1 CONTENT Part 1-a – Theory 1. Indications for Bone Biopsy 2. Decalcification and handling of common specimen 2.1. Decalcification 2.2. Handling of… [619045]

1 CONTENT Part 1-a – Theory 1. Indications for Bone Biopsy 2. Decalcification and handling of common specimen 2.1. Decalcification 2.2. Handling of common specimen 3. Chronic Osteomyelitis 4. Pseudotumoral bone lesions 4.1. Solitary Bone Cyst 4.2. Aneurysmal bone cyst 4.3. Metaphyseal fibrous defect (non-ossifying bone fibroma) 4.4. Fibrous- and osteofibrous dysplasia of the bone 4.5. Langerhans cell histiocytosis 5. Benign tumoral lesions 5.1. Osteochondroma 5.2. Osteoid osteoma 5.3. Chondroma 5.4. Osteoma 5.5. Chondroblastoma 5.6. Chondromyxoid fibroma 6. Malignant tumoral lesions 6.1. Osteosarcoma 6.1.1. Conventional osteosarcoma 6.1.2. Telangiectatic osteosarcoma 6.2. Chondrosarcoma 6.2.1. Conventional Chondrosarcoma 6.2.2. Mesenchymal Chondrosarcoma 6.3. Ewing sarcoma

2 Part 2 – Practical part • Introduction • Material and Method • Results • Discussions • Conclusions Bibliography 1. Indications for Bone Biopsy

3 Due to improved instrumentation, the indications for bone biopsies have been expanded in the past years and now include most metabolic diseases, at a stage where intervention can benefit the patient. These include osteoflurosis, osteoporosis, osteomalacia, rickets, primary and secondary hyperparathyroidism, renal osteodystrophies, as well as inherited bone diseases, (such as osteogenesis imperfecta, polyostotic fibrous dysplasia, Paget’s disease of bone, multiple consecutive fractures, intestinal osteopathies, and unclassified metabolic bone disease. (1–4) 2. Decalcification and handling of common specimen 2.1. Decalcification The bone should ideally be sectioned into slabs of 3-5 mm thickness, using a hand- or band-saw, preferably letting the saw do the cutting, instead of trying to push through the bone. It should be approached with slow movements, in order to avoid thermal damage. Some desktop models often contain water to decrease the harm that could possibly be caused by the heat, together with the amount of bone dust produced. Cleansing and brushing the dust off the freshly cut edges is the next step in the decalcification process, which are subsequently fixed in formalin and cleaned in water. The obtained sections should be placed in fresh dilute acid, hydrochloric and nitric acid being the most commonly used substances. Mixtures of hydrochloric acid, formic acid and ethylenediaminetetraacetic acid (EDTA) are useful alternatives. In order to obtain the best results, the sample should be suspended in the solution with all surfaces being covered equally and constantly stirred by

4 it. The decalcification solution to specimen ratio is kept at 20:1 in regard to the volume. Monitoring of the sample is extremely important, due to possible over-decalcification, leading to destroyed histologic details, ruined specimens and eosinophilic tissues. After the decalcification procedure is completed, it is critical to shorten the specimen to about 3 mm before cassetting it. This provides a reasonable thickness for processing, as well as the removal of embedded bone dust. In addition, the obtained sample should be washed once more, so that the continuation of decalcification is avoided. (5–8) 2.2. Handling of common specimens In case of non-tumor amputations and excisions, the extremities may occasionally require photographs, in order to document their removal for medico-legal reasons. Further handling involves knowledge of the information that is presumably going to be needed by the managing clinical team. For example in ischemic gangrene, it might be helpful to section the supplying vessels, so that the underlying disease can be investigated. Regarding benign tumors and tumor-like conditions, they might have specific considerations, as for instance in a suspected osteoid osteoma, the vascular nidus should be sought (if necessary by specimen X-rays). Again, in a case sent as an aneurysmal bone cyst, it is critical to look for solid areas that may represent the precursor lesion. (5) Furthermore, when it comes to amputations of gangrene, ulcer or trauma, a detailed description of the type, state laterality, measurements and history of prior interventions is crucial. One also has to describe the

5 extent of gangrene, ulcer(s) or trauma, dissect out vessels and comment on patency. (5) In case of Exostosis/Osteochondroma, the pathologist has to describe and measure the size of bony fragment(s) and state if they are in continuity with the underlying cortical bone, as well as indicate if there is a fracture of the stalk. Slicing of the osteochondroma should be done with a bandsaw, followed by measuring the thickness of the cartilage cap. During this procedure, a perpendicular position of the section with the surface needs to be provided. Lastly, samples of the osteochondroma have to be collected, including the cap, the stalk and the base of it. (5) When it comes to Degenerative Joint Disease (DJD) and Osteonecrosis of the femoral head, not only the size of the head needs to be obtained, but also the size of the femoral neck. Moreover, signs of prior procedures should be documented, as well as macroscopic manifestations of DJD. Next, the femoral head should be cut into multiple parallel slices using the bandsaw. A gross evaluation of the fragments follows, and if no focal lesions are found, the pathologist needs to select one that demonstrates the joint changes. This part will be decalcified and processed in one or two cassettes. In case of osteonecrosis, the diagnosis can be made by either macroscopic changes or with radiologic help. (5) In femoral head and pathological fractures, the size of the head and neck needs to be assessed, as mentioned before. The fracture line is usually located at the level of the neck and has to be described, along with the articular pathology if present. Sampling of the femoral neck and

6 additional fragments of the bone should be performed. Additionally, a section of the articular surface should be included. If a pathological fracture is suspected, an X-ray is to be carried out and the sampling should be accomplished using boarder specimens with emphasis on the fracture line, together with the separate fragments. (5) Frozen sections may be required for diagnosing and classifying bone and soft tissue tumors, as well as assessing the margins. As an example, in the surgery of osteoid osteoma, frozen sections might be useful in identifying the nidus. In regards to arthroplasties, frozen sections are used to distinguish between infections and aseptic loosening. Furthermore, the identification of orthopedic hardwares is necessary, if possible. If this is not possible, a general description, measurements and information about failures of the device are to be obtained. (5) In case of resections and amputations of the soft tissue tumors, extensive sampling may be required due to their heterogeneity. The resections should be inked and sampled for margins, followed by slicing. Next, the tumor needs to be described, measured and reserved for special studies. (5) In view of resections and amputations of bone tumors, imaging studies should be reviewed once more, considering their usefulness in delineating the extent of it and identifying skip metastases. The resected sample has to be described, its margins have to be inked and sampled as well. The soft tissues should be sharply dissected and removed from the bone. After sectioning of the specimen using a bandsaw, photographs are needed, as well as a report about the various

7 extensions of the tumor. In case of a primary excision, the tumor can be sampled at this stage for special studies. Identifying plus sampling of lymph nodes and neurovascular bundles, sampling of the tissue, including the marrow space proximal to the tumor, in order to determine skip metastases, sampling of the ligaments around and within the joints, the sub-periosteal regions, the biopsy tract and the soft tissue extension are essential steps in this procedure. Extensive sampling may be needed in case of mesenchymal tumors due to their heterogeneity. Post-chemotherapy tumors have to be mapped in order to estimate the amount of necrosis, which is achieved through photocopying the sample and blocking the central slice entirely. The blockages are marked on the photocopy in order to allow reconstruction of the tumor. (5) 3. Chronic Osteomyelitis Osteomyelitis is defined as infection of the bone and marrow. (9) Chronic Osteomyelitis is usually a result of unresolved acute osteomyelitis, even though it can start de novo. (10) Common organisms include Staphylococcus aureus, Streptococci (group A is more common), Klebsiella, Aerobacter, Proteus, Brucella, Staphylococcus epidermidis, and Bacteriodes, with Staphylococcus aureus being the most common cause of acute and chronic hematogenous osteomyelitis. (10–12) Hematogenous spread occurs more frequently in the long bones, especially the tibia, femur and humerus, of children, before the age of 5. (11–13)

8 Clinical features: Patients usually have a protracted course, interspersed with acute exacerbations. (10) They usually present with swelling, pain, and erythema at the site of infection. (11–13) The bone becomes thickened irregular and deformed. In case of epiphyseal involvement, the limbs may either be mal-aligned in case of asymmetrical, or shortened in case of complete destruction. (10) However, the most common site of infection in hematogenous osteomyelitis affecting the long bones is the metaphysis. (11,13) Surgical Pathology: Macroscopically, we can observe necrotic bone, surrounded by granulation tissue (sequestrum), new bone, and draining sinuses. (10) The finding of necrotic bone is the histopathological hallmark in chronic osteomyelitis. (13) Separation of the sequestrum generally takes month to complete. Being cancellous bone of cortical origin, it is significantly easier absorbed and replaced by viable bone. (10) The involucrum, being new bone formation over injured periosteum, (13) surrounds the focus of chronic osteomyelitis, and has several openings called “cloacae” through which exudate, bone debris, and sequestra exit and pass through sinus tracts to the surface. Scarring and squamous metaplasia of the sinus tract, occurs due to constant destruction of the neighboring soft tissue. (10,13) Microscopically, the sequestrum is recognized by virtue of its anucleate nature, often the edges are jagged owing to the action of proteolytic enzymes and osteoclastic action. (10) Management: The main therapeutic strategy is surgical management, for instance debridement and drainage, under antibiotic therapy. (10,11) To achieve an acceptable rate of cure, the introduction of early antibiotic

9 therapy, before extensive destruction of bone or necrosis, is of uttermost importance. (12) Especially in chronic osteomyelitis, complete debridement of all devitalized bone and soft tissue, is essential for cure. (12,14) 4. Pseudotumoral lesions 4.1. Solitary bone cyst Solitary bone cysts, also called unicameral or simple bone cysts, are common benign tumor-like bone lesions. They are intramedullar lesions, including a, clear or straw coloured, fluid filled unilocular cystic cavity, which is lined by a fibrovascular tissue membrane. The cavity may contain blood in case of traumatic injury and septations are seen with healing. (15–17) It is thought that simple cysts are either a developmental abnormality or the result from a venous obstruction(18) within the bone, but the cause of bone cysts is still unknown. (16,19) Clinical Features: Simple bone cysts usually occur in patients within the first two decades of life. They can occur in the long bones, for instance the proximal humerus, femur and tibia, flat bones, like the ilium, and short tubular bones, like the calcaneus. The most common locations are the proximal humerus or femur, which account for about 80-90%. They have a predilection for males. Patients usually present with pathological fractures, which result in pain, stiffness, and deformities, or sometimes it might be incidentally found on X-ray in asymptomatic patients. A decreased range of motion of the affected extremity may also be present. The age of the patient is an important consideration, because

10 bone cysts tend to be more aggressive the younger the patient is. Also an increased recurrence rate has been observed in younger patients, compared to older patients. (15,16) Surgical Pathology: Due to the fact that these lesions are rarely resected, it is very unusual to receive intact gross specimens. If received the curetted material often consists of irregular fragments of membranous fibro-vascular tissue with reactive bone and multiple ridges. It may contain hemosiderin, granulation tissue, a few giant cells or mild focal chronic inflammatory cells. Some cases present with pink cementum-like rounded material, which might be the result of diffusion and precipitation of supersaturated solutions from the cavity, or, perhaps a peculiar reactive osteoid. Within the cyst, fracture callus or blood products may be seen if a fracture was present. (15,16) Management: There is no consensus on best treatment, but treatment is generally unnecessary in asymptomatic individuals. (16,17) The purpose of treatment is to restore bone strength, cortical thickness and obliteration of the cyst. (17) In case of symptomatic patients, the most popular method of treatment is aspiration of the cyst followed by steroid injections (methylprednisolone), (20) even though many casts either heal spontaneously or following trauma. Healed cyst was described as complete filling of the cyst with restoration of cortical thickness, partial healing was described when small radiolucent areas persist with good bone strength, and a persistent cyst was described as continuous bone lucency and thin or broken cortex without response to treatment. (17) Other cases may require other intra-lesional procedures, or rarely, excision. Bone grafting and curettage tend to be reserved for larger bone cysts or lesions that compromise the integrity of the bone.(16) In case a

11 fracture is imminent the lesions are usually treated to avoid pathological fractures. (15–17) 4.2. Aneurysmal bone cyst Aneurysmal bone cysts (ABCs), also called multilocular or hematic cysts, are benign multi-cystic lesions of bone, which are composed of blood-filled spaces, separated by connective tissue septae containing giant cells and reactive bone. (15) ABCs are considered primary lesions in approximately 70% of cases, with the remaining 30% arising secondary to different primary tumors. (21) Clinical Features: The lesion is common in the first two decades (22), even though the greatest prevalence is seen between the ages 12 and 13 years, (22–24) and can affect any bone but is most often encountered in the methaphysis of long bones, especially the femur, tibia (21) , humerus, and the posterior elements of the vertebrae. (15) In case of long bones being affected, patients usually present with pain and swelling or pathological fractures. In case the vertebrae are affected, there can be compressive neurological symptoms. (15,22) Surgical Pathology: Grossly, if intact, the lesion can be seen to have a thin osseous bony shell surrounding a honey-coombed mass. (15) Microscopically, the main feature is the presence of blood filled cavernous spaces, and the lack of smooth muscle wall and endothelial cells of blood vessels. (15) The fibrous wall is composed of fibroblasts, osteoid, chondroid, and giant cells. Invaginations into normal bone at the periphery of the lesion or extension into the soft tissue has been observed. (15,22)

12 In order to differentiate ABCs from telangiectatic osteosarcoma, we look for the fibroblastic stromal cells, which in case of ABCs, lack atypia, atypical mitoses, and anaplasia. (15) The osteoid often follows the contours of the septate, has been likened to a crinkled paper in appearance and frequently occurs in long, linear depositions. In these areas of osteoid formation, numerous mitotic figures can be observed. Necrosis is only seen in regions around a pathological fracture. (15) Management: After the diagnosis has been confirmed histologically, management generally consists of intra-lesional curettage and bone grafting with or without adjuvant therapy. (22) Also sclerotherapy via feeding vessels, radiation, cryotherapy, and other forms of therapy have been advocated. Radiation has a risk of post-radation sarcoma transformation. (15) Other forms of treatment such as wide resection and reconstruction can be considered for lesions that have destroyed the metaphyseal bone in periarticular areas. (22) 4.3. Metaphyseal fibrous defect (non-ossifying bone fibroma) Benign fibrous histiocytoma, also called Atypical Fibrous Histiocytoma or Non-ossifying Fibroma (NOF), is a benign tumor, which originates from histiocytes. (15,25,26) The intracortical proliferation of fibrous tissue and histiocytes is called a metaphyseal fibrous defect. If the lesions are larger they may involve the medullary cavity. As the bone grows, there have been suggestions, that metaphyseal defects can move from the metaphysis to the diaphysis. (15) The incidence of these lesions, are thought to be age related. Most commonly there are seen between the ages of 4 and 8 years. The majority of the lesions are less than 0.5 cm in size. Under the age of 2

13 and over the age of 14, the incidence falls. Most lesions last about 2 years, before disappearing, due to healing by sclerosis. (15) In case the patients present symptoms, the lesions are usually larger, and they may present with pathological fractures and pain. (15,27) The vast majorities of lesions are located on the extremities, in the distal femur, distal tibia, proximal tibia and fibula. (15,28) Also the orbit retro peritoneum, pelvis, knee, head and neck can be involved.(26) Surgical Pathology: If resected, grossly, the lesions may be rimmed by sclerotic bone and grey/yellow in colour, at times having bright-yellow spots. The boundaries with the surrounding bone are clear cut. (15,25) Microscopically, the lesions are predominantly fibrous, arranged in a storiform pattern. We can observe foamy histiocytes (xanthoma cells), hemosiderin-laden macrophages, and multinucleated giant cells in varying proportions. The cells have roundish-oval nuclei, which may be isolated or in groups. In the healing phase or in the presence of a fracture, reactive woven bone may be present. (15,25,29) Management: Only symptomatic lesions, or in case of diagnostic uncertainty, the lesions will be treated with intralesional procedures. (15) Surgical treatment, restricted to the osteolytic area, provides excellent outcome, with no recurrence in all excised cases. (27,28) 4.4. Fibrous- and osteofibrous dysplasia of the bone Fibrous dysplasia of the bone Fibrous dysplasia (FD) is a benign, mono-ostotic (single bone), or poly-ostotic (multiple bones) proliferation of fibrous tissue and bone.

14 The osseous component is irregularly distributed and consists of woven bone with inconspicuous osteoblastic rimming. (15,30) The polyostotic form generally presents before the age of puberty, and is a proliferation of spindle cells due to a somatic mutational event. In case this form is associated with macular skin lesions, for instance café-au-lait spots, hyperfunctioning endocrinopathies, like precocious puberty, hyperthyroidism, or growth hormone excess, and with or without fibromyxomatous soft tissue tumors, it is known as McCune Albright syndrome. In this syndrome the proliferation of spindle cells occurs in a mosaic pattern early in fetal life. In case it occurs at an isolated site in bone, later in life, the result is a mono-ostotic disease. (15,30,31) Mazabraud syndrome is the association of fibrous dysplasia with a soft tissue or intramuscular maxoma. (15,32) Clinical features are variable depending upon the location as well as the extent of skeletal lesions. Patients usually present with pain, pathological fractures or deformities. (15,30,33) The most common location for polyostotic FD, is the femur, tibia and pelvis, but also small bones of the hands and feet, the ribs, and the skull may show lesions. (15) Surgical Pathology: Grossly, fibrous dysplasia has a variable amount of “grittiness”, being firm, fibrous white or red in color, with some lesions containing visible cartilage, or cystic cavities. (15,25) Microscopically, we can notice trabeculae of woven bone, in variety of shapes, referred to as “Chinese-letters”, in a background of moderately cellular fibrous tissue. Osteoblasts are interspersed in the woven bone, in lesser degree around the trabeculae. Some cases of fibrous dysplasia present with small foci of lamellar bone, showing an infiltrative pattern, at the junction with non-lesional bone. (15,25,34)

15 The fibroblasts nuclei are usually plump and ovoid, but in some areas they may appear elongated a narrow, and collections of foam cells are common. (15,25) Management: The treatment of endocrinopathies plays an essential role, as well as the prevention of fractures, optimization of the function, and the treatment of pain. (30) The surgical management of fibrous dysplasia is technically demanding. Scoliosis is usually managed by surgical fusion and instrumentation, taking care that any fixation is placed in adjacent vertebral segments that are not involved. In the case of upper limb fractures, standard closed management is often appropriate, even though the use of internal fixation may be considered. Lower extremity fractures, in comparison, will almost always require the use of internal fixation, and the use of intramedullary devices is strongly recommended. However, the most effective methods to manage the associated bone deformities remain unclear. (35,36) Osteofibrous dysplasia of the bone Osteofibrous dysplasia, or Campanacci’s disease, is a congenital, cortically based fibro-osseous proliferation with a predilection for the tibia in children and infants. The fibula might be affected less frequently. There is a predilection for the male sex. (15,25,37) The lesions are usually diagnosed in the first 5 years of life. Patients present with a bowing deformity, pathologic fracture, or pseudarthrosis, but the lesions are painless. Involvement is usually limited to a single bone. (15,25) Surgical Pathology: In resected cases, the lesion is contained by the

16 periosteum grossly, the lesional tissue may be fibrous or gritty. (15) The tissue occupying the osteolytic area is compact, whitish, yellowish or reddish. (25) Microscopically, the lesion is characterized by a bone trabeculae showing prominent osteoblastic rimming, and a fibrous background. The fibrous tissue is variably cellular and may show prominent collagenisation. (15,25) Management: Due to the fact that the lesions have the capability to regress spontaneously, stay stationary, usually beyond skeletal maturity, or slowly progress, a conservative approach is indicated. (15,37) A high rate of recurrence has been observed in resections before the age of 15 years. (15,37) Management of deformities, by osteotomy, and fractures, where a non-operative approach is preferred, are the primary goal of the treatment. (15) Some patients with osteofibrous dysplasia require close observation because of the high association risk between osteofibrous dysplasia and adamantinoma.(37) 4.5. Langerhans Cell Histiocytosis Langerhans Cell Histiocytosis, Eosinophilic Granuloma, or Langerhans Granulomatosis, is a proliferation of cells showing differentiation toward activated Langerhans cells and are related to histiocytes. (15) The disease can affect several organ systems in addition to bone. There are three main forms of the disease: Histiocytosis localized in the skeleton (solitary or multiple eosinophilic granuloma of the bone), Chronic disseminated histiocytosis (Hand-Schuller-Christian disease), and Acute or subacute diffused histiocytosis (including Letterer-Siwe disease). (25)

17 The Histiocyte Society proposed a reclassification of the histiocytoses, based upton the predominant cell type within the infiltrate, and not like previously based upton the different clinical manifestations: (1) dendritic cell disorders: Langerhans cell histiocytosis (LCH), secondary dendritic cell processes, juvenile xanthogranuloma, and solitary histiocytomas with a dendritic phenotype; (2) macrophage related disorders: primary and secondary hemophagocytic snydromes, Rosai-Dorfman disease, and solitary hisitocytoma with a macrophage phenotype; and (3) malignant histiocytic disorders: monocyte-related leukemias, extramedullary monocytic tumor, and dendritic cell or macrophage-related histiocytic sarcoma. (38) The disease is more common in the first three decades of life, although no age is completely exempt. (15) Eosinophilic granuloma of the bone occurs mainly during late childhood and adolescence, with a peak in frequency between 5 and 10 years, the chronic disseminated form occurs between 3 and 5 years of age, and the acute form is observed before the age of three. (25) Pain and swelling are the most frequent presentations for patiens with disease limited to osseous involvement. (15,25) Almost any bone and any location within the bone can be involved, (15) however eosinophilic granuloma of bone shows a predilection for the flat and short bones of the trunk. (25) Surgical Pathology: The macroscopic appearance is nonspecific, (15) however due to the fact that the tissue is formed by histiocytes and leukocytes, it is rather soft or semi-liquid, and yellowish-grey in color. (25) Microscopically, the lesions comprise of a proliferation of histiocytoid cells, with variable amounts of cytoplasm. The cell borders may be well defined or syncytium-like. (15) The nuclei have characteristic “grooves”

18 and may be reniform or coffee bean-like, and pale, with a small nucleolus. Multinucleated giant cells may be present. A variable number of mitotic figures may be seen. (15,25) There is frequently an accompanyzing inflammatory response, often rich in eosinophils. The proliferative cells bear ultra-structural resemblance to Langerhans cells of the skin, and have characteristic “Birbeck” granules. Immunohistochemically, they express S-100 protein and CD1a. (15,39) Management: The first step in treatment of Langerhans cell histiocytosis, is to determine the number of organ systems involved. Afterwards, patients who have single system involvement should be further subcategorized based upon the number of sites involved (unifocal or multifocal), whereas patients with multi-organ disease should be subcategorized based upon whether or not organ dysfunction is present. (38) For patients with localized bone lesions, curettage is generally sufficient for both diagnosis and therapy, however, intralesional steroids or low dose radiation may be employed. (38,40) In case of multi-focal bone disease, polychemotherapy, should be applied. (40) 5. Benign tumoral lesions 5.1. Osteochondroma An osteochondroma or osteocartilaginous exostosis, contains a combination of cortical and medullary bone, and is an outgrowth of bone. It grows away from the closest joint, at angle with the cortex of the parent bone, projects from the cortical surface, is covered with a cartilage cap,

19 grows mainly during the period of skeletal growth and matures according to normal enchondral ossification. (15,25) They are most prevalent during the first two decades of life, having a male predominance.(25) They are most commonly found in long bones, formed of enchondral ossification, and are not observed either in a bone with direct ossification, an epiphysis, nor in a bone of the carpus and tarsus, except for the calcaneus. (15,25,41) The most rapid growth is seen during adolescence, where it shows signs between 10 and 18 years of age(25), and quiescents after the closure of the epiphysis. Regression of osteochondromas has been observed, especially in bones which have been irradiated. (15) In familial and sporadic settings, multiple osteochondromas have been observed. In case of familial osteochondroma, the inheritance is autosomal dominant and generally associated with a generalized osseous modelling defect, which may be associated with limb growth asymmetry. (15,42) In pediatric patients, secondary osteochondromas have also been reported after associated autologous hematopoietic stem cell transplant. (15,43) Usually osteochondromas are incidental findings, asymptomatic and solitary. Nearly the only symptom is a painless skeletal excrescence which slowly increases in volume during skeletal growth.(25) Some of them come to attention following impingement on nerves, mechanical blocking of joint motion, a cosmetic deformity, a fracture through the stalk, bursae and subsequent pain or inflammation forming on top of them. Vascular complications such as pseudoaneurysm secondary to frictional trauma may also be present. Long-standing osteochondromas can transform into secondary low-grade chondrosarcomas, but a malignant change is rarely seen. (15)

20 Surgical Pathology: A layer of periosteum with a well-defined bony stalk covers entirely resected specimens, which may be narrow and pedunculated or broad, additionally capped by cartilage. Broader stalks tend to be seen in the multiple forms. It has been observed that the thickness of the cartilage cap varies with age. In younger patients the cap is ticker, in adults it may be entirely eburnated, leaving behind only residual bone. In case of adults presenting with a cartilage cap over 2 cm, it is suspicious of a chondrosarcoma developing on top of an osteochondroma. The bursa, in case it is resected with the osteochondroma, contains deposits of fibrin, more specifically rice bodies, or calcified cartilaginous bodies. Cut section of an osteochondroma may be remarkable for foci of calcified mosaics of cartilage, osteoid, or amorphous debris. (15,25) Microscopically, periosteum can be seen covering the cartilage cap. Chondrocytes in the superficial part of the cap occur in clusters and lacunae, chondrocytes in the base of the cap line up simulating a growth plate. Below this, enchondral ossification is often seen. Binucleate chondrocytes can be found within the cartilage cap in case of actively growing osteochondromas. The stalk shows a medullary cavity containing fatty or hematopoietic marrow, large disorganized masses of cartilage, bone, and amorphous calcified debris, and focally the cartilage may be necrotic. (15,25) Management: Osteochondromas, which are symptomatic or cosmetically distressing, are often excised, but presence of an exostosis is, in itself, an insufficient reason for its surgical excision, especially in isolated cases. (15,41) Treatment should not only aim at surgical resection of the masses but also at prevention of deformities. (44) In case of incomplete

21 removal of the cartilaginous cap or its covering periosteum, which is called subperiosteal resection, recurrences have been observed. Chondrosarcomas supervening on an osteochondroma require a wide excision. (15) 5.2. Osteoid osteoma An osteoid osteoma is a benign neoplasm, that is neither locally aggressive nor does it have the potential for a malignant transformation. (15,45) Clinically, it is characterized by its small size, and its disproportionate pain. (15) Histologically it consists of a nidus, which is a highly vascular, sharply defined osteoblastic proliferation, surrounded by reactive, sclerotic bone. (15) Clinical features: Most of the osteoid osteomas are discovered within the first three decades of life, between the ages of 5 to 25 , with males being three times more likely to be affected. (45) The patients present with severe, unremitting pain, responsive to aspirin, which is predominantly nocturnal in the beginning. (15,46,47) In case the osteoid osteoma was not diagnosed in time the patients may present with scoliosis or joint flexion contractures. Even though almost any bone can be affected, the most frequent encountered location is in the cortex of the diaphysis of long bones. If the osteoid osteomas are located in the short tubular bones or within joints, they can have a periosteal or intramedullary location. Recurrence of the neoplasm may follow if the nidus is not completely excised, accordingly, the removal of the lesion is confirmed by the absence of the nidus. (15) Surgical Pathology: Macroscopically, the nidus is red, spherical, gritty and can almost always be “shelled” out from the surrounding bone.

22 Microscopically, the nidus has a sharp demarcation from the surrounding sclerotic bone. It may be poorly ossified, with a richly vascularized stroma, or, it may be ossified, in which case it presents with calcific or lacy osteoid, rimmed with osteoblasts, that are usually plump and active. The woven bone shows prominent osteoblastic rimming. The only time cartilage can be identified is in the case of a fracture, previous surgery or intra-articular lesions. Marrow hematopoietic elements, fat and acute inflammation are absent, yet scattered lymphocytes and plasma cells can be found. A 0.1-0.2 cm zone of less trabeculated, fibrovascular tissue surrounds the nidus, with a sclerotic compact or spongy lamellar bone on its periphery. (15,45,48) Management: Due to their exquisitely painful presentation, osteoid osteomas are usually managed surgically, even though they may regress spontaneously after many years. Currently, the treatment of choice is CT guided percutaneous radiofrequency ablation, which has shown a success rate as high as 90%. (46,49) Marginal excision with removal of the entire nidus is adequate in most cases. Some tumours have been treated with long-term administration of salicylates. (15) 5.3. Chondroma Benign chondromas are benign cartilaginous neoplasms and occur either in a central location within the bone, in which case they would be referred to as enchondroma, or they occur on the surface, in which case they would be referred to as periosteal chondroma. They are usually situated in the metaphysis or diaphysis of the bones of hands and feet, even though periosteal chondromas are more frequent in the appendicular skeleton. In case of multiple chondromas, called enchondromatosis, they can occur as skeletal dysplasia. They can tend

23 towards unilaterality (Ollier disease), or can, rarely, be associated with angiomas of the soft tissues (Maffucci syndrome). The tumors of Ollier disease are most commonly located at the epiphysis and the adjacent regions of the meta- and diaphysis. In case of Maffucci syndrome, the enchondromas associate with soft tissue hemangiomas as well as vascular malformations, leading to a more bizarre appearance. Both syndromes have an increased risk of malignant transformation to chondrosarcoma and visceral malignancy. (15,25,50) Enchondromas may present at any age, but is most commonly seen in the second decade of life. Enchondromatosis syndromes, like Ollier disease and Maffucci syndrome, present earlier in life, typically before the age of 10. (50,51) Surgical Pathology: Macroscopically, the tumors are small (3-5 cm) and well circumscribed. Periosteal chondromas, may be either covered by a thin shell of periosteum, or reactive bone. (15,50) They appear as grey blue, translucent, hypocellular, non-vascular tumors with abundant hyaline cartilage, and have fairly regular nuclei with few mitotic figures. (50) The semi-translucent hyaline cartilage is observed on cut-section of the condromas. (15) Microscopically, the features of chondromas vary with the location. Regardless of the location of the chondroma, they present with a characteristic lobular configuration of the cartilage, which are separated by fibrous or lamellar bony septae, and may be rimmed by reactive woven bone or calcification. In calcified areas, ischemic necrosis of chondrocytes may occur. (15) Enchondromas in the tubular long bones (excluding hands and feet), show small chondrocytes, lying in lacunae, with round, regular nuclei with condensed chromatin. Calcification, as well as bone formation is often seen surrounding the lobules of cartilage. (15,50)

24 Enchondromas of the hands and feet can be alarmingly cellular, with atypia and still maintain a benign nature. (15,50) Chondrocytes may be present in clusters, or even sheets. Nucleomegaly and binucleation, as well as slight myxoid change of cartilage are permissible. (15) Periosteal chondromas are well-demarcated lesions and show no tendency to permeation, even though they can also show cytologic atypia. (15) Multiple enchondromas can also be quite cellular, with the chondrocytes tending to spindle. (15) Management: Management typically requires marginal excision or curettage and bone graft or methyl methacrylate packing, if needed, but there has been no consensus reached regarding the surgical intervention timing for these patients. In case of recurrences, wide procedures are preferred. (15,52) 5.4. Osteoma Osteomas are tumor-like masses of abnormally dense, cortical, lamellar bone. (15) They occur almost exclusively in the craniofacial bones, and seem to have a periosteal or parosteal origin. The most frequent localization is the frontal cranial sinus. (15,25,53) In case of multiple osteomas, located in the appendicular skeleton, associated with intestinal polyps, soft tissue desmoid tumors and epidermoid cysts, may be observed in Gardeners syndrome. (15,25) Osteomas are usually asymptomatic for a long time, until they alter the sinusal drainage and cause sinusitis, or until they deform the walls of the orbit, or protrude under the oral mucosa or from the surface of the cranial

25 bone. (25) In case they occur in the paranasal sinuses, patients might present with headache, proptosis, epiphora and visual complaints. (53) Surgical Pathology: Macroscopically, the mass has a smooth round-topped surface, covered by periosteum. In case of intrasinusal or buccal forms, it may be covered by mucosa, which may be inflamed.(25) Microscopically, osteomas are composed primarily of lamellar bone. (15,25) Some amount of woven bone is acceptable. (15) A spongy variant of the osteoma has been described which contains a fibrofatty or hematopoietic medullary component. (15,25) Treatment: In case the osteoma is asymptomatic, it does not require any treatment. However, in case paranasal sinus osteomas cause important symptoms, or the location of the osteoma is ethmoidal, treatment of choice is surgical excision. Partial removal of the tumor is done in case the risk of compromising with vital structures, such as the optic nerve or internal carotid artery is present. (25,53–56) In case of surgical excision, a transnasal and transorbital multiportal approach is preferred to avoid facial incisions. (57) 5.5. Chondroblastoma Chondroblastoma is a benign cartilaginous neoplasm, composed of chondroblasts (58), and is most commonly seen in the epiphysis, even though lesions can also occur in secondary epiphyses, and apophyses such as the greater trochanter of the femur, or the tuberosity of the humerus of skeletally immature patients. (15,25,58,59) About 20-30% of chondroblastomas may occur in flat bones or the short tubular bones, like the talus or in the calcaneus. (15) The majority of the neoplasms are diagnosed in the second to third decade of life, with an average age of

26 19-23 years, in patients presenting with long-standing pain. Other symptoms include local swelling, joint stiffness and/or joint serous or serohematic effusion, muscular hypotrophy, and the development of a limp may occur when the epiphysis of a long bone is involved. In tumors arising from the skull bones, symptoms such as seizures and progressive hearing loss may occur. (15,25,59,60) Some chondroblastomas can metastasize, and in these cases, resection of the metastases usually produces good results. (15) Surgical Pathology: Grossly, they are compact, pinkish-tan, soft, circumscribed multifaceted lesions. (15,25,58) A secondary ABC component may be seen, as well as blue-grey areas, which represents cartilage, and yellow gritty areas, which may indicate calcification or secondary woven bone. (15) Microscopically, the tumors show a spectrum of histologic appearances, due to their inconstant amounts of matrix, secondary changes (ABC like), and cytological variability. (15) The chondroblast is typically a polygonal to oval cell with a sharp cytoplasmic border, lightly stained or clear cytoplasm, but in case this feature is missing, it may be referred to as the syncytial variant. The nucleus of the chrondroblast is round to oval, well-stained, with a prominent nuclear grooving, and often have an evident nucleolus or nucleoli. The epitheloid variant of chondroblastomas, consist of cells that have a abundant pink cytoplasm. In addition to that a sprinkling or focal aggregates of spindle cells, scattered osteoclast-type giant cells, a small number of cells with enlarged, hyperchromatic nuclei, or pigmented cells, such as hemosiderin-laden macrophages as well as pigmented chondroblasts, may be seen in many chondroblastomas.(15,25) The matrix often has an eosinophilic quality, calcification may be found focally, or more typically in foci of necrotic chondroblasts, which results

27 in a characteristic “chicken wire” pattern of calcium deposition. These calcification foci may be considered pathognomonic, even though they are not constant. (15,25,58) Management: Treatment of choice is surgical (58), for instance extended curettage and bone graft of methyl methacrylate cement packing, with or without the addition of cryosurgical techniques. (15,61) Recurrences, which occur in up to 35% (61), usually manifest themselves within the first 2 years, and are more common in flat bones. They are associated with soft tissue implantations and care has to be taken during surgery in order to avoid spillage. Furthermore, they are managed by wide excisions, and adjuvant treatments, which have been reported to decrease the recurrences. (61,62) Especially the use of high-speed burr combined with adjuvant intralesional cryotherapy and iliac crest autogenous bone grafting has shown to have a low rate of recurrence. (63) Surgical resection alleviates pain and avoids the propagation into the joint and adjacent soft tissues. (64) About 1% of chondroblastomas may behave aggressively and late pulmonary metastases have been reported, but these instances are extremely rare. Successful resections of pulmonary metastases have been reported with good results. (15,61) 5.6. Chondromyxoid fibroma Chondromyxoid fibroma is a benign but locally aggressive cartilaginous tumor, with a predilection for the male sex. (15,25) It is characterized by lobules of spindle-shaped or stellate cells in a myxoid or chondroid stroma. The majority of patients, present with mild, transient pain, often long-standing, and are between the age of 5 and 30 years. Most

28 chondromyxoid fibromas occur in the long bones of the appendicular skeleton, most commonly the tibia. However, one fourth of cases are seen in the flat bones especially the ilium, yet also short tubular bones of the hands and feet can be involved. (15,25,65,66) Surgical Pathology: Grossly, the lesions are small (1.5 – 5 cm), circumscribed, as well as lobulated, and there is a semi-translucent quality to the sample. (15,67) The tumor is always contained by the periosteum, and the neoplastic tissue is compact and soft. (25) Microscopically, the tumors are variable, and may show several different components in varying proportions. The overall pattern is that of lobules having a hypercellular periphery and septae surrounding hypocellular myxoid matrix, which is variably cellular. (15,25,67)This increased concentration of nuclei observed at the periphery of the well-delimited lobules, which are sharply demarcated from the surrounding uninvolved bone, is a feature of extreme importance in the recognition of these tumors. (67) The fibrous component is usually small and often confined to the septae separating the lobules. (15,67) The septae can contain blood vessels, osteoclast-type giant cells, osteoid, and the cells within the septae may be spindle or stellate. Pleomorphic cells are frequent, but should not be overinterpreted as malignant. Chondromyxoid fibromas show an absence of cellularity in the center of the lobules and very few mitoses. Furthermore, they can have necrotic foci and either a chunky or a fine, lace-like calcification. (15) Management: Intralesional curettage and cementation is the treatment of choice for chondromyxoid fibromas, which provides satisfactory functional results and a low recurrence rate. The En-bloc excision procedures have the lowest rate of recurrence, but result in a functional

29 deficit and cosmetic concerns. Curettage alone shows a recurrence rate of up to 80%. (68) Recurrences, which usually manifest themselves within the first 2 years, are associated with soft tissue implantations and care has to be taken during surgery in order to avoid spillage. They are managed by wide excisions.(15) 6. Malignant tumoral lesions 6.1. Osteosarcoma Osteosarcomas are malignant neoplasms, which are composed of proliferating cells that focally produce osteoid. (15,69) Osteosarcoma has several subtypes. Conventional osteosarcoma, being a high grade, intramedullary variant, is the most common type, and is subdivided into several histological patterns, as for example chondroblastic, osteoblastic, fibroblastic, fibrohistiocytic (malignant fibrous histiocytoma like or MFH-like), giant cell rich, and osteoblastoma like variants. (15,70) Other variants include small cell osteosarcoma, telangiectatic osteosarcoma, low-grade intramedullary, intracortical, surface (parosteal, periosteal and high-grade surface), and multifocal osteosarcoma. (15,70) 6.1.1. Conventional osteosarcoma Conventional Osteosarcoma is the most common type representing 80% of all osteosarcoma cases. (70) The majority arise de novo, although they can also develop secondarily on other lesions such as Paget disease, osteogenesis imperfecta, bone infarct, chronic osteomyelitis, fibrous dysplasia, giant cell tumor or osteoblastoma. (15,25)An

30 association with prior radiation therapy and possibly with metallic or other orthopaedic implants have been reported, as well as familial osteosarcomas, which are associated with different chromosomal mutations. (15) Over 85% of the patients who present with conventional de novo osteosarcoma are under the age of 30 years. (15) Peak incidence is in the second decade of life. (70) The most common location is the metaphysis, which represents 85%, of the long tubular bones, in its active growth phase, even though it can also appear in the diaphysis. (15,25,71) In secondary osteosarcomas, the incidence of flat bone and diaphyseal involvement is much higher. The occurrence in the distal appendicular skeleton, such as the hands and feet is very low. (15,25) Surgical Pathology: Osteosarcomas are often large lesions, generally over 5 cm. The conventional osteosarcomas are intramedullary and centred in the metaphysis. (15) Grossly, the vast majority of osteosarcomas demonstrate penetration of the cortex, with an extraosseous soft tissue extension, and their appearance is variable depending on the predominant differentiation, and is frequently multifaceted. (15,25) Areas of lobular cartilaginous growth and gritty bone may be found within the same mass, as well as foci of haemorrhage and necrosis are as well commonly encountered. Large blood-filled areas may represent a telangiectatic component. The periosteal reaction is frequently visible as spicules or lamellae of the bone. Spread to the joints and along intra-articular ligaments may occur. (15,25)

31 Distant foci, which are termed skip lesions or skip metastases may be found within the marrow cavity of the same bone, and are associated with important potential causes of recurrences. (15,25) Microscopically, osteosarcomas are high-grade, anaplastic tumors and frequently show distinct osteoid production. (15) Usually, the more peripheral areas of the tumor are less ossified, while the central areas are more ossified. (15,25) Osteoblastic, chondroblastic, and fibroblastic differentiation is commonly admixed. Sometimes the amount of osteoid production can be minimal or absent in otherwise typical osteosarcomas, but they may produce heavily ossified metastases, even though the primary tumor has little or no bone production. (15) The neoplastic cells of the osteosarcoma may be plasmacytoid, epitheloid, spindled, or oval, with a marked nuclear pleomorphism and hyperchromatism, a high mitotic rate, and atypical mitotic forms. (15,72) The osteoid may have variable thickness and degrees of mineralization. A thin, highly mineralized pattern (the filigreed pattern) is quite suggestive of neoplastic osteoid if found. Other tumors can be very heavily ossified, and some osteosarcomas can resemble osteoblastomas. (15) The giant cell rich type, characterized by a proliferation of bland giant cells in the middle of a sarcomatous stroma, is particularly troublesome, due to the sparse osteoid production. Attention needs to be paid to the stromal anaplasia, so no incorrect interpretation of this lesion as GCT will result. Usually, these tumors are metaphyseal (like conventional osteosarcomas) rather than epiphyseal (like other GCTs). (15) A tumor that appears to be a GCT histologically but arises in a skeletally immature person should be sampled widely to rule out osteosarcoma, especially if it is accompanied by a visible periosteal reaction. (72) Rarely, an osteosarcoma that resembles a chondroblastoma is seen.(15) In case the chondroblastoma-like osteosarcoma is epiphyseal and well

32 circumscribed, it is a very difficult diagnosis, and it must be made histologically.(72) Such tumors can be diagnosed if attention is paid to the permeative nature. Seeing sheets of cells should be a clue to its malignant nature, since chondroblastomas have a loose arrangement of cells. Furthermore, its bone formation, atypical mitotic activity, and infiltration of adjacent intertrabecular spaces may help distinguish it from chondroblastomas. (15,72) Management: Untreated osteosarcomas, will lead to lung or widespread metastases, and are uniformly fatal. (15,69,73) The current treatment of choice includes neoadjuvant chemotherapy, surgery, and then post-operative adjuvant chemotherapy. (69) Necrosis following neoadjuvant chemotherapy is used by many physicians as a prognostic marker, and is also used to tailor the postoperative chemotherapy regime. The goal for a positive treatment with neoadjuvant chemotherapy is to achieve at least 90% necrosis on the surgically resected tumor. (15,73–75) 6.1.2. Telangiectatic osteosarcoma Telangiectatic osteosarcoma (TO) is a rare subtype of osteosarcoma and considered a high-grade malignant neoplasm. (76,77) Patients usually present with local pain, a soft tissue mass, or pathological fractures. (78) The tumor has a male predominance, and occurs in patients between 15 and 20 years, with a median age of 17.5 years. (78) The most common location at presentation is the metaphyses of long bones, with the distal femur being the most frequently affected. (76,78)

33 Surgical pathology: Macroscopically, the tumor may appear as blood clot, be a hemorrhagic-necrotic mass or be multi-cystic with blood-filled spaces or ABC-like. (15,76) When the blood is washed away, the cyst demonstrates many thin fibrous septa, giving it a “honeycomb” or sponge-like appearance. (76,78) Microscopically, two variants are described, the hemorrhagic-necrotic and the ABC-like variants, corresponding to the gross appearances. (15) In the hemorrhagic-necrotic variant, widely separated malignant cells are present, in a background of blood and necrotic debris. (15) In some cases a delicate lacelike osteoid matrix is identified between the malignant cells. (78) In the ABC-ike variant, necrosis is sparse or absent. Malignant cells can be seen within the cyst wall, as well as benign giant cells, and some osteoid. (15,76) The multinucleated giant cells in combination with the atypical stromal cells is a common microscopic feature. In addition, foci of hemosiderin-laden macrophages are common. (76,78) Management: The extend of surgical resection of the tumor depends on the location, size, and response to chemotherapy. However, when possible, limb-sparing surgery is preferred. The preoperative neo-adjuvant chemotherapy has shown to improve the prognosis, due to the fact that it has been demonstrated that TO is responsive to chemotherapy and potentially curable. (77–80) 6.2. Chondrosarcoma 6.2.1. Conventional Chondrosarcoma Conventional Chondrosarcomas are malignant tumors, in which neoplastic cells differentiate and form chondroid, instead of osteoid. If these tumors

34 arise on a previously normal bone, they are referred to as primary tumors. In case they arise on underlying benign neoplasms, like for example enchondromas or osteochondromas, they are referred to as secondary. (15,81–83) Depending on their location, chondrosarcomas are subdivided into central, peripheral and periosteal subgroups. (25,82) Less than 2% of chondrosarcomas occur in patients under 20 years of age, primary chondrosarcomas occur in the fifth to seventh decade, and secondary osteosarcomas in the fourth and fifth decade. (15) In regards to a central chondrosarcoma, the patients present with pain, with or without a mass. On the other hand, in case of a peripheral chondrosarcoma, they present with a mass, but with or without pain. (15) The symptoms are usually of long duration, and tumors which are located in the skull base, may cause neurological symptoms. (81) Chondrosarcomas are often centred around the trunk and the proximal limbs, whereof two-thirds of chondrosarcomas occur in the limb girdles, femora, and humeri. (15,81,84) Surgical Pathology: High-grade (grade 2 and 3) (83,85) chondrosarcomas are composed of cellular cartilage showing extension into soft tissues and/or permeation of bone with entrapment of pre-existing trabeculae. There may be widespread mitotic activity, multinucleation of chondrocytes, and necrosis. (15,25,86) Low-grade chondrosarcomas (grade 1) (83,85) can be difficult to diagnose, because they resemble benign, yet cellular cartilage lesions such as chondromas. The best way to differentiate is to look at the location of the tumor. Cartilage tumors of the sternum are almost always malignant regardless of the histologic appearance, whereas chondromas of the hands and feet, periosteal chondromas, enchondromas of Ollier’s disease and Maffucci syndrome, synovial chondromatosis, and soft

35 tissue chondromas of the hands and feet are most often benign, in spite of sometimes alarming cellularity. (15,25) Grossly, chondrosarcomas are large tumors, usually grater than 4 cm in size. (86) We can see a lobular architecture with a hyaline quality and foci of hemorrhage, necrosis, and cystic (liquefactive or myxoid) change. The matrix of chondrosarcomas can vary in consistency from firm hyaline cartilage to thin mucus-like (myxoid) cartilage, the latter being very suggestive of chondrosarcoma. The areas of matrix mineralization have a distinctive ring-and arc-like pattern, which reflects enchondral ossification around lobules of well-formed hyaline cartilage. (15,25,81,86) Microscopically, chondrosarcomas are lobular, except at the very periphery, where the lobules are completely coalescent. Necrotic foci can later calcify. Myxoid change, which is frequent, is a “bubbly” transformation of cartilage that can lead to cystification or liquefaction and should be taken seriously because it suggests malignancy, in case of a marked myxoid change or necrosis. (15,25,86) The most helpful clue in diagnosing a chondrosarcoma is an infiltration or entrapment of native bone, which is seen as “islands” of, usually necrotic, bone. Chondrosarcomas also tend to be more cellular, especially in the larger bones, than chondromas. Another indicator of malignancy is an infiltrative border, as well as the creation of a soft tissue mass by the tumor growing out of bone. (15,25,86) Peripheral/secondary chondrosarcomas, especially those arising on osteochondromas, often lack an infiltrative quality and frequently demonstrate a “pushing” border. Matrix deposition can vary from minimal to extensive and can be hyaline or myxoid. In case of chondrosarcomas developing on osteochondromas, wide fibrous septae are seen in some cases, as well as an increased thickness of the cartilage cap, and the normal columnar arrangement of chondrocyte columns is lost. Nodules of cartilage can sometimes be found lying in

36 the adjacent soft tissues in such instances. Calcification can be present, and is often seen around the lobules of cartilage. (15,25,86) Management: The primary treatment modality is surgical excision. Intralesional curettage, burring and surgical adjuvant application such as hydrogen peroxide is appropriate for low-grade central chondrosarcomas. Wide excision is preferred for larger tumors, tumors with intra-articular or soft tissue involvement, and axial or pelvic tumors, due to their higher local recurrence rate. En bloc excision is the best surgical approach for high-grade or intermediate grade chondrosarcomas. Chemotherapy has not been effective in chondrosarcomas. Radiotherapy is indicated for high-grade incomplete resected tumors or locally recurrent tumors that are unresectable. (15,82,87,88) Resected patients should undergo lifelong surveillance, due to the possibility of late local and systemic recurrence.(84) 6.2.2. Mesenchymal Chondrosarcoma Mesenchymal chondrosarcomas are malignant cartilaginous tumors that are primarily composed of small round to oval cells arranged in a hemangiopericytoma- or alveolar-like pattern along with low-grade cartilage. The characteristic histologic feature is a bimorphic pattern. Frequently there is an abrupt transition to low-grade cartilage from small round cell areas of osteoid. The majority of patients are under the age of 40 years, with a peak incidence in the third decade of life, however the range involves children as young as 7 years and elderly as old as 80 years. They present with mesenchymal chondrosarcomas in the maxilla, mandible, ribs, vertebrae pelvis, and femur. Involvement of other long and short tubular bones, including multicentric lesions, and lesions occurring in the soft tissues and meninges have also been reported.

37 (15,25,86,89) Surgical Pathology: Macroscopically, the sample may appear lobulated, soft, grey, or tan, and often well demarcated. (15) Microscopically, the tumor is composed of anaplastic small stromal cells, which may vary from “small, round, blue” stained cells to spindle-shaped cells, and are usually arranged in a hemangiopericytoma, or less commonly, an alveolar or even a herring-bone fashion, as well as islands of benign appearing chondroid. Interspersed within the stromal cells is low-grade cartilage, which may form only a small component of the neoplasm, and may be calcified, or even ossified. The border between the two components is usually sharp. (15,25,86) Management: The therapy of choice is wide resection followed by chemotherapy. Chemotherapy should offer a benefit in disease-free survival. (15,90–92) Radiation therapy has been successful in some cases. (15,92) The outcome of this tumor is unpredictable. Late metastases have been reported. (15) 6.3. Ewing sarcoma Ewing sarcoma, also called Ewing tumour, is a primary osseous neoplasm composed of small round cells, with no matrix production. (15,25) It is considered to be one of the less differentiated tumours from the group of neoplasms with neuroectodermal differentiation. Tissue culture studies in the presence of differentiation agents including cAMP, have shown that the tumour develops neural features. (15,93,94) Ewing sarcoma tends to affect patients in the first two decades of life. (15) Highest incidence of frequency is between 10 and 20 years. There is predilection for the male sex. (25,95) Most

38 patients present with localized pain and a mass. The swelling is tense, elastic, tender and increases rapidly. Remittent fever, anemia, leucocytosis increase in serum LDH, weight loss, and an increased erythrocyte sedimentation rate may be present, as well as skeletal metastasis at the time of presentation, which is present in up to 10% of patients. (15,25,96) The lungs are the most common site for metastases, followed by bone and bone marrow. (96) The tumour shows preference for the diaphysis of tubular and flat bones, as for instance the femur, pelvis and ribs, even though any bone may be affected. (15,25) Surgical Pathology: Grossly, the tumour may be firm, glistening, or more friable, mimicking pus. Haemorrhage and cystic changes may be evident. Microscopically, the tumour is very cellular and consists of sheets and large nests of uniform, small, round to polygonal cells with scanty cytoplasm. The chromatin is finely dispersed, usually with no nucleoli and with a rare, scarce, or variable, yet not anomalous number of mitotic figures. In areas of necrosis, perivascular cuffing may be evident. The immunohistochemical stain, Mic 2 (CD 99) brings into evidence the protein expression of a pseudo-autosomal gene located on the X- and the Y-chromosomes, and demonstrates membranous positivity in the large majority of Ewing’s sarcoma. Ewing tumours show a characteristic t(11;22) chromosomal translocation. (15,25,97–100) Management: Progress in treatment has led to a 70-80% survival rate, excluding patients with metastases present at the time of the diagnosis. (96) The primary modality of treatment is surgery, together with chemotherapy, with or without neo-adjuvant and adjuvant radiation. (15,100)

39 1. Shih MS. Bone histomorphometry and undecalcified sections. In: Bone Pathology. 2009. 2. Trueba D, Sawaya BP, Mawad H, Malluche HH. Bone biopsy: indications, techniques, and complications. Semin Dial [Internet]. 16(4):341–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12926408 3. Rauch F. Bone Biopsy: Indications and Methods. In: Calcium and Bone Disorders in Children and Adolescents [Internet]. Basel: KARGER; 2009. p. 49–57. Available from: https://www.karger.com/Article/FullText/223688 4. Roth A, Abendroth K, Lehmann G. Indikationen und Voraussetzungen zur Knochenbiopsie. Z Orthop Unfall [Internet]. 2012 Oct 17;150(05):495–8. Available from: http://www.thieme-connect.de/DOI/DOI?10.1055/s-0032-1315064 5. Khurana JS, Arguello-Guerra V. Grossing of bone and soft tissue (common specimens and procedures). In: Bone Pathology. 2009. 6. Bussolati G. A fixation-decalcification procedure for bone biopsies. Histopathology [Internet]. 1978 Sep;2(5):329–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/363590 7. Choi S-E, Hong SW, Yoon SO. Proposal of an Appropriate Decalcification Method of Bone Marrow Biopsy Specimens in the Era of Expanding Genetic Molecular Study. J Pathol Transl Med [Internet]. 2015 May 15;49(3):236–42. Available from: http://jpatholtm.org/journal/view.php?doi=10.4132/jptm.2015.03.16 8. Naresh KN. Optimal processing of bone marrow trephine biopsy: the Hammersmith Protocol. J Clin Pathol [Internet]. 2006 Sep 1;59(9):903–11. Available from: http://jcp.bmj.com/cgi/doi/10.1136/jcp.2004.020610 9. Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology Ninth Edition. Robbins basic pathology. 2013.

40 10. Khurana JS. The Surgical Pathology of Bone Infections. In: Bone Pathology. Totowa, NJ: Humana Press; 2009. p. 179–86. 11. Schmitt SK. Osteomyelitis. Infect Dis Clin North Am [Internet]. 2017 Jun;31(2):325–38. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0891552017300107 12. Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med [Internet]. 1997 Apr 3;336(14):999–1007. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM199704033361406 13. Momodu II, Savaliya V. Osteomyelitis [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30335283 14. Calhoun J, Manring MM, Shirtliff M. Osteomyelitis of the Long Bones. Semin Plast Surg [Internet]. 2009 May 30;23(02):059–72. Available from: http://www.thieme-connect.de/DOI/DOI?10.1055/s-0029-1214158 15. Khurana JS. The surgical pathology of bone tumors and tumor-like lesions. In: Bone Pathology. 2009. 16. Evans J, Blake J. Unicameral Bone Cyst [Internet]. StatPearls. StatPearls Publishing; 2019 [cited 2019 Apr 25]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29262165 17. Kadhim M, Thacker M, Kadhim A, Holmes L. Treatment of unicameral bone cyst: systematic review and meta analysis. J Child Orthop [Internet]. 2014 Mar;8(2):171–91. Available from: http://online.boneandjoint.org.uk/doi/10.1007/s11832-014-0566-3 18. Chigira M, Maehara S, Arita S, Udagawa E. The aetiology and treatment of simple bone cysts. J Bone Joint Surg Br. 2018; 19. Mehlman Charles T. Unicameral Bone Cyst [Internet]. 03.05.2017. 2017 [cited 2019 Apr 23]. Available from: https://emedicine.medscape.com/article/1257331-overview#showall 20. Scaglietti O, Marchetti P, Bartolozzi P. The effects of

41 methylprednisolone acetate in the treatment of bone cysts. Results of three years follow-up. J Bone Joint Surg Br. 2018; 21. Cottalorda J, Kohler R, Sales de Gauzy J, Chotel F, Mazda K, Lefort G, et al. Epidemiology of aneurysmal bone cyst in children: a multicenter study and literature review. J Pediatr Orthop B [Internet]. 2004 Nov;13(6):389–94. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15599231 22. Rapp TB, Ward JP, Alaia MJ. Aneurysmal Bone Cyst. J Am Acad Orthop Surg [Internet]. 2012 Apr;20(4):233–41. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00124635-201204000-00010 23. Zehetgruber H, Bittner B, Gruber D, Krepler P, Trieb K, Kotz R, et al. Prevalence of aneurysmal and solitary bone cysts in young patients. Clin Orthop Relat Res [Internet]. 2005 Oct;439:136–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16205152 24. Leithner A, Windhager R, Lang S, Haas OA, Kainberger F, Kotz R. Aneurysmal bone cyst. A population based epidemiologic study and literature review. Clin Orthop Relat Res [Internet]. 1999 Jun;(363):176–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10379320 25. Campanacci M, Bertoni F, Bacchini P. Bone and Soft Tissue Tumors [Internet]. Berlin, Heidelberg: Springer Berlin Heidelberg; 1990. Available from: http://link.springer.com/10.1007/978-3-662-29279-2 26. Prasanna Kumar D, Umesh, Rathi T, Jain V. Benign Fibrous Histiocytoma: A Rare Case Report and Literature Review. J Maxillofac Oral Surg [Internet]. 2016 Mar 8;15(1):116–20. Available from: http://link.springer.com/10.1007/s12663-014-0721-x 27. Grohs JG, Nicolakis M, Kainberger F, Lang S, Kotz R. Benign

42 fibrous histiocytoma of bone: a report of ten cases and review of literature. Wien Klin Wochenschr [Internet]. 2002 Jan 15;114(1–2):56–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12407938 28. Nguyen A, Vaudreuil A, Haun P, Caponetti G, Huerter C. Clinical Features and Treatment of Fibrous Histiocytomas of the Tongue: A Systematic Review. Int Arch Otorhinolaryngol [Internet]. 2018 Jan 2;22(01):094–102. Available from: http://www.thieme-connect.de/DOI/DOI?10.1055/s-0037-1602819 29. Smaranda D, Stefana M, Doina M, Petru P, Anamaria C, Ingrid M. Benign Fibrous Histiocytoma in a Child -A Case Report. Am J Med Case Reports, Vol 4, 2016, Pages 19-21 [Internet]. 2016 Jan 22 [cited 2019 May 12];4(1):19–21. Available from: http://pubs.sciepub.com/ajmcr/4/1/6/index.html 30. Boyce AM. Fibrous Dysplasia [Internet]. Endotext. 2000. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26561700 31. Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis [Internet]. 2008 Dec 19;3(1):12. Available from: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-3-12 32. Munksgaard PS, Salkus G, Iyer V V, Fisker RV. Mazabraud’s syndrome: case report and literature review. Acta Radiol Short Reports [Internet]. 2013 May 31;2(4):204798161349253. Available from: http://journals.sagepub.com/doi/10.1177/2047981613492532 33. Anitha N, Sankari Sl, Malathi L, Karthick R. Fibrous dysplasia-recent concepts. J Pharm Bioallied Sci [Internet]. 2015;7(5):173. Available from: http://www.jpbsonline.org/text.asp?2015/7/5/173/155892 34. Feller L, Wood NH, Khammissa RA, Lemmer J, Raubenheimer EJ. The nature of fibrous dysplasia. Head Face Med [Internet].

43 2009 Dec 9;5(1):22. Available from: https://head-face-med.biomedcentral.com/articles/10.1186/1746-160X-5-22 35. Stanton RP, Ippolito E, Springfield D, Lindaman L, Wientroub S, Leet A. The surgical management of fibrous dysplasia of bone. Orphanet J Rare Dis [Internet]. 2012;7(Suppl 1):S1. Available from: http://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-S1-S1 36. Stanton RP. Surgery for Fibrous Dysplasia. J Bone Miner Res [Internet]. 2006 Dec;21(S2):P105–9. Available from: http://doi.wiley.com/10.1359/jbmr.06s220 37. Hahn SB, Kim SH, Cho NH, Choi CJ, Kim BS, Kang HJ. Treatment of Osteofibrous Dysplasia and Associated Lesions. Yonsei Med J [Internet]. 2007;48(3):502. Available from: https://synapse.koreamed.org/DOIx.php?id=10.3349/ymj.2007.48.3.502 38. Satter EK, High WA. Langerhans Cell Histiocytosis: A Review of the Current Recommendations of the Histiocyte Society. Pediatr Dermatol [Internet]. 2008 May;25(3):291–5. Available from: http://doi.wiley.com/10.1111/j.1525-1470.2008.00669.x 39. Pushpalatha G, Prashanthy, Aruna D, Galgali S. Langerhans cell histiocytosis. J Indian Soc Periodontol [Internet]. 2011;15(3):276. Available from: http://www.jisponline.com/text.asp?2011/15/3/276/85675 40. Titgemeyer C, Grois N, Minkov M, Flucher-Wolfram B, Gatterer-Menz I, Gadner H. Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol [Internet]. 2001 Aug;37(2):108–14. Available from: http://doi.wiley.com/10.1002/mpo.1178 41. de Souza AMG, Bispo Júnior RZ. Osteochondroma: ignore or investigate? Rev Bras Ortop (English Ed [Internet]. 2014

44 Nov;49(6):555–64. Available from: https://linkinghub.elsevier.com/retrieve/pii/S225549711400161X 42. Schmale GA, Conrad EU, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am [Internet]. 1994 Jul;76(7):986–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8027127 43. Bordigoni P, Turello R, Clement L, Lascombes P, Leheup B, Galloy M, et al. Osteochondroma after pediatric hematopoietic stem cell transplantation: report of eight cases. Bone Marrow Transplant [Internet]. 2002 Apr 30;29(7):611–4. Available from: http://www.nature.com/articles/1703424 44. Saglik Y, Altay M, Unal VS, Basarir K, Yildiz Y. Manifestations and management of osteochondromas: a retrospective analysis of 382 patients. Acta Orthop Belg [Internet]. 2006 Dec;72(6):748–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17260614 45. Dookie AL, Joseph RM. Osteoid Osteoma [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30725964 46. Laurence N, Epelman M, Markowitz RI, Jaimes C, Jaramillo D, Chauvin NA. Osteoid osteomas: a pain in the night diagnosis. Pediatr Radiol [Internet]. 2012 Dec 23;42(12):1490–501. Available from: http://link.springer.com/10.1007/s00247-012-2495-y 47. Swee RG, McLeod RA, Beabout JW. Osteoid Osteoma. Radiology [Internet]. 1979 Jan;130(1):117–23. Available from: http://pubs.rsna.org/doi/10.1148/130.1.117 48. O’Connell JX, Nanthakumar SS, Nielsen GP, Rosenberg AE. Osteoid osteoma: the uniquely innervated bone tumor. Mod Pathol [Internet]. 1998 Feb;11(2):175–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9504688 49. Motamedi D, Learch TJ, Ishimitsu DN, Motamedi K, Katz MD,

45 Brien EW, et al. Thermal Ablation of Osteoid Osteoma: Overview and Step-by-Step Guide. RadioGraphics [Internet]. 2009 Nov;29(7):2127–41. Available from: http://pubs.rsna.org/doi/10.1148/rg.297095081 50. Biondi NL, Varacallo M. Enchondroma [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30725623 51. Bierry G, Kerr DA, Nielsen GP, Rosenberg AE, Huang AJ, Torriani M, et al. Enchondromas in children: imaging appearance with pathological correlation. Skeletal Radiol [Internet]. 2012 Oct 27;41(10):1223–9. Available from: http://link.springer.com/10.1007/s00256-012-1377-6 52. Zhou X, Zhao B, Keshav P, Chen X, Gao W, Yan H. The management and surgical intervention timing of enchondromas. Medicine (Baltimore) [Internet]. 2017 Apr;96(16):e6678. Available from: http://insights.ovid.com/crossref?an=00005792-201704210-00061 53. Sinha A, Jha D, Deka RC. Osteoma of the paranasal sinuses. Indian J Otolaryngol Head Neck Surg [Internet]. 2003 Jul;55(3):166–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23119969 54. CHILDREY JH. OSTEOMA OF THE SINUSES, THE FRONTAL AND THE SPHENOID BONE: REPORT OF FIFTEEN CASES. Arch Otolaryngol – Head Neck Surg [Internet]. 1939 Jul 1;30(1):63–72. Available from: http://archotol.jamanetwork.com/article.aspx?articleid=563140 55. Strek P, Zagólski O, Składzień J, Kurzyński M, Dyduch G. Osteomas of the paranasal sinuses: surgical treatment options. Med Sci Monit [Internet]. 2007 May;13(5):CR244-50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17476198 56. Lee DH, Jung SH, Yoon TM, Lee JK, Joo YE, Lim SC.

46 Characteristics of paranasal sinus osteoma and treatment outcomes. Acta Otolaryngol [Internet]. 2015 Jun 3;135(6):602–7. Available from: http://www.tandfonline.com/doi/full/10.3109/00016489.2014.1003093 57. Badran KW, Suh JD, Namiri N, Wrobel B, Ference EH. Pediatric Benign Paranasal Sinus Osteoneogenic Tumors: A Case Series and Systematic Review of Outcomes, Techniques, and a Multiportal Approach. Am J Rhinol Allergy [Internet]. 2018 Nov 22;32(6):465–72. Available from: http://journals.sagepub.com/doi/10.1177/1945892418793475 58. Limaiem F, Rawla P. Cancer, Chondroblastoma [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30725632 59. Chen W, DiFrancesco LM. Chondroblastoma: An Update. Arch Pathol Lab Med [Internet]. 2017 Jun;141(6):867–71. Available from: http://www.archivesofpathology.org/doi/10.5858/arpa.2016-0281-RS 60. Sailhan F, Chotel F, Parot R. Chondroblastoma of Bone in a Pediatric Population. J Bone Jt Surgery-American Vol [Internet]. 2009 Sep;91(9):2159–68. Available from: https://insights.ovid.com/crossref?an=00004623-200909000-00013 61. Özer D, Arıkan Y, Gür V, Gök C, Akman YE. Chondroblastoma: An evaluation of the recurrences and functional outcomes following treatment. Acta Orthop Traumatol Turc [Internet]. 2018 Nov;52(6):415–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1017995X17304753 62. Turcotte RE, Kurt A-M, Sim FH, Krishnan Unni K, McLeod RA. Chondroblastoma. Hum Pathol [Internet]. 1993 Sep;24(9):944–9.

47 Available from: https://linkinghub.elsevier.com/retrieve/pii/004681779390107R 63. Mashhour MA, Abdel Rahman M. Lower recurrence rate in chondroblastoma using extended curettage and cryosurgery. Int Orthop [Internet]. 2014 May 19;38(5):1019–24. Available from: http://link.springer.com/10.1007/s00264-013-2178-9 64. Limaiem F, Singh R. Cancer, Osteoblastoma [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30725639 65. Rouas L, Malihy A, Cherradi N, Lamalmi N, Alhamany Z. [Chondromyxoid fibroma of bone: a rare benign bone tumor in children]. Rev Med Brux [Internet]. 2004 Dec;25(6):521–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15688891 66. CRABBE WA. Chondromyxoid fibroma of bone. Proc R Soc Med [Internet]. 1962 May;55:353–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13881933 67. Dahlin DC. Chondromyxoid fibroma of bone, with emphasis on its morphological relationship to benign chondroblastoma. Cancer [Internet]. 1956 Jan;9(1):195–203. Available from: http://doi.wiley.com/10.1002/1097-0142%28195601/02%299%3A1%3C195%3A%3AAID-CNCR2820090121%3E3.0.CO%3B2-C 68. Bhamra JS, Al-Khateeb H, Dhinsa BS, Gikas PD, Tirabosco R, Pollock RC, et al. Chondromyxoid fibroma management: a single institution experience of 22 cases. World J Surg Oncol [Internet]. 2014;12(1):283. Available from: http://wjso.biomedcentral.com/articles/10.1186/1477-7819-12-283 69. Lindsey BA, Markel JE, Kleinerman ES. Osteosarcoma Overview. Rheumatol Ther [Internet]. 2017 Jun 8;4(1):25–43. Available from: http://link.springer.com/10.1007/s40744-016-0050-2

48 70. Misaghi A, Goldin A, Awad M, Kulidjian AA. Osteosarcoma: a comprehensive review. SICOT-J [Internet]. 2018 Apr 9;4:12. Available from: https://www.sicot-j.org/10.1051/sicotj/2017028 71. Fox M, Trotta B. Osteosarcoma: Review of the Various Types with Emphasis on Recent Advancements in Imaging. Semin Musculoskelet Radiol [Internet]. 2013 May 14;17(02):123–36. Available from: http://www.thieme-connect.de/DOI/DOI?10.1055/s-0033-1342969 72. Klein MJ, Siegal GP. Osteosarcoma. Am J Clin Pathol [Internet]. 2006 Apr 1;125(4):555–81. Available from: http://ajcp.metapress.com/openurl.asp?genre=article&id=doi:10.1309/UC6K-QHLD-9LV2-KENN 73. Ozaki T, Flege S, Liljenqvist U, Hillmann A, Delling G, Salzer-Kuntschik M, et al. Osteosarcoma of the spine: experience of the Cooperative Osteosarcoma Study Group. Cancer [Internet]. 2002 Feb 15;94(4):1069–77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11920477 74. Picci P, Bacci G, Campanacci M, Gasparini M, Pilotti S, Cerasoli S, et al. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor. Cancer [Internet]. 1985 Oct 1;56(7):1515–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3861228 75. Hughes DP. Strategies for the targeted delivery of therapeutics for osteosarcoma. Expert Opin Drug Deliv [Internet]. 2009 Dec 18;6(12):1311–21. Available from: https://www.tandfonline.com/doi/full/10.1517/17425240903280422 76. Limaiem F, Khaddour K. Cancer, Telangiectatic Osteosarcoma [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30725994 77. Weiss A, Khoury JD, Hoffer FA, Wu J, Billups CA, Heck RK, et al.

49 Telangiectatic osteosarcoma: The St. Jude Children’s Research Hospital’s experience. Cancer [Internet]. 2007 Apr 15;109(8):1627–37. Available from: http://doi.wiley.com/10.1002/cncr.22574 78. Sangle NA, Layfield LJ. Telangiectatic Osteosarcoma. Arch Pathol Lab Med [Internet]. 2012 May;136(5):572–6. Available from: http://www.archivesofpathology.org/doi/abs/10.5858/arpa.2011-0204-RS 79. Rosen G, Huvos AG, Marcove R, Nirenberg A. Telangiectatic osteogenic sarcoma. Improved survival with combination chemotherapy. Clin Orthop Relat Res [Internet]. 1986 Jun;(207):164–73. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2424660 80. Bacci G, Ferrari S, Ruggieri P, Biagini R, Fabbri N, Campanacci L, et al. Telangiectatic osteosarcoma of the extremity: Neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand [Internet]. 2001 Jan 8;72(2):167–72. Available from: http://www.tandfonline.com/doi/full/10.1080/000164701317323426 81. Limaiem F, Sticco KL. Cancer, Chondrosarcoma [Internet]. StatPearls. 2019. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30844159 82. Nazeri E, Gouran Savadkoohi M, Majidzadeh-A K, Esmaeili R. Chondrosarcoma: An overview of clinical behavior, molecular mechanisms mediated drug resistance and potential therapeutic targets. Crit Rev Oncol Hematol [Internet]. 2018 Nov;131:102–9. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1040842818300416 83. van Praag (Veroniek) VM, Rueten-Budde AJ, Ho V, Dijkstra PDS, Fiocco M, van de Sande MAJ, et al. Incidence, outcomes and prognostic factors during 25 years of treatment of

50 chondrosarcomas. Surg Oncol [Internet]. 2018 Sep;27(3):402–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960740418300070 84. Sangma MMB, Dasiah S. Chondrosarcoma of a rib. Int J Surg Case Rep [Internet]. 2015;10:126–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S221026121500173X 85. Thorkildsen J, Taksdal I, Bjerkehagen B, Haugland HK, Børge Johannesen T, Viset T, et al. Chondrosarcoma in Norway 1990–2013; an epidemiological and prognostic observational study of a complete national cohort. Acta Oncol (Madr) [Internet]. 2019 Mar 4;58(3):273–82. Available from: https://www.tandfonline.com/doi/full/10.1080/0284186X.2018.1554260 86. Murphey MD, Walker EA, Wilson AJ, Kransdorf MJ, Temple HT, Gannon FH. From the Archives of the AFIP. RadioGraphics [Internet]. 2003 Sep;23(5):1245–78. Available from: http://pubs.rsna.org/doi/10.1148/rg.235035134 87. Gelderblom H, Hogendoorn PCW, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AHM, et al. The Clinical Approach Towards Chondrosarcoma. Oncologist [Internet]. 2008 Mar 1;13(3):320–9. Available from: http://theoncologist.alphamedpress.org/cgi/doi/10.1634/theoncologist.2007-0237 88. Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical Management of Conventional Grade I Chondrosarcoma of Long Bones. Clin Orthop Relat Res [Internet]. 2007 Jul;PAP. Available from: https://insights.ovid.com/crossref?an=00003086-900000000-98793 89. El Beaino M, Roszik J, Livingston JA, Wang W-L, Lazar AJ, Amini B, et al. Mesenchymal Chondrosarcoma: a Review with Emphasis

51 on its Fusion-Driven Biology. Curr Oncol Rep [Internet]. 2018 May 26;20(5):37. Available from: http://link.springer.com/10.1007/s11912-018-0668-z 90. Cesari M, Bertoni F, Bacchini P, Mercuri M, Palmerini E, Ferrari S. Mesenchymal chondrosarcoma. An analysis of patients treated at a single institution. Tumori [Internet]. 93(5):423–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18038872 91. Shakked RJ, Geller DS, Gorlick R, Dorfman HD. Mesenchymal Chondrosarcoma: Clinicopathologic Study of 20 Cases. Arch Pathol Lab Med [Internet]. 2012 Jan;136(1):61–75. Available from: http://www.archivesofpathology.org/doi/abs/10.5858/arpa.2010-0362-OA 92. Xu J, Li D, Xie L, Tang S, Guo W. Mesenchymal Chondrosarcoma of Bone and Soft Tissue: A Systematic Review of 107 Patients in the Past 20 Years. Loeb DM, editor. PLoS One [Internet]. 2015 Apr 7;10(4):e0122216. Available from: https://dx.plos.org/10.1371/journal.pone.0122216 93. Cavazzana AO, Miser JS, Jefferson J, Triche TJ. Experimental evidence for a neural origin of Ewing’s sarcoma of bone. Am J Pathol. 1987; 94. Jaffe R, Santamaria M, Yunis EJ, Tannery NH, Agostini RM, Medina J, et al. The neuroectodermal tumor of bone. Am J Surg Pathol [Internet]. 1984 Dec;8(12):885–98. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6083729 95. Burchill SA. Ewing’s sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol [Internet]. 2003 Feb 1;56(2):96–102. Available from: http://jcp.bmj.com/cgi/doi/10.1136/jcp.56.2.96 96. Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol [Internet]. 2010 Feb;11(2):184–92. Available from:

52 https://linkinghub.elsevier.com/retrieve/pii/S1470204509702864 97. Grier HE. The Ewing family of tumors. Ewing’s sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am [Internet]. 1997 Aug;44(4):991–1004. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9286296 98. Aurias A, Rimbaut C, Buffe D, Zucker JM, Mazabraud A. Translocation involving chromosome 22 in Ewing’s sarcoma. A cytogenetic study of four fresh tumors. Cancer Genet Cytogenet [Internet]. 1984 May;12(1):21–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6713357 99. Turc-Carel C, Philip I, Berger MP, Philip T, Lenoir GM. Chromosome study of Ewing’s sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12). Cancer Genet Cytogenet [Internet]. 1984 May;12(1):1–19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6713356 100. Ozaki T. Diagnosis and treatment of Ewing sarcoma of the bone: a review article. J Orthop Sci [Internet]. 2015;20(2):250–63. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0949265815301159