Radiologic approach to pediatric lytic bone lesions

Radiologic approach to pediatric lytic bone lesions Poster No.: C-1177 Congress: ECR 2016 Type: Educational Exhibit Authors: J. L. LERMA GALLARDO, I. de la Pedraja, A. Lancharro 1 1 1 2 1 1 Zapata, J. C. Monte Gonzalez, D. Llanos ; MADRID/ES, 2 Guadalajara/ES Keywords: Neoplasia, Infection, Education, MR, Digital radiography, CT, Paediatric, Musculoskeletal system, Bones DOI: 10.1594/ecr2016/C-1177 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 78

Learning objectives To review the differential diagnosis of the most common lytic bone lesions in children and its radiologic features and management. Page 2 of 78

Background Lytic bone lesions are a matter of concern in children as they can be malignant. Radiograph is the first and most important modality of imaging of bone lesions. However, bone lesions often do require additional imaging (CT, MRI). The differential diagnosis can often be limited by the radiographic appearance (aggressive or nonaggressive), age, location of the lesion and number of lesions [1]. Lytic bone lesions can be classified as "aggressive" or "nonaggressive" according to their plain film appearance. Nonaggressive lesions show well defined margins with a narrow zone of transition, particularly with sclerosis, and benign periosteal reaction (solid or unilamellated). Aggressive lesions show poorly defined margins with a wide zone of transition, "moth-eaten" or permeative bone destruction and aggressive periosteal reaction (multilamellated or "onionskin", spiculated or "hair-on-end", sunburst pattern and Codman triangle) [1, 2, 3]. The zone of transition is usually easier to characterize than the periostitis, and it is always present to evaluate (many lesions have no periostitis), therefore, zone of transition is the most important x-ray film indicator for aggressive vs. nonaggressive lesions [2]. An aggressive lesion may have a well-defined margin on MRI; as a result, the zone of transition is only of value on conventional radiograph [1, 2]. Page 3 of 78

Fig. 1: Diagram illustrates nonaggressive radiograph appearance: (A) well defined lytic lesion with sclerotic margin and (B) well defined lytic lesion without sclerotic margin and aggressive radiograph appearance: (C) ill-defined lytic lesion (D) motheaten lytic lesion and (E) permeative lytic lesion. Adapted from Miller TT. Bone tumors and tumorlike conditions: analysis with conventional radiography Radiology. 2008 Mar;246(3):662-74. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 4 of 78

Images for this section: Fig. 1: Diagram illustrates nonaggressive radiograph appearance: (A) well defined lytic lesion with sclerotic margin and (B) well defined lytic lesion without sclerotic margin and aggressive radiograph appearance: (C) ill-defined lytic lesion (D) moth-eaten lytic lesion and (E) permeative lytic lesion. Adapted from Miller TT. Bone tumors and tumorlike conditions: analysis with conventional radiography Radiology. 2008 Mar;246(3):662-74. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 5 of 78

Findings and procedure details The initial differential diagnosis of a nonaggressive lesion in a child depends on its age. In infants, toddlers and young children, most of these lesions are Langerhans cell histiocytosis (LCH). In older children (>10 years) the differential is wider, including fibrous dysplasia, fibrous cortical defect / nonossifying fibroma, simple bone cyst, aneurismal bone cyst, enchondroma and LCH [1, 4]. Aggressive lesions in infants and toddlers (< 5 years) include osteomyelitis, LCH and metastatic neuroblastoma. In older children, osteosarcoma, Ewing sarcoma, bone involvement by leukemia/lymphoma, osteomyelitis and LCH should be considered [1, 4]. Knowing the location of the lesion and the number of lesions (unifocal or multifocal) will narrow even more the differential diagnosis [1-4]. Aggressive radiograph appearance suggests a malignant process, while a nonaggressive appearance suggest a benign one, but this is not always true. There are bone lesions such as osteomyelitis and LCH which are benign lesions and can have aggressive appearance [2, 3]. Page 6 of 78

Fig. 2: Differential diagnosis of pediatric lytic bone lesions. *Osteomyelitis is preponderantly a disease of infants and young children; more than 50% of the cases occur before 5 years of age. **Most patients of LCH are younger than 15 years at presentation, with a peak incidence between 1 and 5 years of age. Focal lesions are found in slightly older children aged 10 to 12 years. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES NONAGGRESSIVE LESIONS Fibrous dysplasia Fibrous dysplasia (FD) is a benign congenital non-inherited process (fibro-osseous tissue replaces the normal medullary space) that can look like almost any pathologic process radiographically [1, 2]. FD can be monostotic (70-80%) or polyostotic and it is more common in girls. Monostic disease is more frequent in adolescents or young adults. Polyostotic disease is often seen in patients younger than 10 years old [1]. Page 7 of 78

FD can affect any bone. Skull base, pelvis, proximal femur and ribs are the most common localizations. When it is present in the pelvis, it is invariably present in the ipsilateral proximal femur. Lesions involve metaphysis and diaphysis, while spare epiphysis before physeal fusion [1, 2]. The condition is often an incidental finding and is usually painless. Patients may have pain, edema, deformity or pathologic fracture [1, 2]. In McCune-Albright syndrome, unilateral polyostotic FD occurs in association with cafe au lait spots on the skin and precocious puberty [1, 2]. Imaging The radiograph appearance varies from appearing lytic (usually with sclerotic margin and small cartilaginous calcifications) to having a ground glass matrix. Early lesions tend to be radiolucent, while older ones, as the matrix calcifies, may be more sclerotic. FD in the long bones causes expansion of the medullary cavity and endosteal scalloping. Bowing of the bone is also seen. No periosteal reaction is present unless there is a fracture [1, 2, 5]. Similar findings are evident with CT. The MRI characteristics of fibrous dysplasia are variable depending on the composition of the lesion, showing signal intensity that is isointense to the muscle on T1-weighted imaging and intermediate to high (more frequent) on T2. Lesion shows heterogeneous enhancement after administration of gadolinium [1, 5]. Page 8 of 78

Fig. 3: Fibrous dysplasia in an 11-year-old patient. Radiograph shows a lesion in the supracetabular portion of the ilium and ipsilateral proximal femur (arrows) with welldefined sclerotic margins and ground-glass matrix. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 9 of 78

Fig. 4: Fibrous dysplasia in the same patient of figure 3. T1-weighted (A and C) and T2-weighted fat-saturated (B and D) coronal views demonstrate well-defined lesions in the supracetabular portion of the ilium and ipsilateral proximal femur. Both are isointense to the muscle on T1 and slightly hyperintense on T2. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 10 of 78

Fig. 5: Fibrous dysplasia in an 18-year-old patient. A) Radiograph demonstrates a lytic expansile lesion with ground-glass matrix and cortical thinning in the posterior portion of the 9th left rib. B) CT shows the same findings of the radiograph. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 11 of 78

Fig. 6: Polyostotic fibrous dysplasia in a 19-year-old patient. Mixed lytic-sclerotic lesions involve the pelvis as well as the proximal femurs with severe deformity of pelvis and Shepherd's crook deformity and fractures of both proximal femurs. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 12 of 78

Fig. 7: Fibrous dysplasia in an 11-year-old patient. A and B) Axial TC shows right craniofacial bones expanded with an intact cortex and lose of the normal corticomedullary differentiation, replaced by a homogeneous ground glass appearance. There is compression of the right maxillary sinus and extrinsic compression of the right orbit resulting in a slightly exophthalmos. D) 3D volume reconstruction which shows bone involvement of fibrous dysplasia in grey colour. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Management Imaging findings are diagnostic. Surgical treatment of fibrous dysplasia is indicated in the prevention or treatment of fractures or major deformity [1]. Fibrous cortical defect / Nonossifying fibroma Fibrous cortical defects (FCD) or nonossifying fibromas (NOF), also known as fibroxanthomas, are probably the most common bone lesion encountered by radiologists. Lesions smaller than 2 cm in length are FCD and lesions larger than 2 cm are called NOF [1, 2, 4]. They are seen in 40% of children during development in patients who are less than 20 years old. These lesions usually spontaneously regress with skeletal maturation. It is very rare seen it after 30 years old [1, 2, 4]. Most common localization is in the cortex of metaphysis of a long bone of the lower extremity, especially at the knee (distal femur, proximal tibia). They are more likely to involve the posterior or medial cortex. Single or multiple lesions can be seen (multiple lesions may be associated with neurofibromatosis) [1, 7]. Page 13 of 78

FCD and NOF are asymptomatic lesions, usually detected incidentally [1, 2]. NOFs are not commonly associated with pathological fractures; however, when they occur, it is usually in larger NOFs (> 50% of the transverse diameter of the bone or if it measured > 33 mm in length) and almost always in the lower extremity [6]. Imaging On radiography, FCDs are seen as small, well-defined, ovoid lesions. NOFs appear to be similar but are larger, more lobular, and multilocular with a characteristic "soap bubble" appearance. They classically have a thin, sclerotic border that is scalloped and expansile. Over time the lesions become more sclerotic and eventually resolve [1, 2, 4]. Radiographic appearance is similar on CT. If a CT is obtained, there will often appear to be interruption of the cortex, which can be misinterpreted as cortical destruction [1, 2]. On MRI, low signal is seen on T1, and T2 signal and enhancement with gadolinium depends on the stage of lesion development. Early lesions are high signal on T2-weighted imaging, and they may enhance. Involuting lesions are low signal on T2 and do not enhance [1]. Page 14 of 78

Fig. 9: FCD evolution in an 11-year-old patient. A) Radiograph demonstrates a nonaggressive lytic lesion with well-defined sclerotic margins and narrow zone of transition in the medial aspect of the proximal tibia metaphysis (arrows). B and C) Radiographs obtained 1 and 2 years later, respectively, show that the lesion becomes more sclerotic and almost resolve. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Fig. 10: FCD in a 15-year-old patient. A) Radiograph shows a lytic lesion with welldefined, sclerotic and expansile margins in the posterior cortex of the proximal fibula metaphysis (arrows). CT axial (B) and sagittal (C) view demonstrate the same finding. A) T1-weighted coronal view (D) and T2-weighted fat-saturated coronal view show a hypointense lesion in the same localization as described in the radiograph. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 16 of 78

Fig. 11: NOF in an 11-year-old patient. A and B) Radiographs show a large nonaggressive lytic-sclerotic lesion with well-defined sclerotic margins and narrow zone of transition in the posterior cortex of the distal femur metaphysis. It associates a pathological fracture (red arrow) and a nonaggressive unilamellated periosteal reaction. Interruption of the periosteal reaction by the fracture is seen (white arrow). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 17 of 78

Fig. 12: NOF in the same patient as Fig 11. A) T1-weighted sagittal view (D) and T2weighted fat-saturated sagittal view shows a predominantly hypointense lesion in the posterior cortex of the distal femur metaphysis. C) T2-weighted fat-saturated sagittal view depicts the pathological fracture (red arrow) and periosteal reaction. Interruption of the periosteal reaction by the fracture is seen (white arrow). Surrounding bone marrow and soft-tissue edema is also noted. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Management When the characteristic radiographic pattern is identified, no further imaging or followup is necessary [1, 2, 4]. Simple bone cyst Simple bone cysts (SBC) are also called solitary bone cysts or unicameral bone cysts (UBC). However, they are not always unicameral (one compartment) [1, 2]. Page 18 of 78

SBC are more frequent in boys. These lesions are seen in patients between 10-25 years old [1]. They most commonly involve the central metaphysis of a long bone. Majority of these lesions occur in the proximal humerus (50%) and proximal femur (20%) [1, 2]. They begin at the physeal plate in long bones and grow into the shaft of the bone; however, uncommonly, they can extend up into an epiphysis after the plate closes [2]. SBC in the calcaneus, typically near of the neck of it, are occasionally found [1, 2]. SBC are asymptomatic and are found incidentally unless they are complicated by fracture. It is the most common cause of pathologic fracture of children (75% of patients with a SBC present with a pathological fracture) [1, 2, 6]. Imaging On radiography, they are centrally-located well-defined lytic lesions with or without sclerotic margins and medullary expansion. When fracture occurs, a bone fragment may be seen in the dependent portion of the lesion ("fallen-fragment" sign). It is a very uncommon finding but it is considered pathognomonic for a SBC. They rarely form periostitis (even when pathologic fractures occur) [1, 2, 6]. CT is not usually necessary, but it is of value confirming the lesion and the fallen fragment [1]. MRI is performed in atypical cases. MRI can confirm the cystic nature of the lesion (low signal on T1 and high signal on T2). If they are complicated with fracture, they may show septations, fluid-fluid levels and heterogeneous fluid signal and they may have rim, septations and adjacent soft tissue enhancement, but the content of the cyst should not enhance [1, 8]. Therefore, SBC can mimic an aneurysmal bone cyst (ABC), but we should consider a complicated SBC (instead of an ABC) when the diameter of the lesion is smaller than the thickest diameter of the affected bone [1]. Page 19 of 78

Fig. 13: Simple bone cyst with pathologic fracture in a 12-year-old patient. A) Radiograph demonstrates a centrally-located well-defined lytic lesion with cortex expansion in the meta-diaphysis of the left proximal humerus in a patient who suffered a fracture through the lesion. B) T1-weighted coronal view shows a hypointense lesion and C) T2-weighted fat-saturated sagittal view shows a hyperintense lesion with septations (white arrow) and a fluid-fluid level (red arrow). D) T1-weighted fat-saturated post-gadolinium axial view depicts rim and septations enhancement. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 20 of 78

Fig. 14: Simple bone cyst with pathologic fracture in a 14 -year-old patient. Radiograph demonstrates a centrally-located well-defined lytic lesion with cortex expansion in the femur diaphysis. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 21 of 78

Fig. 15: SBC in a 13-year-old patient. A) Radiograph shows well defined lytic lesion with partially sclerotic margins located near the neck of the calcaneus. B and C) MRI demonstrates a well-defined uncomplicated multicameral cystic lesion (low signal on T1 and high signal on T2). References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Management Fracture cysts can heal spontaneously with simple immobilisation of the extremity. Larger cyst with or without fracture are usually treated with curettage and bone grafting. When the fracture is unstable or in a weight-bearing area, there may be need fracture fixation and treatment of the cyst [1, 6]. Aneurysmal bone cyst An aneurysmal bone cyst (ABC) is an expansile lesion that contains blood-filled cystic cavities [7]. There are two types of ABC. A primary type, which has no known cause and a secondary type, which occurs associated with a wide variety of benign or malignant lesions or secondary to trauma [1, 2]. ABC is slightly more common in girls. The lesion is most frequent in patients between 10-30 years old [1, 2]. They can occur anywhere in the skeleton, but the most common localisation is the metaphyses of long bones (especially around the knee), the posterior elements of spine Page 22 of 78

and the craniofacial bones. Lesions of long bones can be classified as intramedullary or juxtacortical [1, 2, 7]. Patients usually come with pain and swelling and rarely (20%) come with pathological fracture [2, 6, 7]. Imaging Radiography demonstrates a lytic, virtually always expansile ("aneurysmal"), "soapbubble" lesion with well-defined margins (sometimes sclerotic). The cortex is usually intact but may be markedly thinned. Occasionally they are multiloculated showing a trabeculated pattern. ABCs of long bones are eccentric cortically based lesions, their tendency is for eccentric expansion but they can grow involving the medullary cavity [1, 2, 7]. Due to its expansion, if the lesion diameter is greater than the widest part of the affected normal bone, an ABC (instead of a SBC) should be considered [1]. CT and MRI (more sensible) can demonstrate single or multiple fluid-fluid levels within separate loculations, which are characteristic but nonspecific of ABCs. This nonspecific finding is due to sedimentation of blood products and can be demonstrated in multiple benign and malignant bone lesions (including fibrous dysplasia, chondroblastoma, giant cell tumor, nonossifying fibroma, simple bone cyst and osteosarcoma, particularly the telangiectasic variant). Any solid component suggest underlying tumor. The greater extension of fluid-fluid levels within the focal bone lesion (at least 2/3 of the lesion) is related with benign lesions [1, 2, 9]. Page 23 of 78

Fig. 16: ABC in a 14-year-old patient. A) and B) Radiographs demonstrate a yuxtacortical expansile well-defined lytic lesion in the proximal metaphysis of the tibia (arrow). The anterior cortex of the tibia is thinned (white arrows). T1-weighted coronal (C) and axial (D) view depicts an expansile hypointense lesion. T2-weighted fat-saturated sagittal (E) and axial (F) view shows a cystic lesion with multiple and characteristic fluid-fluid levels (red arrows). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Fig. 17: ABC in a 13-year-old patient. A) Average CT reconstruction shows a welldefined expansile lytic lesion with trabeculated pattern located in the metacarpal of the 4th finger. The cortex is markedly thinned. B) T2-weighted fat-saturated axial image Page 24 of 78

shows multiple fluid-fluid levels within separate loculations (arrows). C) 3D volume CT reconstruction evidences the trabeculated pattern in the described lesions. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Management In most cases, surgical treatment is recommended. Open curettage and bone grafting is the most accepted management option. Surgical biopsy is recommended in all lesions and MRI can identify any solid component to guide the surgeon [1, 6]. Enchondroma Failure of normal endochondral ossification adjacent to a physis forms an enchondroma. Enchondromas become more common with age and are most frequently diagnosed with a peak incidence of 10-30 years [1]. Enchondromas occur in any bone formed from cartilage. They are most frequently located in the small tubular bones of the hands (mostly in proximal phalanges and metacarpals) and feet and in the metaphyses and metadiaphyses of the long bones. An enchondroma is the most common benign lytic lesion in the phalanges and also represent 80% of primary hand tumors in children [1, 2]. Enchondromas are usually asymptomatic, unless they are complicated by a pathological fracture or malignant transformation into a low grade chondrosarcoma (very rare in children). If an enchondroma is painful in the absence of a fracture, it should be considered malignant and warrant surgical investigation [1, 2, 6]. Ollier disease (enchondromatosis) is a non-heritable disease characterized by multiple enchondromas (3 or more) which involve tubular or flat bones (most commonly seen in phalanges and metacarpals). Lesions are often bilateral but usually asymmetric in severity. Patients have an increased risk of chondrosarcoma, so 5% of patients with chondrosarcoma have Ollier disease [1, 10]. Maffucci syndrome is an enchondromatosis associated with vascular malformations (hemangiomas) [1, 10]. Imaging Page 25 of 78

On radiography, enchondromas are well-defined lytic lesions with thin eggshell-like margins that may be sclerotic. They may be central or eccentric, expansile or nonexpansile. Periosteal reaction is absent. They invariably contain calcified chondroid matrix anywhere except in the phalanges [1, 2, 10]. In Ollier disease, longitudinal "channel-like" lytic columns perpendicular to the physis in the long bones are characteristic [1, 2, 10]. MRI demonstrates a lesion isointense with muscle on T1 and heterogeneous predominantly hyperintense on T2 (multiple lobules that show homogeneously high signal intensity on T2, usually separated by thin, low signal intensity septa). Signal of the lesion is similar to cartilage on all sequences. Following contrast administration, enchondromas exhibit central ring and arc enhancement [1, 10]. Fig. 18: Enchondroma in a 15-year-old patient. A and B) Radiographs show a welldefined expansile lytic lesion with thin sclerotic eggshell-like margins located in the 2º proximal phalange and complicated with a fracture (arrow). C) CT coronal view demonstrates the same findings. MRI (D and E) shows an expansile lesion hypointense on T1 and predominantly hyperintense with septations on T2 suggestive of cartilaginous lesion. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 26 of 78

Fig. 19: Enchondromatosis (Ollier disease) in a 7 year old patient. Radiographs show multiple lesions (arrows) in both proximal femurs, the right iliac bone and in the metadiaphyses of the right distal femur, right proximal fibula, right proximal tibia, right distal tibia, left distal tibia and left distal fibula. They are well defined well-defined lytic lesions; some of them are expansile and most of them are "channel-like" lytic columns perpendicular to the physis, which are characteristic of Ollier disease. References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Page 27 of 78

Fig. 20: Enchondromatosis (Ollier disease) in the same patient of Fig 19. MRI demonstrates multiple longitudinal lesions, perpendicular to the physis, isointense to the muscle on T1 (A) and hyperintense on T2 (B) in the metadiaphyses of the right distal femur and proximal tibia. References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Management Treatment is conservative and image following is not required, unless new symptoms of pain or pathologic fracture occur [1]. INDETERMINATE LESIONS Langerhans cell histiocytosis Page 28 of 78

Langerhans cell histiocytosis (LCH), also known as histiocytosis X is an idiopathic disease characterized by abnormal proliferation of Langerhans cells and that can manifest as localized or systemic disease [1, 4]. There are 3 forms of LCH: eosinophilic granuloma (localized form in bone or lung, it accounts for 70% of cases of LCH, the prognosis is excellent and most cases have a single lesion), Letterer-Siwe disease (acute disseminated, often fatal, form) and Hand-Schuller-Christian disease (chronic systemic form, its morbidity is high) [1, 2, 4]. These forms may be merely different phases of the same disease [1, 2]. The bony manifestations of all three disorders are similar [2]. The disease is more common in white boys. Most patients are younger than 15 years at presentation, with a peak incidence between 1 and 5 years of age. Focal lesions are found in slightly older children aged 10-12 years [1]. LCH is most often monostotic, but it can be polyostotic (25% of patients). The most common localisations of LCH are the skull (most frequent site), ribs, femur, pelvis, spine and mandible. LCH can also affect tubular bones (long bones, clavicle, hands and feet). Long bone lesions occur in the metaphysis or diaphysis [1, 4]. Patients with LCH solitary lesions usually come with local pain, soft tissue swelling and occasional palpable mass [1, 7]. Imaging Radiographically, skull lesions appear as a well-defined lytic lesion. Skull lesion may have "bevelled edges" which is related to differential destruction of the inner (more destruction) and outer skull tables [1, 4]. Vertebral lesions (most frequent in thoracic spine) produce compression deformities, often a "vertebra plana" with severe collapse [1, 4]. In the extremities, most lesions are lytic with well defined, minimally sclerotic margins. Many lesions are expansile with endosteal scalloping and even cortical disruption. Some lesions are ill defined or have a permeative pattern that mimics Ewing sarcoma. Periosteal reaction, when present, is typically benign in appearance (unilamellated, thick, uniform, wavy) but can be aggressive (multilamellated). LCH lesions might or might not have a soft tissue mass associated [1, 2]. On MR, the imaging appearance depends on the activity of the lesion. Active lesions are composed of soft tissue, which has low signal on T1 and high signal on T2 and it enhances homogeneously. 50% of the lesions may demonstrate extent bone marrow and soft tissue edema. Lesions with cortical disruption may have a soft tissue mass. The Page 29 of 78

edema and the soft tissue mass may simulate an aggressive lesion such as osteomyelitis or Ewing sarcoma. Involuting lesions appear as low signal on T1 and T2 images [1, 11]. Fig. 21: LCH in an 8-month-old patient. Lateral skull radiograph shows a nonaggressive lytic lesion with well-defined, minimally sclerotic margins in the frontal bone of the skull (arrow). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 30 of 78

Fig. 22: LCH in a 3-year-old patient. A) Radiograph illustrates a nonaggressive lytic lesion with well-defined, partially sclerotic margins in the right iliac bone (arrow). B) MRI T2 weighted imaged demonstrates a high signal mass located in the right iliac bone with extensive adjacent bone and soft tissue edema. References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Fig. 23: LCH in a 6 year-old-patient. A and B) Radiographs show an aggressive lytic lesion with ill-defined margins moth-eaten bone destruction and cortical disruption in the metadiaphysis of the proximal tibia. Unilamellated periosteal reaction is also shown (arrow). C) CT coronal view demonstrates the same findings. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 31 of 78

Fig. 24: LCH in the same patient of Fig 23. MRI shows a lesion hypointense on T1 (A) and hyperintense on T2 (B) with bone marrow and soft-tissue edema. T1 weighted fat-saturated pre-gadolinium (C) and post-gadolinium (D) axial views demonstrate enhancement of the lesion and the surrounding soft-tissue. Cortical disruption is also noted (arrow). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Management A child who presents with a radiographic lesion suspicious for LCH should be evaluated by radiographic skeletal survey to identity other lesions and to find the best site for biopsy. Whole-body MRI may be the best method for identifying and following multifocal bone disease. The patient should be also evaluated by a chest radiograph to exclude pulmonary involvement [1, 4]. LCH localized to skeleton has an excellent prognosis and solitary lesions are followed and usually regress spontaneously. Symptomatic lesions may need a more aggressive therapy (curettage, ablative techniques). Multiple bone lesions and/or systemic disease usually are treated with chemotherapy and steroids [1]. Page 32 of 78

AGGRESSSIVE LESIONS Osteomyelitis (acute pyogenic osteomyelitis) Osteomyelitis may occur from hematogenous or direct inoculation; acute hematogenous osteomyelitis is the most common form of musculoskeletal infection (many patients have a recent history of otitis media or respiratory tract infection). Bacteria are the most common agents and Staphylococcus aureus is the most common organism [1, 4, 12]. It is preponderantly a disease of infants and young children; more than 50% of the cases occur before 5 years of age. It appears to be more frequent in boys [1, 4, 12]. Hematogenous osteomyelitis tends to occur in the metaphyses of the fastest growing bones due to the rich blood supply to these regions. Therefore, 75% of cases involve the metaphyses of long bones and it usually involves the distal femur and radius and the proximal tibia and humerus (70% of infections are about the knee: distal femur, proximal tibia). The other 25% of cases occur within metaphyseal equivalents of flat bones, most typically involving the bony pelvis [1, 4, 12]. Infection can spread into several sites: medullary canal, subperiosteal abscess, penetration of periosteum and extend to the adjacent soft tissues, across the grow plate into the epiphysis and to the joint space [1, 4]. The presentation is often nonspecific, because of the young age of most of the patients. Pain, fever and reduce range of motion are frequent clinical features. Erythrocyte sedimentation rate (ESR) and C reaction protein (CRP) are elevated in a vast majority of cases [1, 4, 12]. Imaging On radiography, the earliest finding of osteomyelitis is deep soft tissue swelling evidenced by displacement or obliteration of the fat planes adjacent to a metaphysis, but this is difficult to detect. Osseous changes may not be present until 7-10 days after the initial symptoms. Initial bony changes consist of one or more poorly defined lucencies (motheaten bone destruction); these lytic areas can become confluent. Periosteal new bone formation usually begins after the second or third week [1, 4, 12]. MR imaging has become the best modality for the evaluation of bone infection, particularly when radiographs are negative, because MRI demonstrates abnormal findings earlier after the onset of symptoms (bone marrow involvement, extension in adjacent soft tissue or joints) and also identifies drainable fluid collections (abscesses) for surgical planning. [1, 4, 12]. Page 33 of 78

CT is not a primary modality for imaging acute osteomyelitis. It is of value in advanced disease in order to demonstrate sequestrum [1, 12] Fig. 25: Osteomyelitis in a 10-year-old girl. Radiograph demonstrates multiple poorly defined lucencies (moth-eaten destruction pattern) in the proximal metadiaphysis of the left humerus. Multilamellated "onion-skin" periostitis is also noted (arrow). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 34 of 78

Fig. 26: Osteomyelitis in the same patient of Fig 25. T1-weighted coronal view (A) and T2-weighted fat-saturated coronal view shows bone marrow and adjacent soft tissue edema. T1-weighted fat-saturated post-gadolinium coronal (C) and axial (D) views demonstrate enhancement of bone marrow and adjacent soft-tissue and also a rimenhancing lesion with non-enhancing fluid consistent with abscess can be seen in the axial view (arrow). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 35 of 78

Fig. 27: Osteomyelitis in a 3-year-old patient. Frontal (A) and lateral (B) radiographs reveal a moth-eaten bony destruction pattern involving the tibia, primarily distal metaphysis and diaphysis. Soft tissue swelling and unilamellated and thick periostitis are also demonstrated (arrows). References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Page 36 of 78

Fig. 28: Fig 28. Osteomyelitis in the same patient of fig 27. A) T1-weighted sagittal view demonstrates bone marrow abnormality involving the entire tibia, sparing the epiphyses. B) T1-weighted fat-saturated post-gadolinium axial view shows a rimenhancing lesion with non-enhancing fluid consistent with abscess formation (white arrow) and cortical destruction with communication (cloaca) between bone marrow and adjacent soft tissues (red arrow). Periostitis (arrowhead) and soft tissue inflammation is also noted. References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Management A diagnosis of osteomyelitis requires the recovery of the organism from the focus of infection, or a positive blood culture with a clinical picture and radiographical image consistent with bone infection [12]. Osteosarcoma Osteosarcoma is the most common malignant primary bone tumor. It typically occurs in patients 10-25 years of age and it is slightly more frequent in boys than girls [1, 2, 4]. Page 37 of 78

It typically appears in the medullary cavity of the metaphysis of a long bone (70% of cases); more than 50% of osteosarcomas involve the bones of the knee [1, 2]. The clinical presentation of all types of osteosarcoma is usually nonspecific, with bone pain occasionally accompanied by a soft-tissue mass or swelling. Patients usually have a history of trauma, which brings the lesion to clinical attention. Pathologic fracture is seen in approximately 5-13% of cases at presentation [6, 13]. Intramedullary or central osteosarcoma can be classified in two-categories: conventional osteosarcoma and telangiectasic osteosarcoma Conventional osteosarcoma On radiography, conventional osteosarcoma typically appears as an ill-defined large lyticsclerotic mass with "cloudlike" sclerotic mineralization. Sclerosis is usually present from either tumor new bone formation or reactive sclerosis. It often causes cortical erosion and destruction. It is often associated with aggressive periosteal reaction; "sunburst" pattern and Codman triangle are the most frequent. However, conventional osteosarcoma can be pure lytic [1, 2, 13]. Radiographs and CT often underestimate the extension of bone involvement [1]. MRI is the imaging procedure of choice for determining the extent of a malignant bone tumor, both in the skeleton and in the soft tissues [2]. It is important to assess possible epiphyseal involvement (80% of metaphyseal tumors [1]. The tumor appears as a bone marrow mass which is hypointense on T1 images and can be either hyperintense or hypointense on T2 images depending on the amount of bone formation. The tumor is associated with soft-tissue mass in 80-90% of cases and it is also frequently accompanied by edema of the adjacent soft tissues [1, 13]. Osteosarcoma can restrict diffusion, demonstrating low ADC values [14]. Page 38 of 78

Fig. 29: Conventional osteosarcoma in an 11-year-old patient. Radiograph shows an aggressive predominantly lytic lesion with ill-defined margins, wide zone of transition, cortical destruction and aggressive periosteal reaction (Codman triangle; arrow) in the distal femur metaphysis. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 39 of 78

Fig. 30: Conventional osteosarcoma in a 14-year-old patient. Radiograph demonstrates a lytic-sclerotic mass with ill-defined margins and aggressive periosteal reaction ("sunburst" pattern; arrow) in the proximal fibula metadiaphysis. It is associated with a soft-tissue mass. References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Page 40 of 78

Fig. 31: Conventional osteosarcoma in the same patient of Fig 30. A) T2-weighted fat-saturated coronal view shows a heterogeneous predominantly hyperintense mass with "sunburst" periosteal reaction and with a large soft-tissue mass and edema of the adjacent soft-tissues. B) T1-weight fat-saturated post-gadolinium axial view shows diffuse enhancement of the intraosseus mass and the extraosseus component. The tumor shows restricted diffusion, being hyperintense on DWI (C) and hypointense on ADC image (D). References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Page 41 of 78

Fig. 32: Conventional osteosarcoma in a 20-year-old-patient. A) Radiograph shows an ill-defined pure lytic lesion with cortical disruption and unilamellated periosteal reaction (white arrow). CT coronal (B) and sagittal (C) views demonstrate the same findings. MRI T1-weighted fat-saturated post-gadolinium sagittal (C) and axial (D) views reveal heterogeneous enhancement of the lesion with a central area of low enhancement consistent with tumoral necrosis. There is enhancement of the adjacent soft-tissues and the tumor is associated with an enhancing soft-tissue mass (white arrow). Cortical disruption is also noted (red arrow). References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Telangiectasic osteosarcoma Telangiectasic osteosarcoma is an uncommon histopathological subtype that represents 2% of all osteosarcomas. They are composed of single or multiple cavities that contain blood or necrotic tumor with septa of anaplastic cells [1, 13]. Radiography usually shows an ill-defined lytic lesion with a wide zone of transition. They tend to expand the cortex, rather than destroy it. They may also be associated with a soft tissue mass [1, 13]. On MRI, the appearance of telangiectasic osteosarcoma and ABC may be similar. Both may have single or multiple fluid-fluid levels produced by blood products. The most important feature for distinguish these lesions is that the telangiectasic osteosarcoma has enhancing soft tissue in the periphery and septations of the tumor. However, biopsy is necessary to differentiate telangiectasic osteosarcoma from an ABC [1, 13]. Fig. 33: Telangiectasic osteosarcoma in an 8-year-old patient. A) Radiograph shows an ill-defined lytic lesion with wide zone of transition and cortical disruption. B) CT coronal view demonstrates the same lesion which is associated with a pathological Page 42 of 78

fracture (red arrow). C) T2-weighted fat-saturated sagittal view depicts multiple fluidfluid levels. D) T2*-weighted coronal view reveals blooming effect of the blood products inside the fluid-fluid levels. E) T1-weighted fat-saturated post-gadolinium coronal view shows enhancing soft tissue in the periphery of the tumor. References: Department of Radiology, Hospital Materno Infantil del Gregorio Marañón, Madrid, Spain. Management Treatment consists of preoperative chemotherapy, limb sparing surgery (more frequent) or aggressive surgical resection with amputation and postoperative chemotherapy. Pulmonary metastatic disease (most common type of metastases) is evaluated by CT and skeletal metastatic disease (15% of patients) is evaluated by skeletal scintigraphy [1, 4]. Ewing sarcoma Ewing sarcoma is the second most common primary malignant bone tumor in children after osteosarcoma. It is a radium-sensitive, aggressive, small, round, blue cell tumor similar to primitive neuroectodermal tumor (PNET) [1, 4]. They occur primarily in patients between 10 and 25 years of age. It is extremely rare in children younger than 5 years of age. The tumor is slightly more often in boys and is much more common in whites [1, 4]. The most frequent affected bones are femur, pelvis, tibia, humerus and ribs. Two thirds of patients have involvement of pelvis or femur. Most lesions involve the metaphysis and diaphysis of long bones. Most tumors arise in the medullary cavity [1, 2, 4]. Local pain is the most common symptom. Systemic symptoms including fever, leukocytosis and elevation of ESR may be present. Occasionally, pathological fractures also occur [1, 2, 6]. Imaging The classic Ewing sarcoma is a permeative lesion with a multilamellated "onionskin" periosteal reaction in the metadiaphysis of a long bone. If non aggressive periostitis is present, other lesions should be considered instead, such as infection and LCH. Ewing sarcoma may be an aggressive lytic lesion with poorly defined borders. 40% of the tumors demonstrate sclerosis with a mixed lytic-sclerotic pattern [1, 2, 4]. Page 43 of 78

The differential diagnosis for a permeative lesion in a child is Ewing sarcoma, infection, LCH and metastatic leukemia/lymphoma. These four entities can appear radiologically identical [2, 4]. MRI demonstrates a destructive bony mass, often with an associated soft tissue component. Intramedullary mass is usually isointense to muscle on T1 images and heterogeneous hyperintense on T2 images. Ewing sarcoma can permeate haversian canals and grow into the soft tissues without causing a big area of cortical destruction. Indeed soft tissues masses tend to be large in comparison to the bone destruction [1, 4]. Fig. 34: Ewing sarcoma in a 14-year-old patient. A) Radiograph shows multiple poorly defined and small lucencies (permeative destruction pattern) with multilamellated "onion-skin" periosteal reaction (arrow) in the medullary cavity and cortex of distal femur diaphysis. A) CT bone window axial view demonstrate permeative bone destruction pattern. B) CT soft window axial view reveals a large enhancing soft-tissue mass (arrow). D) PET-CT shows intense uptake of FDG within bone lesion and softtissue mass. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 44 of 78

Management Multimodal treatment combines surgery, chemotherapy, and radiation therapy. 25% of patients have metastases at diagnosis; most of these are in the lung, metastases rarely involve local and regional lymph nodes and metastases in bone or bone marrow (skip metastases) are less frequent than in osteosarcoma. Therefore, thoracic TC and bone scintigraphy should be performed [1, 7]. Metastasic disease In children, the most common primary neoplasms to metastasize to bone are neuroblastoma and leukemia/lymphoma [4]. Metastatic neuroblastoma should be considered in any child younger than 5 years of age, especially younger than 3 years of age, with an aggressive lytic bone lesion. Bony metastases of neuroblastoma are much more frequent than a primary bone tumor at this age [4]. Metastatic leukemia/lymphoma should be considered in patients older than 5 years of age with an aggressive lytic bone lesion. They often appear as nonspecific lucent metaphyseal bands also called leukemic lines [4]. Any bone lesion, regardless of its appearance, could be a metastatic lesion and would be suspicious in a patient with a known primary tumor [2]. Page 45 of 78

Fig. 35: Neuroblastoma metastasis in a 4-year-old patient. A) Radiograph shows an aggressive lytic lesion with ill-defined margins and wide zone of transition (arrow). T2weighted fat-saturated axial view reveals a hypointense lesion with bone marrow and adjacent soft-tissue edema. C) T1-weighted fat-saturated post-gadolinium axial view demonstrates enhancement of the lesion and the adjacent soft tissues. References: HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 46 of 78

Images for this section: Fig. 2: Differential diagnosis of pediatric lytic bone lesions. *Osteomyelitis is preponderantly a disease of infants and young children; more than 50% of the cases occur before 5 years of age. **Most patients of LCH are younger than 15 years at presentation, with a peak incidence between 1 and 5 years of age. Focal lesions are found in slightly older children aged 10 to 12 years. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 47 of 78

Fig. 3: Fibrous dysplasia in an 11-year-old patient. Radiograph shows a lesion in the supracetabular portion of the ilium and ipsilateral proximal femur (arrows) with welldefined sclerotic margins and ground-glass matrix. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 48 of 78

Fig. 4: Fibrous dysplasia in the same patient of figure 3. T1-weighted (A and C) and T2weighted fat-saturated (B and D) coronal views demonstrate well-defined lesions in the supracetabular portion of the ilium and ipsilateral proximal femur. Both are isointense to the muscle on T1 and slightly hyperintense on T2. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 49 of 78

Fig. 5: Fibrous dysplasia in an 18-year-old patient. A) Radiograph demonstrates a lytic expansile lesion with ground-glass matrix and cortical thinning in the posterior portion of the 9th left rib. B) CT shows the same findings of the radiograph. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 50 of 78

Fig. 6: Polyostotic fibrous dysplasia in a 19-year-old patient. Mixed lytic-sclerotic lesions involve the pelvis as well as the proximal femurs with severe deformity of pelvis and Shepherd's crook deformity and fractures of both proximal femurs. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 51 of 78

Fig. 8: NOF in a 14-year-old boy. Radiographs depict a nonaggressive lytic lesion with well-defined, sclerotic and slightly expansile margins and narrow zone of transition in the posterior aspect of the distal femur metaphysis (arrows). HOSPITAL CLINICO SAN CARLOS - MADRID/ES Fig. 9: FCD evolution in an 11-year-old patient. A) Radiograph demonstrates a nonaggressive lytic lesion with well-defined sclerotic margins and narrow zone of transition in the medial aspect of the proximal tibia metaphysis (arrows). B and C) Radiographs obtained 1 and 2 years later, respectively, show that the lesion becomes more sclerotic and almost resolve. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Fig. 10: FCD in a 15-year-old patient. A) Radiograph shows a lytic lesion with welldefined, sclerotic and expansile margins in the posterior cortex of the proximal fibula metaphysis (arrows). CT axial (B) and sagittal (C) view demonstrate the same finding. Page 53 of 78

A) T1-weighted coronal view (D) and T2-weighted fat-saturated coronal view show a hypointense lesion in the same localization as described in the radiograph. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Fig. 11: NOF in an 11-year-old patient. A and B) Radiographs show a large nonaggressive lytic-sclerotic lesion with well-defined sclerotic margins and narrow zone of transition in the posterior cortex of the distal femur metaphysis. It associates a pathological fracture (red arrow) and a nonaggressive unilamellated periosteal reaction. Interruption of the periosteal reaction by the fracture is seen (white arrow). HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 54 of 78

Fig. 13: Simple bone cyst with pathologic fracture in a 12-year-old patient. A) Radiograph demonstrates a centrally-located well-defined lytic lesion with cortex expansion in the meta-diaphysis of the left proximal humerus in a patient who suffered a fracture through the lesion. B) T1-weighted coronal view shows a hypointense lesion and C) T2-weighted fat-saturated sagittal view shows a hyperintense lesion with septations (white arrow) and a fluid-fluid level (red arrow). D) T1-weighted fat-saturated post-gadolinium axial view depicts rim and septations enhancement. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 56 of 78

Fig. 14: Simple bone cyst with pathologic fracture in a 14 -year-old patient. Radiograph demonstrates a centrally-located well-defined lytic lesion with cortex expansion in the femur diaphysis. HOSPITAL CLINICO SAN CARLOS - MADRID/ES Page 57 of 78