show heterogeneous high signal on T2-weighted images, with an extensive mixed soft tissue component (Fig. 20,21). Histologically, the tumour is composed of densely packed, uniform, small round tumour cells which have a palestaining round or oval nucleus and scanty cytoplasm (Fig. 22). There is often abundant necrosis and haemorrhage within the tumour, which contains few reticulin fibres. Tumour cells contain glycogen. A minority of Ewing’s sarcomas contain tumour cells with large pleomorphic nuclei, some of which have prominent nucleoli. These

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tumours are termed atypical Ewing’s sarcoma or large cell Ewing’s sarcoma.89,90 Immunohistochemistry shows that the tumour cells react strongly for the MIC2 gene product CD99.91,92 This is a membrane glycoprotein, which is a product of the MIC2 gene located on the short arm of chromosome 6. MIC2 is found in up to 90% of Ewing’s sarcomas; MIC2 has also been noted in tumour cells of acute lymphoblastic lymphoma/leukaemia, small cell osteosarcoma, rhabdomyosarcoma, mesenchymal chondrosarcoma and less commonly other sarcomas.29,30 Ewing’s sarcomas also commonly express FLI-1 protein.33 NSE expression is believed to provide evidence of neuroectodermal differentiation in some Ewing’s/PNETs.93 As noted earlier, cytogenetic and molecular genetic analysis can be used to determine the characteristic 11;22 translocation, which is found in 85–95% of cases.40,87,94 This translocation may be determined by several means including cytogenetics, metaphase/interphase fluorescence in situ hybridisation (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR). Ewing’s sarcoma/PNETs need to be differentiated from other malignant round cell tumours that may involve bone, including metastatic neuroblastoma, embryonal rhabdomyosarcoma, small cell osteosarcoma, mesenchymal chondrosarcoma, lymphoma and leukaemia. Correlation of the clinical and radiological findings is required for diagnosis. Tumour necrosis of 90% or more following pre-operative chemotherapy is a good prognostic feature. Non-Hodgkin’s lymphoma Non-Hodgkin’s lymphoma rarely occurs as a primary malignant tumour of bone in children without evidence of disease in other reticuloendothelial tissues. Of children with lymphoma, 5.5% have primary bone disease.4 The tumour arises most often in the spine and the diaphysis of large long bones. The tumour is often large at the time of diagnosis.95,96 Radiologically, the tumour causes extensive moth-eaten bone destruction which is usually centred on the diaphysis. These tumours characteristically show increased isotope uptake on bone scan and low signal intensity on T2-weighted MRI images. Histologically, most lymphomas of bone are high grade, diffuse large B cell lymphomas (Fig. 23). B lymphoma cells have a more lymphoid appearance and are larger and more polymorphous than those of Ewing’s sarcoma. The tumour stroma contains abundant reticulin. Lymphoblastic lymphoma is encountered most commonly in children;97 it is characterised by the presence of numerous small lymphoid cells that have relatively large round nuclei containing a fine chromatin pattern. Immunohistochemically, B cell lymphomas strongly express CD45 and B cell markers, such as CD20. Rarely, T cell and anaplastic lymphomas of bone can occur. CD45 is not expressed by Ewing’s sarcoma cells. Hodgkin’s disease Hodgkin’s disease rarely occurs in children less than 10 years of age.98 Hodgkin’s disease rarely presents as a primary bone tumour but bone involvement can occur in up to 15% of patients. Tumour involvement in bone may result in a lytic or sclerotic lesion. Histologically, Hodgkin’s disease is characterised by the presence of Sternberg-Reed cells and lacunar cells which are CD15þ and CD30þ.

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Leukaemia Leukaemia involving bone rarely presents as a primary bone tumour; this occurs most commonly with granulocytic leukaemias (granulocytic sarcoma). Bone changes in leukaemia are reported to occur in more than 20% of cases and are characterised by osteoporosis, radiolucent bands, osteolytic lesions, periostitis and rarely osteosclerosis. There may be prominent periosteal thickening affecting all long bones. Systemic mastocytosis occurs more commonly in adults than children but can result in tumour-like lytic or sclerotic lesions.

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TUMOURS OF VASCULAR ORIGIN AND OTHER VASCULAR LESIONS OF BONE Most benign and malignant vascular tumours have been described in bone but they rarely present as primary bone tumours in the paediatric population.5,99,100 These include various forms of haemangioma and haemangioendothelioma. Less than 5% of haemangiomas are detected in children and adolescents. They are found most commonly in the vertebral column and cranium and consist of capillaries and vascular spaces lying between bone trabeculae. Angiosarcomas are very rare in children. Gorham-Stout disease (massive osteolysis) occurs most commonly in children and adolescents but is a very rare tumour.101,102 It is characterised by the proliferation of blood or lymphatic vessels and the presence of vascular spaces that are not obviously lined by endothelial cells (Fig. 24). The rapid growth of this lesion is associated with active resorption of bone. Gorham-Stout disease and haemangioendothelioma are distinguished from haemangioma and angiosarcoma in that they contain lymphatic vessels which express the lymphatic endothelial markers, podoplanin and LYVE-1.103,104 Regional and disseminated (cystic) angiomatosis in children and adolescents has also been described.56,105,106 The latter is probably congenital and may present in the first two decades of life; it may be associated with soft tissue and visceral haemangiomas. Most commonly, the appearances are those of cavernous haemangioma-like vascular spaces. Lymphangiomatosis occurs mainly in children.56

FIBROUS AND FIBROHISTIOCYTIC TUMOURS OF BONE Fibrous and fibrohistiocytic tumours of bone include desmoplastic fibroma of bone, congenital multiple fibromatosis, benign and malignant fibrous histiocytoma and non-ossifying fibroma.4,57,107 Desmoplastic fibroma Desmoplastic fibroma is a fibromatosis-like lesion composed of scattered fibroblast-like spindle cells and abundant collagen.4,107,108 It is a very rare tumour, which occurs most commonly in the second and third decades. It can rarely arise in childhood. The tumour can arise in any bone but has been reported most commonly in the mandible. Radiologically, it is usually a lytic lesion, which has a sclerotic border; it returns low signal intensity in both T1- and T2-weighted images.

Pathology (2008), 40(2), February

The tumour is locally aggressive and may recur if not completely excised. Myofibromatosis Myofibromatosis (congenital multiple fibromatosis) is a rare condition, characterised by the presence of solitary or multicentric tumours in which there are numerous fibroblasts and myofibroblasts.109,110 Most lesions are present at birth. In the multicentric form, muscles and bones are frequently affected.111,112 The lesions are found mostly in subcutaneous tissue and muscle. They grow in the first few months of life but may regress in some cases. Visceral organs may be affected. In bone, lytic or cystic lesions are seen, most commonly in the metaphysis of long bones; the skull, ribs, pelvis and spine may also be affected. There is some overlap between this condition and infantile haemangiopericytoma. Cells in the lesion express smooth muscle actin and are negative for desmin. Lesions confined to soft tissues and bone can be treated by excision. Visceral involvement is associated with a poor prognosis with many of the patients dying in infancy. Non-ossifying fibroma Non-ossifying fibroma is a common fibrohistiocytic lesion, which arises in the metaphysis of long bones.4,5,57 Large lesions which involve the medulla, are termed non-ossifying fibroma and smaller lesions that are confined to the cortex are termed metaphyseal fibrous defect or fibrous cortical defect. Although clonal karyotypic abnormalities have been reported in this condition,113 it is considered by some observers not to be a neoplasm but rather a developmental abnormality of bone modelling which occurs as a consequence of increased subperiosteal osteoclastic resorption at sites of ligament or tendon insertion into bone. Most lesions are noted as incidental findings radiographically and require no treatment. Symptomatic lesions present most often in late childhood or adolescence. Males and females are equally affected. Non-ossifying fibroma is uncommon in children under 5 years. Radiologically the lesion is well-defined, lytic and lies against the cortex with which it has a sclerotic often scalloped border (Fig. 25). Histologically, the lesion is composed of fibroblasts and macrophages, which are arranged in a prominent storiform pattern (Fig. 26). There may be scattered osteoclastlike giant cells, foamy macrophages and haemosiderin deposits. There may be secondary aneurysmal bone cyst change. Bone or osteoid formation is not seen within the lesion but reactive bone may be seen around the lesion. Treatment of non-ossifying fibroma is required if fracture is imminent. Although it is not uncommon to have more than one metaphyseal fibrous defect, these lesions can be seen in a number of syndromes including Jaffe-Campanacci syndrome, neurofibromatosis and cherubism, usually in the form of multiple non-ossifying fibromas.55,114,115 Benign fibrous histiocytoma and malignant fibrous histiocytoma Both lesions occur over a wide age range but are rarely encountered in paediatric patients.57 Most cases of malignant fibrous histiocytoma (MFH) occur in adolescence and

DIAGNOSIS OF PAEDIATRIC BONE TUMOURS AND LESIONS

show features of the storiform-pleomorphic variant of this tumour. They are large destructive lesions that are centred on the metaphysis of a long bone. Other connective tissue tumours, such as benign and malignant schwannoma and tumours of fat, have only rarely been reported in children and adolescents.

occur.121 This contains abundant cellular fibrous tissue in which there are numerous scattered macrophages and osteoclast-like giant cells as well as areas of osteoid and woven bone formation. Clonal karyotypical abnormalities of 16q22 and 17p13 have been reported in aneurysmal bone cysts.122

OTHER TUMOURS AND TUMOUR-LIKE LESIONS OF BONE

Periosteal desmoid Periosteal desmoid (avulsive cortical irregularity) is a tumour-like fibrotic lesion that occurs in the posteromedial aspect of the distal femur. It occurs primarily in adolescent boys and is due to avulsion of the insertion of the adductor muscle tendon into the distal femur. It may be an incidental radiological finding or patients may present with pain. Radiologically, there is a longitudinal area of lucency in the distal posteromedial femoral cortex. Histologically, there is a proliferation of fibroblasts showing no cytological atypia within ligamentous or tendon tissue. Similar avulsion injuries and stress fractures can occur in active adolescents at other sites including the anterior superior iliac spine, the ischial apophysis, the trochanters of the femur and the proximal humeral shaft.

Tumour-like lesions of bone occur commonly in childhood and adolescence. They comprise a heterogeneous group of lesions that are thought to be developmental, posttraumatic or reactive in nature.

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Simple (unicameral) bone cyst This is a relatively benign, solitary cystic lesion which develops most often in the metaphysis of long bones.57 It occurs in children and adolescents; males are affected more commonly than females.116,117 Most lesions occur in long tubular bones, particularly the proximal humerus and proximal femur. Patients usually present with pain due to pathological fracture. Radiologically, the lesion lies in the metaphysis and extends into the diaphysis; it usually lies just below the growth plate and is well-defined, osteolytic and occasionally trabeculated. A fallen fragment sign may be seen if a piece of the fractured cortex lies in the distal part of the cyst. MRI shows a high signal on T2-weighted images. This is consistent with the high fluid content of the lesion. Histologically, the cyst wall is composed of cellular and collagenous fibrous tissue and may contain scattered haemosiderin deposits, macrophages and giant cells, as well as organised reactive bone if there has been an associated fracture (Fig. 27). Fibrinoid and cementum-like material may also be present. This lesion has a tendency to recur following treatment especially if it lies close to the growth plate. Aneurysmal bone cyst Aneurysmal bone cyst is an uncommon, benign, expansile, multicystic, lytic lesion of bone, which is characterised by the presence of numerous blood-filled spaces.57,117–119 Most aneurysmal bone cysts arise in children and adolescents. Seventy per cent of all patients are younger than 20 years of age. Any bone may be involved but most aneurysmal bone cysts arise in the vertebrae, long tubular bones and pelvis. In long bones, the lesion most commonly develops in the metaphysis and does not penetrate through the growth plate. Radiologically, the lesion is osteolytic and commonly results in eccentric expansion of the affected bone (Fig. 28). CT and MRI are useful in establishing the multicystic nature of the lesion and in identifying fluid within the cyst (Fig. 29).120 Histologically, the lesion contains numerous blood-filled spaces that are separated by cellular fibrous tissue, which contains osteoclast-like giant cells and macrophages (Fig. 30). Reactive osteoid and woven bone formation may be seen in fibrous septa separating the cystic spaces. The lesion has a well-defined margin with adjacent uninvolved bone. Secondary aneurysmal bone cyst change occurs in many tumours and tumour-like lesions (e.g., giant cell tumour, osteoblastoma). A solid variant of aneurysmal bone cyst is known to

Fibrous dysplasia Fibrous dysplasia is a relatively common benign fibroosseous lesion of bone which is composed of cellular fibrous tissue and irregular woven bone trabeculae.4,5,57,123 It accounts for approximately 8% of all bone tumours but its exact incidence is not known as many cases do not present clinically. It is not a true neoplasm of bone but most likely represents a developmental abnormality associated with a localised defect in ossification. Most cases involve only a single bone (monostotic). In 20% of cases the condition is polyostotic. An activating mutation of the GSa-subunit gene had been found to occur in the McCuneAlbright syndrome where polyostotic fibrous dysplasia is associated with precocious puberty and endocrine dysfunction.124 A similar molecular abnormality has been noted in other cases of polyostotic and some cases of monostotic fibrous dysplasia.125 The GSa-subunit stimulates the activity of adenyl cyclase and results in elevation of intracellular cyclic AMP. This results in over-expression of the FOS protein in mesenchymal precursor cells and interference with normal osteoblast differentiation. Monostotic fibrous dysplasia is most often diagnosed in the first three decades of life. Males and females are affected equally. Fibrous dysplasia may develop in any bone, including large tubular bones, bones of the jaw, skull and ribs. Patients may present with bone swelling or pain. Many cases of long bone fibrous dysplasia are asymptomatic and only found incidentally on radiographs. Radiologically, lesions of fibrous dysplasia are well-defined radiolucent lesions, which have a ground-glass appearance. There is often a sclerotic rim around the lesion which may exhibit patchy sclerosis. MRI studies may show low and high signal intensity on T1- and T2-weighted images, respectively (Fig. 31). Histologically, fibrous dysplasia is characterised by the finding of small irregular woven bone trabeculae, many of which have a characteristic fish-hook appearance. These bone trabeculae appear to arise directly by fibro-osseous metaplasia and are separated by abundant cellular or collagenous fibrous tissue (Fig. 32). The bone

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trabeculae are composed of woven bone with prominent cement lines and are not rimmed by osteoblasts. Foamy macrophages, osteoclast-like giant cells, islands of cartilage and areas of myxoid/cystic degeneration or aneurysmal bone cyst change may be seen; cystic change may be associated with rapid growth of the lesion. Sarcomatous transformation to osteosarcoma, fibrosarcoma or chondrosarcoma can occur in fibrous dysplasia but is rare and often associated with previous radiation therapy.126,127 Fibrous dysplasia enters into the differential diagnosis of many bone tumours, including benign and malignant bone-forming tumours, fibrous and fibrohistiocytic tumours and giant cell-containing lesions of bone. Fibrocartilaginous dysplasia Fibrocartilaginous dysplasia (fibrocartilaginous mesenchymoma) is a rare lesion that most often develops in young patients, particularly children and adolescents.57,128–130 It may represent a rare variant of fibrous dysplasia. It occurs most commonly in the metaphyseal region of long bones, especially the proximal femur, tibia and fibula. It is associated with the presence of fibrous dysplasia-like tissue as well as islands of cartilage which show a columnar, growth plate-like arrangement of cartilage cells. These islands may be small or large and are often surrounded by fibrous tissue (Fig. 33). They may undergo endochondral ossification with formation of trabecular bone. Myxoid change may be present in the fibrous stroma. This lesion needs to be distinguished from fibrous dysplasia and benign and malignant cartilage tumours and needs to be followed carefully as recurrence can occur and there are documented cases of aggressive behaviour. Osteofibrous dysplasia Osteofibrous dysplasia (ossifying fibroma) is a rare benign fibro-osseous lesion of bone. It presents most often in the first decade.131,132 It arises most commonly in the midshaft of the tibia, but less often may arise in the fibula or, very rarely, may affect both bones. Clinically, it presents with deformity, particularly anterior bowing of the tibia, or pathological fracture. Radiologically, the lesion is based on the cortex, which is expanded, and contains one or more lucent areas surrounded by sclerotic bone (Fig. 34). There is usually a lack of periosteal reaction. Lesions are hot on bone scan and MRI shows high signal intensity on T2-weighted images. Histologically, there is a fibrous dysplasia-like cellular fibrous stroma in which there are a variable number of bone trabeculae that frequently anastomose with each other and merge with surrounding thickened cortical bone. There is prominent osteoblastic rimming of bone trabeculae. Cytokeratin-positive cells may be found within the cellular fibrous tissue.133,134 Cartilage is not usually a component of this lesion. Osteofibrous dysplasia-like areas may be found in adamantinomas of long bones, particularly in the differentiated form of this tumour. In most cases, lesions regress or resolve in adolescence but progression to adamantinoma has been documented in a few cases. Various karyotypic abnormalities have been found but chromosome 19 abnormalities, noted in adamantinoma, have not been described. In contrast to fibrous

Pathology (2008), 40(2), February

dysplasia, there is no evidence of a mutation in the GSasubunit gene. Mesenchymal (vascular-cartilaginous) hamartoma of the chest wall This is a benign chondro-osseous lesion that involves the ribs. It presents at birth or soon after as a well-defined, lobulated, chest wall mass that may cause cardiac or respiratory symptoms.135,136 Radiologically, it is evident that the mass is intrathoracic but extrapleural; it is centred on one or more of the ribs, which are commonly destroyed, and may contain areas of calcification and evoke a periosteal reaction. Histologically, the lesion contains cystic spaces, cartilage and fibrous tissue as well as areas of spindle cell proliferation (Fig. 35). Cartilage within the lesion is hypercellular and shows growth plate-like organisation with formation of woven bone trabeculae. Woven bone is formed in areas of spindle cell proliferation. Cystic spaces resemble those seen in aneurysmal bone cyst. There may be prominent mitotic activity but no atypical mitotic figures are seen. The lesion is benign and may resolve spontaneously but surgical intervention may be required to relieve respiratory distress.

Langerhans cell histiocytosis Langerhans cell histiocytosis (LCH; histiocytosis X; eosinophilic granuloma) designates a group of conditions which are characterised by the presence of a mixed inflammatory cell infiltrate that contains numerous Langerhans cells.137–139 Langerhans cell proliferation in LCH may produce single or multiple lesions in the skeleton. Langerhans cells are antigen-presenting cells, which are found in skin, lymph nodes and other tissue. They are characterised ultrastructurally by the presence of intacytoplasmic inclusion bodies called Birbeck granules. Langerhans cells are positive for CD68, HLA-DR, S-100 and CD1a. It is not certain whether the proliferation of Langerhans cells in LCH represents a reactive or a neoplastic process, but X chromosome studies suggest that LCH lesions are clonal.140 LCH affects children and adolescents, occurring most often in the first decade of life. Multifocal LCH usually presents within the first 3 years of life. Patients may be asymptomatic or present with bone pain, local tenderness or pathological fracture. Solitary lesions (eosinophilic granuloma) occur most commonly and may arise in any bone. The skull, jaw, ribs, vertebral bodies and proximal long bones are most often affected. Up to 10% of patients with eosinophilic granuloma may present with fever and a peripheral blood eosinophilia. Radiologically, these lesions may show a variety of appearances from well-defined round or oval osteolytic lesions, often with no surrounding sclerosis, to large lytic lesions. A periosteal reaction may or may not be present. Lesions may be poorly defined and show permeative or moth eaten bone destruction, suggesting infection or malignancy. Histologically, the lesion contains a polymorphous inflammatory cell infiltrate including Langerhans cells, macrophages, giant cells, eosinophils, lymphocytes and plasma cells (Fig. 36). Langerhans cells may be scanty or numerous and are usually identified as large oval cells that have abundant cytoplasm and a

DIAGNOSIS OF PAEDIATRIC BONE TUMOURS AND LESIONS

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variably shaped indented or lobulated nucleus with a longitudinal groove. Electron microscopy shows the presence of Birbeck granules. The differential diagnosis of LCH is wide and includes osteomyelitis, granulomatous inflammatory disorders of bone, lymphoma and, often on account of the clinical and radiological features, round cell tumours of bone such as Ewing’s sarcoma. Bone lesions in eosinophilic granuloma tend to stabilise or regress spontaneously. Multifocal disease is more difficult to treat; the prognosis depends on the age of onset and the presence or absence of extraosseous involvement. In general, patients with generalised disease confined to bone have a good prognosis. Onset of disease in the first 2 years of life significantly worsens the prognosis. Multifocal bone involvement, similar to that seen in LCH can occur in a variety of conditions in the paediatric population. The most common conditions are listed in Table 8.

METASTATIC BONE DISEASE Metastatic bone disease is much rarer in children than in adults.141,142 Most tumours that metastasise to bone in children are small round cell tumours, notably neuroblastoma. Uncommonly, other tumours metastasising to bone may present as a primary bone tumour, such as Wilms’ tumour, rhabdomyosarcoma and retinoblastoma. Metastasis occurs by haematogenous spread, as bone does not contain lymphatics.103 Metastatic neuroblastoma in bone is derived from a primary tumour of the adrenal medulla or sympathetic chain.142 These tumours contain numerous small round cells and may produce an isolated skeletal metastasis that mimics a primary bone sarcoma. Neuroblastoma most commonly metastasises to the skull and to the metaphysis of long bones, particularly the humerus and femur. The tumour arises in young children, predominantly in patients 5 years or younger. Radiologically, metastatic neuroblastoma produces poorly defined moth-eaten or permeative areas of bone destruction; there may be areas of sclerosis and cortical destruction and there is often a prominent periosteal reaction. Histologically, the tumour consists of a solid proliferation of round cells with scanty cytoplasm and round or oat-shaped hyperchromatic nuclei (Fig. 37). Occasional rosette-like structures are seen. The tumour cells do not contain glycogen and express neural markers including neuron-specific enolase, synaptophysin and chromogranin. Catecholamine levels in blood and urine are increased. In general, bone involvement is a poor prognostic feature but some patients with stage 4 neuroblastoma, which have secondary disease confined to the bone

TABLE 8

Multiple paediatric bone lesions

Langerhans cell histiocytosis Fibrous dysplasia Enchondromatosis Angiomatosis Multiple non-ossifying fibromas Leukaemia/lymphoma Metastasis Osteomyelitis Hyperparathyroidism

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marrow and no radiological evidence of bone metastasis, are said to have a relatively favourable prognosis. NAA and MV would like to ACKNOWLEDGEMENTS thank EuroBoNeT (European Network to promote research into uncommon cancers in adults and children: pathology, biology and genetics of bone tumours) for help in writing this review. Address for correspondence: Professor N. A. Athanasou, Nuffield Department of Pathology, Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Oxford OX3 7LD, United Kingdom. E-mail: [email protected]

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