Abstract
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Bone tumours are frequent in children but most of them are benign. Moreover, the incidence and type of tumours differ from those of adults.
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As an orthopaedic surgeon, we will likely encounter a bone lesion in a child and we must be able to distinguish if it is a benign lesion or has malignant characteristics and it is necessary to refer it to a centre specialized in tumours.
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We will discuss the key points we would have to ask in the medical history, look at the physical examination and the radiological characteristics that will allow us to distinguish between a benign and a malignant bone lesion in a child.
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When there are doubts about the malignancy of a bone lesion or if the diagnosis is not clear, a biopsy should be performed following certain rules in a specialized centre.
Introduction
Bone tumours are more common in children than in adults, being the vast majority benign. So, it is common for an orthopaedic surgeon to face his professional career with bone lesions in children that may raise doubts about whether they are benign or malignant. For this reason, it is very important to know what are the main signs that help in the differential diagnosis (DD). The correct diagnosis can be provided in >80% of cases with careful consideration of the history of the patient and clinical and radiographic findings based on radiographs alone (1, 2, 3).
The majority of bone lesions in the extremities can be detected on radiographs at an early stage, but lesions of the spine and pelvis are only diagnosed after the destruction of a large volume of bone.
Another important issue of paediatric tumours is that the DD must always be made with osteomyelitis, a highly prevalent pathology at this age.
We are going to analyse the characteristics that allow us to distinguish a benign tumour from a malignant one and define in which cases a biopsy should be performed and by whom.
Medical history and physical examination
Medical history and physical examination are the pillar for diagnosis and must be as complete and exhaustive as possible.
One of the first steps is to know what the typical bone tumour distribution is, based on the radiographic findings and according to the age of the patients (3, 4). Most bone tumours are located in the metaphysis that is nearest to the principal growing physes – especially around the knee. And this is true for benign and malignant tumours (Fig. 1). Furthermore, some tumours are almost exclusive to children, like metastatic neuroblastoma, and others are most exclusive to adults like chondrosarcoma.
Diagram representing the most common bone lesions in childhood according to their location within the bone.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
Tumours can present as an incidental finding, pathological fracture, asymptomatic lump, or with pain.
Some benign tumours such as fibrous cortical defects present as an incidental finding when an X-ray is performed, for example, due to a trauma. Normally these asymptomatic lesions are benign but we have to be sure that the radiological characteristics also confirm this benignity.
Bone tumours can weaken the bone and can present as a pathological fracture described as a sudden severe pain in a bone that had not shown symptoms or, on the contrary, has been sore for a few months and breaks with an inadequate trauma. Although a pathological fracture through a bone tumour in a child is more likely to be due to a benign tumour, the radiological findings of the underlying lesion must be carefully assessed to determine if there are any signs of aggressivity (5).
Sometimes there is a lump that can be painful or not. It is important to know the duration and rapidity of growth of the mass. A rapidly growing mass in a few months is a suspicious sign of malignancy (6).
When the main complaint is pain, it is very important to characterize it. Pain that worsens at night has been described as typical of malignancy, but this is not a constant finding. If with time the pain becomes constant without relief and gets worse with activity, especially during the night time, it is very suggestive of malignancy (6).
Pelvic and spine tumours can grow to a large volume before being detected. They usually present with pain and it is also difficult just by clinical examination to distinguish whether it is a benign or malignant tumour. In general, if the pain is focal, occurs at night, wakes the child from sleep, increases in intensity over time, and is unrelated temporally to activity, malignancy should be suspected. A warning sign for locally aggressive or malignant tumours is a very rapid increase in the intensity of pain over a short period or any pain of severe intensity (7). Pelvic and spine tumours can present with neurological deficits as a main complaint, and again this type of presentation is not indicative of benignity or malignancy (7, 8).
The DD with an infection is mandatory in children, as this is far more common than sarcoma in all paediatric ages (9). Trauma is also very common in paediatric ages, so previous traumatic events namely penetrating, closed, repetitive, or minor trauma should be excluded.
The presence of constitutional signs and symptoms are considered red flag signs, namely fever, cold chills, night sweats, malaise, anorexia, fatigue, and weight loss.
Past personal history of malignancy must be investigated, for example, osteosarcoma has been related to prior retinoblastoma. The history of some specific predisposing genetic conditions must also be ruled out like Maffucci’s syndrome, neurofibromatosis, Li–Fraumeni syndrome, Rothmund–Thompson syndrome, and Bloom and Werner syndromes (10).
A detailed physical examination is imperative during the workup of a paediatric patient with a suspected bone lesion. It must include a general review, a review of all organs and systems, and a complete neurovascular exam. The local exam should be focused on the inspection and palpation of the area of tenderness in the vicinity of the lesion and range of motion deficits are important to note. If a mass is present, its size, consistency, limits, position, and mobility must be assessed. Any mass that is over 5 cm is a red flag sign.
A gait abnormality may be appreciated, which may be a sign of the mass abutting neurovascular structures or impeding joint range of motion. Neurovascular involvement can be seen in cases when osteochondromas place pressure on a nerve as well as when more aggressive malignancies encompass these structures.
If a pelvic or spine tumour is suspected, a thorough physical examination must be carried out including observation of the child’s gait, skin changes, and deformities. Scoliosis or kyphosis frequently develop in children with spine tumours in response to pain, very typical in osteoid osteoma and osteoblastoma, or asymmetric vertebral destruction. The pattern of scoliosis is also important because left thoracic curves are unusual in patients with idiopathic scoliosis. Any child with left thoracic scoliosis should be carefully evaluated and should undergo MRI to assess for spinal cord pathology.
In children, making a DD with an infection is mandatory, as this is far more common than sarcoma (9). For this reason, we will often request an analysis with acute infection parameters such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), although these parameters will not always be altered in osteomyelitis, mainly in subacute ones.
Image studies
Image studies are very important to get the diagnosis. Simple radiography remains the mainstay for the initial diagnosis and it should always be the first exam to be asked by any general physician or orthopaedist. Other advanced imaging modalities, such as MRI, CT scans, bone scintigraphy and PET can be useful especially if malignancy is suspected to evaluate the extent of the lesion and its local and distant staging.
X-rays
Conventional radiographs are still the first and the most valuable image technique to study a bone tumour (11, 12, 13). It is accessible in every hospital and it is a relatively inexpensive technique. Orthogonal radiographs of the local area should be completed for all lesions. Although the radiologist’s report can help us to interpret them, all orthopaedic surgeons should have the basic knowledge to be able to discern a concerning lesion from a benign one.
In general, benign lesions have well-delineated borders, sclerotic edges, do not break the cortex and do not have soft tissue mass (Fig. 2). On the contrary, malignant lesions have undefined borders, a speckled pattern within the lesion, may break the cortex, may have soft tissue mass and usually have periosteal reactions reflecting the rapid growth of these lesions (Fig. 3).
Radiograph of a benign bone lesion where it can be seen that it has well-defined borders, with sclerotic edges, does not break the cortex and does not associate with a soft tissue mass. The lesion corresponds to a non-ossifying fibroma.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
Radiograph of a malignant bone lesion where it can be seen that it has undefined borders, a speckled pattern within the lesion, breaks the cortex, has soft tissue mass, and has periosteal reaction, reflecting the rapid growth of the lesion. The lesion corresponds to an osteosarcoma.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
Enneking described four essential questions to be asked when suspicion of a bone tumour is raised in a plain radiograph (14).
Where is the lesion?
It is important to know the bone segment where the lesion is located and in which part of the bone. For example, a tumour located in the epiphysis in a child can be, most likely, a chondroblastoma (Fig. 4). By contrast, osteosarcoma, one of the most frequent malignant bone tumours in children, is usually located in the metaphysis of the long bones (Fig. 5).
CT image showing an osteolytic lesion in the proximal epiphysis of the tibia that corresponds to a chondroblastoma.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
Radiograph showing an osteoblastic lesion in the proximal metaphysis of the tibia that corresponds to an osteosarcoma.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
What is the lesion doing to the bone?
The majority of the bone tumours are osteolytic, but they can also be osteoblastic. The osteolysis in a bone tumour is performed by osteoclasts which are activated via the RANK ligand pathway (11).
Lodwick described three patterns of bone destruction that help us to identify the aggressiveness of the bone lesion (2, 15).
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Type 1 Geographic bone destruction with three variants:
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– 1A When a lesion has borders well defined with sclerotic margins corresponding to the least aggressive lesions such as fibrous cortical defect and non-ossifying fibroma (Fig. 6A).
Figure 6 Patterns of bone destruction described by Lodwick. Type I Geographic. (A) Type IA, radiograph of a non-ossifying fibroma with well-defined borders and sclerotic margins. (B) Type 1B, radiograph of an aneurysmal bone cyst with well-defined borders without sclerotic margins but with a narrow zone of transition between the lesion and the normal bone. (C) Type 1C, radiograph of an osteosarcoma with ill-defined and indistinct margins and a wide zone of transition, corresponding to aggressive bone tumours.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
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– 1B When a lesion has well-defined borders without sclerotic margins but a narrow zone of transition between the lesion and the normal bone such as aneurysmal bone cyst (Fig. 6B).
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– 1C Includes lesions with ill-defined and indistinct margins, with a wide zone of transition, corresponding to aggressive bone tumours, most of them malignant, such as small/early osteosarcoma (Fig. 6C).
Type I patterns imply benign or less aggressive lesions.
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Type II Moth-eaten appearance: when a lesion has areas of bone destruction with ragged edges. This is indicative of a malignant process rapidly expanding into the bone. Ewing’s sarcoma commonly has this pattern of bone destruction (Fig. 7).
Figure 7 Type II moth-eaten appearance pattern of bone destruction in the Lodwick grading system. Radiograph of an osteosarcoma with areas of bone destruction with ragged edges. This is indicative of a malignant process rapidly expanding into the bone.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
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Type III Permeative appearance: when the tumour moves through the bone without destroying all the trabeculae with a zone of transition between pathological and normal bone. This pattern is typical of lymphoma and leukaemia (Fig. 8).
Figure 8 Type III permeative pattern of bone destruction in the Lodwick grading system. Radiograph of an osteosarcoma without a zone of transition between pathological and normal bone corresponding to the tumour moving through the bone without destroying all the trabeculae.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
In 2016, Caracciolo et al. described the modified Lodwick–Madewell grading system to classify osteolytic bone tumours based on their risk of malignancy into low risk, moderate risk, and high risk; they expanded the original system and added two more patterns, changing margination and radiographically occult, and reclassified into three grades: grade I refers to grades IA and IB in the Lodwick system; grade II refers to grade IC in the Lodwick system, and grade III is subdivided into grade IIIA (changing margination), grade IIIB (moth-eaten and permeative), and grade IIIC (radiographically occult). This system correlates the grade of the tumour with its biological activity and risk of malignancy: grade I tumours are usually benign (low risk), grade II tumours are associated with a moderate risk of malignancy, and grade III tumours are associated with a high risk of malignancy (16) (Fig. 9).
The modified Lodwick–Madewell classification described by Caracciolo based on their risk of malignancy.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
What is the bone doing?
The response of the bone depends on the tumour histology and grade and the rapidity of its growth.
A benign lesion growing slowly may cause a white halo around the lesion representing new bone formed. Some lesions, such as osteoid osteoma, may cause a solid thickening of the bone around them.
Malignant lesions with fast growth do not let the periosteum produce bone to contain them producing different patterns of periosteal reactions. Layers that form parallel to the long axis of the bone describe an ‘onionskin’ periosteal reaction. Bony spicules that form perpendicular to the cortex are found in a ‘sunburst’ or ‘hair-on-end’ periosteal reaction. The periosteal reaction at the interface between the bone and tumour extending into adjacent soft tissue is termed the ‘Codman triangle’ and all are characteristic of malignant bone lesions like osteosarcoma (15, 17) (Fig. 10).
Different periosteal reactions. (A) Radiograph of an osteoid osteoma with a solid thickening of the bone around the lesion. It represents a slow growth. (B) Radiograph of an Ewing sarcoma with a sunburst or hair-on-end periosteal reaction representing bony spicules that form perpendicular to the cortex characteristic of malignant bone lesions with fast growth. (C) Radiograph of an osteosarcoma with a Codman triangle representing the periosteal reaction at the interface between the bone and tumour extending into adjacent soft tissue, characteristic, also, of malignant bone lesions with fast growth.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
What is in the lesion?
The content of the lesion can give us a clue to the histological diagnosis. An osseous matrix appears white and a chondroid matrix may have an appearance of ‘rings and arcs’.
Summing up, the radiographic warning signs for a suspect malignant lesion are diffuse changes of bone, ill-defined limits, rupture of the cortex, periosteal reaction, and a soft tissue invasion in conjunction with a painful tumour mass.
The principal limitation of conventional radiography is when the lesion is located in complex anatomical locations like iliac bones and the spine, especially in posterior elements of vertebrae, where the overlapping of structures on 2D planes limits the evaluation (11, 15). Another important limitation is the evaluation of soft tissue invasion and the precise extent of medullary involvement (11, 15).
Computed tomography
CT is the imaging study of choice when we want to study the bone, permitting better visualization of minor bony changes, small calcifications, tumour mineralization, cortical changes, and periosteal reactions (12, 17, 18, 19). It also allows precise anatomical delineation and evaluation of the lesions in complex anatomical locations, where radiographs are not sufficient due to limited contrast resolution (12, 17, 18). The clear disadvantage, especially in young children, is the dose of radiation that it implies.
CT can further be very useful, especially when a 3D evaluation is needed, providing images in all planes that are very useful in planning surgery (Fig. 11) and is commonly used to guide biopsies (11, 12, 18, 19).
3D CT scan reconstruction images of a forearm with multiple osteochondromas for pre-surgery planning.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
Magnetic resonance imaging
MRI is much more sensitive than conventional radiographs. Lytic bone lesions can be seen on plain radiographs only when there is more than 30–50% loss of mineralization (18, 19). If a patient continues to have symptoms and radiographs do not show any abnormality, MRI is the preferred modality to assess bone marrow (17, 18, 19). Nevertheless, MRI should always be interpreted with concurrent radiographs.
MRI is very useful when assessing the characteristics within the lesion and the presence of soft tissue mass that can orient to malignancy is considered the gold standard modality for local assessment and staging of a malignant bone tumour (11, 12, 15, 17, 18, 19, 20) (Fig. 12). It is recommended that it should be performed in a specialist institution with a radiologist with experience in malignant bone tumours and preferably where it is going to be treated.
MRI images of a tibial osteosarcoma. (A) STIR (short tau inversion recovery) and (B) T1-weighted scan with intravenous contrast combined with a fat-suppressed sequence that permits better delineation enhancement of the tumour.
Citation: EFORT Open Reviews 9, 5; 10.1530/EOR-24-0031
Bone scintigraphy
The technetium-99m bone scan is highly sensitive but with a low specificity as it only measures the osteoblast activity. Lesions with minimal osteoblastic activity can be missed, but usually a technetium bone scan is very useful in detecting active lesions (11, 17, 18, 19, 20).
Positron emission tomography
FDG uptake alone is not appropriate to characterize primary bone tumours (15). It helps stage the morphologic and metabolic analysis of the lesion, but its role is most important in monitoring the treatment response and especially in determining the presence of recurrence.
Differential diagnosis with infections
DD should always be made with bone infections because the radiological appearance can be very similar and in children, we will not always find analytical alterations in infections (9). Furthermore, in some tumours such as Ewing’s sarcoma, there may be analytical alterations that resemble an infectious process.
In acute osteomyelitis, pain is usually present and laboratory findings show an acute inflammatory reaction. Initial radiography is normal but changes in bone marrow signal can be seen on MRI.
Sub-acute osteomyelitis creates more DD problems with a tumour, usually benign. The DD is difficult since the symptoms will be the same, pain, and the analytical alterations typical of an infectious process are usually absent. In the X-ray, an osteolytic lesion can be seen, which may or may not be surrounded by reactive bony edges (Brodie abscess). This is usually found in the metaphysis and may extend to the epiphysis along the physeal cartilage. The main DDs are eosinophilic granuloma and osteoid osteoma.
It can also present as a diaphyseal lesion with a plurilamellar periosteal reaction, requiring DD with Ewing’s sarcoma.
In the case of epiphyseal lesions, the DD must be done with chondroblastoma. Radiographically, it is not easy to make the DD either, since both pathologies present as an osteolytic lesion with well-defined borders of epiphyseal location. No significant differences are seen in MRI signal characteristics on T2-weighted and T1-weighted imaging. The only clues to make the DD would be peripheral location, T1-weighted hypointense rim, and substantial marrow oedema on MRI that might favour a diagnosis of chondroblastoma over osteomyelitis (21).
Chronic osteomyelitis can mimic a malignant bone tumour-like osteosarcoma or Ewing’s sarcoma. Making the DD between osteomyelitis and Ewing’s sarcoma is especially difficult even in specialized centres. A biopsy is usually necessary to reach a diagnosis (22).
MRI helps in making the DD and several signs have been described, such as the penumbra sign to diagnose a Brodie abscess, which according to some studies appears to be very specific (99%). However, the sensitivity varies from 27% to 75% according to studies (22). The penumbra sign described on T1-weighted sequences represents the internal ring which has a relatively high-density signal compared to the other layers of the target. Histologically, this represents the granulation tissue surrounding all abscess cavities and appears to be due to the presence of paramagnetic free radicals produced by activated macrophages (23).
Biopsy
Sometimes it is easy to distinguish a benign lesion from a malignant one, for example when a unicameral bone cyst, a non-ossifying fibroma, a fibrous cortical defect, an enchondroma, an osteochondroma, an osteoid osteoma present the typical radiological characteristics of these lesions (24).
Other lesions are more difficult to diagnose only with image studies because their characteristics are less typical, like an osteoblastoma, histiocytosis or an aneurismal bone cyst that can be confused with telangiectatic osteosarcoma. In these cases or whenever there are doubts, a biopsy may be necessary.
The biopsy is the last step in the diagnosis and it should be always performed after the MRI. The biopsy must always be performed under the direction of the surgeon to perform the surgical treatment (11, 13, 24). It is a fact that biopsies performed in a non-specialist centre can lead to diagnostic errors, can cause a change in the treatment plan, increase local recurrence, and may also result in unnecessary amputation mainly when the lesion is malignant (11, 24).
There should be absolute respect for the oncologic biopsy technique, following Mankins’s guidelines recommendations: guarantee an aseptic environment, biopsy tracts should be clearly marked and in line with incision for definitive tumour resection, only through one anatomic compartment and away from neurovascular bundle and growth cartilage.
Biopsy techniques may be percutaneous, incisional, or excisional. Excisional biopsy is reserved only for small lesions with very low malignant potential.
The surgical biopsies were classically considered the gold standard. However, with recent literature, the core-needle biopsy demonstrated a high diagnostic accuracy with lower risks of complications than surgical biopsies, namely in bleeding, neuropraxia, and infection (25). Nowadays, percutaneous biopsy is the usual technique employed. It can be performed with a needle or with a mini-incisional approach with a trephine or bone trocar. Be sure to have sufficient material, which is well conditioned, and guarantee the rapid transport with proper and complete information with it. The biopsy must be discussed by the interventional radiologist, the tumour surgeon, and the histopathologist to plan the site, the entry point, direction, and the target of the needle biopsy to obtain a representative tissue that allows the diagnosis. It must be taken into account that if the result is a malignant tumour the biopsy tract requires excision at the time of surgery (11, 24, 26). A percutaneous biopsy can be carried out accurately using ultrasound, CT, or MRI guidance. In a specialist centre, a 98% diagnostic accuracy has been described (11, 26).
When more pathological tissue is needed, or the radiologist cannot safely access the lesion, an incisional biopsy can be performed. The surgeon should plan the biopsy at the planned site of definitive treatment to avoid seeding a separate biopsy tract. The surgeon should maintain hemostasis to prevent a hematoma from contaminating the surgical bed, remain unicompartmental, only use longitudinal incisions, place any drains through or in line with the incision, and avoid exposing neurovascular structures (11).
It is always mandatory to take samples for microbiological culture. If the pathologist is not sure about the diagnosis, considering an open biopsy or even requesting a second opinion is always recommended.
If the lesion turns out to be malignant, the tumour should be classified with the Enneking Classification, regarding the location, histologic grade, and the presence of metastasis. Bone tumours are classified as Enneking stage I or II for a low and high grade; A or B for intra or extra-compartmental; and III for metastatic disease. This staging will define the proper surgical margins needed for the resection.
Conclusion
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A detailed clinic history and physical examination with a simple radiography can lead us to the diagnosis of a benign or malignant bone lesion in most cases.
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In the simple radiograph, benign bone lesions usually have well-defined borders, they do not break the cortex nor are they associated with a soft tissue mass. On the contrary, malignant bone lesions usually have ill-defined borders, break the cortex, and associate soft tissue mass.
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Some benign bone lesions have special characteristics in radiological studies that lead us to the diagnosis without the necessity of a biopsy.
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If malignancy is suspected, the patient should be referred to a specialized centre to undergo a biopsy that has to be planned according to oncological principles.
ICMJE Conflict of Interest Statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this instructional lecture.
Funding Statement
This instructional lecture did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
References
- 1↑
Errani C, Tsukamoto S, & Mavrogenis AF. Imaging analyses of bone tumors. JBJS Reviews 2020 8 e0077. (https://doi.org/10.2106/JBJS.RVW.19.00077)
- 2↑
Lodwick GS, Wilson AJ, Farrell C, Virtama P, & Dittrich F. Determin ing growth rates of focal lesions of bone from radiographs. Radiology 1980 134 577–583. (https://doi.org/10.1148/radiology.134.3.6928321)
- 3↑
Nomikos GC, Murphey MD, Kransdorf MJ, Bancroft LW, & Peterson JJ. Primary bone tumors of the lower extremities. Radiologic Clinics of North America 2002 40 971–990. (https://doi.org/10.1016/s0033-8389(0200038-6)
- 4↑
Longhi A, Errani C, De Paolis M, Mercuri M, & Bacci G. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treatment Reviews 2006 32 423–436. (https://doi.org/10.1016/j.ctrv.2006.05.005)
- 5↑
Chaib B, Malhotra K, Khoo M, & Saifuddin A. Pathological fracture in paediatric bone tumours and tumour-like lesions: a predictor of benign lesions? British Journal of Radiology 2021 94 20201341. (https://doi.org/10.1259/bjr.20201341)
- 6↑
Widhe B, & Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. Journal of Bone and Joint Surgery 2000 82 667–674. (https://doi.org/10.2106/00004623-200005000-00007)
- 7↑
Garg S, & Dormans JP. Tumors and tumor-like conditions of the spine in children. Journal of the American Academy of Orthopaedic Surgeons 2005 13 372–381. (https://doi.org/10.5435/00124635-200510000-00002)
- 8↑
Kadhim M, Oyoun NA, Womer RB, & Dormans JP. Clinical and radiographic presentation of pelvic sarcoma in children. SICOT-J 2018 4 44. (https://doi.org/10.1051/sicotj/2018040)
- 9↑
McCarville MB. The child with bone pain: malignancies and mimickers. Cancer Imaging 2009 9 S115–S121. (https://doi.org/10.1102/1470-7330.2009.9043)
- 10↑
Hameed M, & Mandelker D. Tumor syndromes predisposing to osteosarcoma. Advances in Anatomic Pathology 2018 25 217–222. (https://doi.org/10.1097/PAP.0000000000000190)
- 11↑
Plant J, & Cannon S. Diagnostic work up and recognition of primary bone tumours: a review. EFORT Open Reviews 2016 1 247–253. (https://doi.org/10.1302/2058-5241.1.000035)
- 12↑
Redondo A, Bagué S, Bernabeu D, Ortiz-Cruz E, Valverde C, Alvarez R, Martinez-Trufero J, Lopez-Martin JA, Correa R, Cruz J, et al.Malignant bone tumors (other than Ewing's): clinical practice guidelines for diagnosis, treatment and follow-up by Spanish Group for Research on Sarcomas (GEIS). Cancer Chemotherapy and Pharmacology 2017 80 1113–1131. (https://doi.org/10.1007/s00280-017-3436-0)
- 13↑
Salom M, Chiari C, Alessandri JMG, Willegger M, Windhager R, & Sanpera I. Diagnosis and staging of malignant bone tumours in children: what is due and what is new? Journal of Children’s Orthopaedics 2021 15 312–321. (https://doi.org/10.1302/1863-2548.15.210107)
- 15↑
Costelloe CM, Chuang HH, Chasen BA, Pan T, Fox PS, Bassett RL, & Madewell JE. Bone windows for distinguishing malignant from benign primary bone tumours on FDG PET/CT. Journal of Cancer 2013 4 5 24–530.
- 16↑
Caracciolo JT, Temple HT, Letson GD, & Kransdorf MJ. A modified Lodwick-Madewell grading system for the evaluation of lytic bone lesions. AJR. American Journal of Roentgenology 2016 207 150–156. (https://doi.org/10.2214/AJR.15.14368)
- 17↑
Heck RK Jr, Peabody TD, & Simon MA. Staging of primary malignancies of bone. CA: A Cancer Journal for Clinicians 2006 56 366–375. (https://doi.org/10.3322/canjclin.56.6.366)
- 18↑
Goyal N, Kalra M, Soni A, Baweja P, & Ghonghe NP. Multi-modality imaging approach to bone tumors - State-of-the art. Journal of Clinical Orthopaedics and Trauma 2019 10 687–701. (https://doi.org/10.1016/j.jcot.2019.05.022)
- 19↑
Stacy GS, Mahal RS, & Peabody TD. Staging of bone tumors: a review with illustrative examples. American Journal of Roentgenology 2006 186 967–976. (https://doi.org/10.2214/AJR.05.0654)
- 20↑
Steffner RJ, & Jang ES. Staging of bone and soft-tissue sarcomas. Journal of the American Academy of Orthopaedic Surgeons 2018 26 e269–e278. (https://doi.org/10.5435/JAAOS-D-17-00055)
- 21↑
El-Ali AM, Coblentz A, & Degnan AJ. Solitary long-bone epiphyseal lesions in children: radiologic-pathological correlation and epidemiology. Pediatric Radiology 2020 50 1724–1734. (https://doi.org/10.1007/s00247-020-04752-8)
- 22↑
McCarville MB, Chen JY, Coleman JL, Li Y, Li X, Adderson EE, Neel MD, Gold RE, & Kaufman RA. Distinguishing osteomyelitis from Ewing sarcoma on radiography and MRI. AJR. American Journal of Roentgenology 2015 205 640–650. (https://doi.org/10.2214/AJR.15.14341)
- 23↑
Moser T, Ehlinger M, Chelli Bouaziz M, Fethi Ladeb M, Durckel J, & Dosch JC. Pitfalls in osteoarticular imaging: how to distinguish bone infection from tumour? Diagnostic and Interventional Imaging 2012 93 351–359. (https://doi.org/10.1016/j.diii.2012.01.021)
- 24↑
Blank AT, Otsuka NY, & Rapp TB. Evaluation and management of pediatric bone lesions. Bulletin of the Hospital for Joint Diseases 2018 76 62–70.
- 25↑
Errani C, Traina F, Perna F, Calamelli C, & Faldini C. Current concepts in the biopsy of musculoskeletal tumors. TheScientificWorldJournal 2013 2013 Article ID 538152. (https://doi.org/10.1155/2013/538152)
- 26↑
Traina F, Errani C, Toscano A, Pungetti C, Fabbri D, Mazzotti A, Donati D, & Faldini C. Current concepts in the biopsy of musculoskeletal tumors: AAOS exhibit selection. Journal of Bone and Joint Surgery 2015 97 e7. (https://doi.org/10.2106/JBJS.N.00661)
