Decalcification and handling of common specimen Decalcification Handling of common specimen Chronic Osteomyelitis Pseudotumoral bone lesions Solitary… [306554]

CONTENT

Part 1 – Theory

Indications for Bone Biopsy

Decalcification and handling of common specimen

Decalcification

Handling of common specimen

Chronic Osteomyelitis

Pseudotumoral bone lesions

Solitary Bone Cyst

Aneurysmal bone cyst

Metaphyseal fibrous defect (non-ossifying bone fibroma)

Fibrous- and osteofibrous dysplasia of the bone

Langerhans cell histiocytosis

Benign tumoral lesions

Osteochondroma

Osteoid osteoma

Chondroma

Osteoma

Chondroblastoma

Chondromyxoid fibroma

Malignant tumoral lesions

Osteosarcoma

Conventional osteosarcoma

Telangiectatic osteosarcoma

Conventional Chondrosarcoma

Ewing sarcoma

Part 2 – Practical part

Introduction

Material and Method

Results

Discussions

Conclusions

Bibliography

Part 1 – THEORY

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2. Decalcification and handling of common specimen

2.1. Decalcification

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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 areas that may symbolize the precursor lesion. These areas are usually solid. (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 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 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 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)

Staphylococcus aureus, Streptococci (especially group A), Klebsiella, Aerobacter, Proteus, Brucella, Staphylococcus epidermidis, and Bacteriodes, are the common organisms responsible for the infection. Staphylococcus aureus is considered to be the most frequent 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)

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) Generally, it takes month to complete the separation of the sequestrum. 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, containing multiple openings known as “cloacae”. Through these openings, “exudate, bone debris, and sequestra exit” (14) to the surface by passing through sinus tracts. “Scarring and squamous metaplasia of the sinus tract”, (14) 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” (14) owing to the “action of proteolytic enzymes and osteoclastic action”. (14)

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 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. (12,15)

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 covered by a fibrovascular tissue membrane. It is possible for the cavity to contain blood in case of traumatic injury and septations are seen with healing. (16–18)

It is thought “that simple cysts are either be a developmental abnormality or may result from a venous obstruction” (16,19) within the bone, but the cause of bone cysts is still unknown. (17,20)

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. (16) The most frequent encountered “locations are the proximal humerus and femur”, (21) 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 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. (16,17)

Surgical Pathology: Due to the fact that these lesions are rarely resected, an intact macroscopic specimen is seldomly received. If received the curetted material usually “consists of irregular fragments of membranous fibrovascular tissue, often with reactive bone” (16) and multiple ridges. It may contain “hemosiderin, granulation tissue, a few giant cells or mild focal chronic inflammatory cells”. (16) Some cases present with “pink cementum-like rounded material”, (16) which might “be the result of diffusion and precipitation of supersaturated solutions from the cavity, or, perhaps a peculiar reactive osteoid”. (16) Within the cyst, fracture callus or blood products may be seen if a fracture was present. (16,17)

Management: There is no consensus on best treatment, but treatment is generally unnecessary in asymptomatic individuals. (17,18) “The purpose of treatment is to restore bone strength, cortical thickness and obliteration of the cyst.” (18) In case of symptomatic patients, the most popular method of treatment is “aspiration of the cyst followed by steroid injections” (16) (methylprednisolone), (22) 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”, (18) partial healing was described “when small radiolucent areas persist with good bone strength”, (18) and a persistent cyst was described as “continuous bone lucency and thin or broken cortex” (18) without response to treatment. (18) 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. (17) In case a fracture is imminent the lesions are usually treated to avoid pathological fractures. (16–18)

4.2. Aneurysmal bone cyst

Aneurysmal bone cysts (ABCs), also called multilocular or hematic cysts, are benign multi-cystic lesions of bone. They consist of of “blood-filled spaces, separated by connective tissue septa”. (23) Inside these spaces we can see giant cells and reactive bone. (16) “ABCs are considered primary lesions in approximately 70% of cases, with the remaining 30% arising secondary to different primary tumors.” (24,25)

Clinical Features: The lesion is common in the first twenty years of life, (26) even though the greatest prevalence is seen between the ages 12 and 13 years, (26–28) and can affect all bones but is most often encountered in the metaphysis of long bones, especially the femur, tibia (25) , humerus, and the posterior elements of the vertebrae. (16)

In case of long bones being affected, patients usually present with pain and swelling, but also presentations with pathological fractures have been encountered. In case the vertebrae are affected, neurological symptoms can occur, due to compression. (16,26)

Surgical Pathology: Macroscopically, if the ABC is resected intact, the lesion can be seen to have a “thin osseous bony shell surrounding a honeycombed mass”. (16)

Microscopically, the presence of blood filled cavernous spaces is the main feature. Specific about these spaces is their lack of “smooth muscle wall and endothelial cells of blood vessels”. (16)

The fibrous wall is composed of fibroblasts, osteoid, chondroid, and giant cells. “ABCs may invaginate into normal bone at the periphery of the lesion or extend into the soft tissue.” (16,26)

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. (16)

The “osteoid often follows the contours of the septate. It has been likened to a crinkled paper in appearance and frequently occurs in long, linear depositions”. (16) In these areas of osteoid formation, numerous mitotic figures can be observed. Necrosis is only seen in regions around a pathological fracture. (16)

Management: After the diagnosis has been confirmed histologically, management generally consists of intra-lesional “curettage and bone grafting with or without adjuvant therapy”. (26) Also “sclerotherapy via feeding vessels, radiation, cryotherapy, and other forms of therapy have been advocated. Radiation has a risk of postradiation sarcoma transformation.” (16) Other forms of treatment can be considered for lesions that have destroyed the metaphyseal bone in periarticular areas. In these cases wide resection and reconstruction can be considered. (26)

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. (16,29,30) 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.” (16)

The incidence of these lesions, are thought to be age related. Most lesions are seen between the ages of four and eight years. The size, for majority of the lesions, does not surpass 0.5cm. Under the age of 2 and over the age of 14, the incidence falls. Most lesions disappear, due to healing by sclerosis, after about 2 years. (16) In case the patients present symptoms, the lesions are usually larger, and they may present with pathological fractures and pain. (16,31) The vast majorities of lesions are located on the extremities, in the distal femur, distal tibia, proximal tibia and fibula. (16,32) Also the orbit retro peritoneum, pelvis, knee, head and neck can be involved.(30)

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. (16,29) Microscopically, the lesions are arranged in a storiform pattern, being mainly fibrous. (16) We can observe “foamy histiocytes, hemosiderin-laden macrophages, and multinucleated giant cells” (16) in different amounts. 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. (16,29,33)

Management: Only symptomatic lesions, or in case of diagnostic uncertainty, the lesions will be treated with intralesional procedures. (16)

Surgical treatment, restricted to the osteolytic area, “provides excellent outcome, with no recurrence in all excised cases”. (31,32)

4.4. Fibrous- and osteofibrous dysplasia of the bone

Fibrous dysplasia of the bone

Fibrous dysplasia (FD) is a benign, proliferation of fibrous tissue and bone, including either a single bone or multiple bones. “The osseous component is irregularly distributed and consists of woven bone with inconspicuous osteoblastic rimming.” (16,34)

The polyostotic form generally presents before the age of puberty, and is a “proliferation of spindle cells” (16) that usually occurs due to a somatic mutation. In case this form is associated with macular skin lesions, for instance café-au-lait spots, hyperfunctioning endocrinopathies, such as precocious puberty, growth hormone excess, or hyperthyroidism, and “with or without fibromyxomatous soft tissue tumors”, (16) 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 later in life, at an isolated site in bone, the result is a mono-ostotic disease. (16,34,35)

“Mazabraud syndrome is the rare combination of fibrous dysplasia and soft tissue” (36)or intramuscular maxoma. (16,37)

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. (16,34,38)

The most common location for polyostotic FD, is the femur, tibia and pelvis. (16) However, “small bones of the hands and feet, the ribs, and the skull may also be involved.” (14,16)

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. (16,29)

Microscopically, we can notice trabeculae of woven bone, in variety of shapes, referred to as “Chinese-letters”. The background consists of slightly cellular fibrous tissue. Osteoblasts are interspersed in the woven bone, in lesser degree around the trabeculae. (16,29,39)

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. (16,29)

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. (34)

The surgical treatment of fibrous dysplasia is difficult, speaking from technical point of view. Scoliosis is usually managed by surgical fusion and instrumentation, taking care that any fixation is placed in neighboring 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. In comparison, a fracture of the lower extremities will most of the times require the use of internal fixation, and the use of intramedullary devices is strongly recommended. However, there is no agreement on what the most effective methods are, in regards of managing the associated bone deformities. (40,41)

Osteofibrous dysplasia of the bone

Osteofibrous dysplasia, or Campanacci’s disease, is a congenital, “cortically based fibro-osseous proliferation” (14) with a preference for the tibia in children and infants. The fibula might be affected less frequently. There is a predilection for the male sex. (16,29,42)

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. (16,29)

Surgical Pathology: The lesion is enclosed by the periosteum grossly, in resected cases. Macroscopically, the lesional tissue may be fibrous or gritty. (16) The tissue occupying the osteolytic area is compact, whitish, yellowish or reddish. (29) Microscopically, the lesion is characterized by “bony trabeculae showing prominent osteoblastic rimming, and a fibrous background. The fibrous tissue is variably cellular and may show prominent collagenisation.” (16,29)

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. (16,42) A high rate of recurrence has been observed in resections before the age of 15 years. (16,42)

Management of deformities, by osteotomy, and fractures, where a non-operative approach is preferred, are the primary goal of the treatment. (16)

“Some patients with osteofibrous dysplasia require close observation because of the high association risk between osteofibrous dysplasia and adamantinoma.” (42)

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”. (16)

The disease can also affect various organ systems. 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). (29)

The “Histocyte Society proposed a reclassification of the histiocytoses, based upon the predominant cell type within the infiltrate”, (43) 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 sydromes, Rosai-Dorfman disease, and solitary histocytoma with a macrophage phenotype; and (3) malignant histiocytic disorders: monocyte-related leukemias, extramedullary monocytic tumor, and dendritic cell or macrophage-related histiocytic sarcoma.” (43,44)

The disease is more common up until 30 years of age, although all ages can be affected. (16) 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. (29)

In case the disease is limited to the bones, patients usually present with pain and swelling.(16,29)

“Almost any bone and any location within the bone can be involved”, (16) however, eosinophilic granuloma of bone shows a predilection for the flat and short bones of the trunk. (29)

Surgical Pathology: The macroscopic appearance is nonspecific, (16) 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. (29)

“Microscopically, the lesions comprise of a proliferation of histiocytoid cells, with variable amounts of cytoplasm. The cell borders may be well defined or syncitium-like.” (16) The nuclei have particular “grooves”, resembling coffee beans, pale, with a small nucleolus. “Multinucleated giant cells may be present. A variable number of mitotic figures may be seen”. (16,29) “There is frequently an accompanying inflammatory response, often rich in eosinophils.” (16) The proliferative cells bear “ultrastructural resemblance to Langerhans cells of the skin, and have characteristic “Birbeck” granules. Immunohistochemically, they express S-100 protein and CD1a.” (16,45)

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 multiorgan disease should be subcategorized based upon whether or not organ dysfunction is present.” (43)

“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.” (43,46)

In case of multi-focal bone disease, polychemotherapy, should be applied. (46)

5. Benign tumoral lesions

5.1. Osteochondroma

An osteochondroma, also called, osteocartilaginous exostosis, contains a combination of cortical and medullary bone, and is an outgrowth of bone. It grows “away from the closest joint, and at an angle with the cortex of the parent bone”, (16) projects from the cortical surface, is enclosed within a cartilage cap, grows mainly during the period of skeletal growth and matures according to normal enchondral ossification. (16,29)

They are most prevalent during the first two decades of life, having a male predominance.(29) 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. (16,29,47) The most rapid growth is seen during adolescence, where it shows signs between 10 and 18 years of age(29), and quiescents after the closure of the epiphysis. Regression of osteochondromas has been observed, especially in bones which have been irradiated. (16)

In familial and sporadic settings, multiple osteochondromas have been observed. Familial osteochondroma, is inherited in an autosomal dominant way, and usually “associated with a generalized osseous modelling defect, which may be associated with limb growth asymmetry”. (16,48)

In pediatric patients, secondary osteochondromas “have also been reported after associated autologous hematopoietic stem cell transplant”. (16,49)

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. (29) Some osteochondromas are discovered due to their “impingement on nerves, mechanical blocking of joint motion”, a fracture through the stalk, a cosmetic deformity, bursae and subsequent pain or inflammation forming on top of them, vascular complications such as a pseudoaneurysm secondary to frictional trauma”. (16) Long-standing osteochondromas can transform into secondary low-grade chondrosarcomas, but a malignant change is rarely seen. (16)

Surgical Pathology: A layer of periosteum with a distinct 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”. (16) In younger patients the cap is thicker, in adults it “may be entirely eburnated, leaving behind only residual bone”. (16) In case of adults presenting with a cartilage cap over 2 cm, it “is suspicious of a chondrosarcoma developing on an osteochondroma”. (16)

The bursa, in case it is cut out together with the osteochondroma, contains “deposits of fibrin (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.” (16,29)

Microscopically, periosteum can be seen covering the cartilage cap. “Chondrocytes of the superficial portion of the cap occur in clusters and in lacunae”, (16) chondrocytes in the base of the cap line up simulating a growth plate.

“Below this, enchondral ossification is often seen.” (16) 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”, (16) vast “disorganized masses of cartilage, bone, and amorphous calcified debris”, (16) and focally the cartilage may be necrotic. (16,29)

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”. (16,47) Treatment should not only aim at “surgical resection of the masses” (50) but also at “prevention of deformities”. (50) In case of incomplete removal of the “cartilaginous cap or its covering periosteum, called subperiosteal resection”, (16) recurrences have been observed. “Chondrosarcomas supervening on an osteochondroma require a wide excision.” (16)

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. (16,51) Clinically, it is “characterized by small size, and disproportionate pain”. (16) Histologically it consists of a nidus, which “is a highly vascular, sharply defined osteoblastic proliferation”, (16) surrounded by reactive, sclerotic bone. (16)

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. (51) The patients present with severe, unremitting pain, responsive to aspirin, which is predominantly nocturnal in the beginning. (16,52,53)

In case the osteoid osteoma was not diagnosed in time the patients “may present with scoliosis or joint flexion contractures”. (16) Even though no bone is excluded from this lesion, 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”, (16) accordingly, the removal of the lesion is confirmed by the absence of the nidus. (16)

Surgical Pathology: Macroscopically, “the nidus is red, spherical, and gritty” (16) and can most of the times “be “shelled” out from the surrounding bone”. (16)

Microscopically, the nidus has a clear delimitation from the “surrounding sclerotic bone”. (16) It may be “poorly ossified, with a richly vascularized stroma, or, it may be ossified”, (16) in which case it presents with “calcific or lacy osteoid, rimmed with osteoblasts”, (16) that are usually plump and active. “The woven bone shows prominent osteoblastic rimming.” (16) 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 may be found”. (16) A “0.1-0.2 cm zone of less trabeculated, fibrovascular tissue” (14) surrounds the nidus, with a “sclerotic compact or spongy lamellar bone” (14) on its periphery. (14,16,51,54)

Management: Due to their exquisitely painful presentation, osteoid osteomas are usually managed surgically, even though they “may regress spontaneously after many years”. (16) Currently, the treatment of choice is CT guided percutaneous radiofrequency ablation, which has shown a success rate as high as 90%. (52,55) Marginal excision with removal of the entire nidus is adequate in most cases. Some tumours have been treated with long-term administration of salicylates. (16)

5.3. Chondroma

Benign chondromas are “benign cartilaginous neoplasms occurring in either in a central location within the bone”, (56) 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”. (16) In case of multiple chondromas, called enchondromatosis, they can occur as skeletal dysplasia. They can “tend toward unilaterality (Ollier disease)”, (16) or can, “rarely, be associated with angiomas of the soft tissues (Maffucci syndrome)”. (16) 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. (16,29,57)

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. (57,58)

Surgical Pathology: Macroscopically, the tumors are small (3-5 cm) and well circumscribed. “Periosteal chondromas, may be covered in a thin shell of periosteum, or reactive bone.” (16,57) They appear as grey blue, translucent, hypocellular, non-vascular tumors with abundant hyaline cartilage, and have fairly regular nuclei with few mitotic figures. (57) The semi-translucent hyaline cartilage is observed on cut-section of the condromas. (16)

“Microscopically, the features of chondromas vary with the location.” (16) 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”, (14) and “may be rimmed by reactive woven bone or calcification”. (14) In calcified areas, ischemic necrosis of chondrocytes may occur. (16)

“Enchondromas in the tubular long bones (excluding the hands and feet), show small chondrocytes, lying in lacunae, with round, regular nuclei” (14) with condensed chromatin. Calcification, as well as “bone formation is often seen surrounding the lobules of cartilage”. (16,57)

“Enchondromas of the hands and feet can be alarmingly cellular”, (14) with atypia and still maintain a benign nature. (16,57)

“Chondrocytes may be present in clusters, or even sheets. Nucleomegaly and binucleation, as well as slight myxoid change of cartilage are permissible.” (16)

Periosteal chondromas are “well-demarcated lesions and show no tendency to permeation”, (16) even though they can also show cytologic atypia. (16)

“Multiple enchondromas can also be quite cellular, with the chondrocytes tending to spindle.” (16)

Management: Management typically requires “marginal excision or curettage and bone graft or methyl methacrylate packing, if needed”, (16) but there has been no consensus reached regarding the surgical intervention timing for these patients. In case of recurrences, wide procedures are preferred. (16,59)

5.4. Osteoma

Osteomas are tumor-like masses of “abnormally dense, cortical, lamellar bone”. (16)

They occur almost solely in the craniofacial bones, and seem to have a periosteal or parosteal origin. The most frequent localization is the frontal cranial sinus. (16,29,60)

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. (16,29)

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 bone. (29) In case they occur in the paranasal sinuses, patients might present with headache, proptosis, epiphora and visual complaints. (60)

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.(29)

Microscopically, “osteomas are composed primarily of lamellar bone”. (16,29) “Some amount of woven bone is acceptable.” (16) “A spongy variant of the osteoma has been described which contains a fibrofatty or hematopoietic medullary component.” (16,29)

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. (29,60–63) In case of surgical excision, a transnasal and transorbital multiportal approach is preferred to avoid facial incisions. (64)

5.5. Chondroblastoma

Chondroblastoma is a benign cartilaginous neoplasm, composed of chondroblasts (65), 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 tuburosity of the humerus” (16) of skeletally immature patients. (16,29,65,66) “About 20-30% of chondroblastomas may occur in flat bones or the short tubular bones”, (16) like the talus or in the calcaneus. (16) The majority of the neoplasms are diagnosed in the second to third decade of life, with an average age of 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. (16,29,66,67)

“Some chondroblastomas can metastasize, and in these cases, resection of the metastases usually produces good results.” (16)

Surgical Pathology: Grossly, they are compact, pinkish-tan, soft, circumscribed multifaceted lesions. (16,29,65) “A secondary ABC component may be seen. Blue gray areas may represent cartilage, yellow gritty areas may represent calcification or secondary woven bone.“ (16)

Microscopically, the tumors can have a variety of appearances, due to their “inconstant amounts of matrix, secondary changes” (14) (ABC like), and cytological variability. (16)

The chondroblast is typically a “polygonal to oval cell with a sharp cytoplasmic border, and lightly stained or clear cytoplasm”, (14) but in case this feature is missing, it “may be referred to as the syncytial variant”. (14) The nucleus of the chrondroblast is “round to oval”, (14) 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”, (16) “scattered osteoclast-type giant cells”, (16) a “small number of cells with enlarged, hyperchromatic nuclei”, (16) or pigmented cells, such as “hemosiderin-laden macrophages as well as pigmented chondroblasts”, (16) may be seen in many chondroblastomas. (16,29)

The matrix often has an eosinophilic quality, “calcification may be found focally”, (16) or more typically in “foci of necrotic chondroblasts”, (14) which results in a “characteristic “chicken wire” pattern of calcium deposition”. (14) These calcification foci may be considered pathognomonic, even though they are not constant. (16,29,65)

Management: Treatment of choice is surgical (65), for instance extended “curettage and bone graft or methyl methacrylate cement packing”, (16) with or without the addition of cryosurgical techniques. (16,68)

Recurrences, which occur in up to 35% (68), usually occur within 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. (16) Furthermore, they are managed by wide excisions, and adjuvant treatments, which have been reported to decrease the recurrences. (68,69) Especially the “use of high-speed burr combined with adjuvant intralesional cryotherapy and iliac crest autogenous bone grafting” (16) has shown to have a low rate of recurrence. (70)

Surgical resection alleviates pain and avoids the propagation into the joint and adjacent soft tissues. (71)

“About 1% of chondroblastomas may behave aggressively” (16) and late pulmonary metastases “have been reported, but these instances are extremely rare. Successful resections of pulmonary metastases have been reported with good results”. (16,68)

5.6. Chondromyxoid fibroma

“Chondromyxoid fibroma is a benign but locally aggressive cartilaginous tumor”, (16) with a predilection for the male sex. (16,29) It is “characterized by lobules of spindle-shaped or stellate cells in a myxoid or chondroid stroma”. (14) The majority of patients, present with mild, transient pain, often long-standing, and are between the age of 5 and 30 years. Most chondromyxoid fibromas “occur in the long bones of the appendicular skeleton, especially the tibia”. (16) However, one fourth of “cases are seen in the flat bones especially the ilium”, (16) yet also “short tubular bones of the hands and feet” (16) can be involved. (16,29,72,73)

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. (16,74) The tumor is always contained by the periosteum, and the neoplastic tissue is compact and soft. (29)

“Microscopically, the tumors are variable, and may show several different components in varying proportions.” (16)

“The overall pattern is that of lobules” (16) having a “hypercellular periphery and septae surrounding hypocellular myxoid matrix”, (16) which is variably cellular. (16,29,74) 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. (74) “The fibrous component is usually small and often confined to the septae separating the lobules.” (14,16,74)

“The septae occasionallly contain blood vessels, osteoclast-type giant cells, and osteoid”, (14) and the cells within the septae may be spindle or stellate. “Pleomorphic cells are frequent, and should not be overinterpreted as malignant.” (16) Chondromyxoid fibromas show an “absence of cellularity in the center of the lobules and very few mitoses”. (16) Furthermore, they can have necrotic foci and either a chunky or a fine, lace-like calcification. (16)

Management: “Intralesional curettage and cementation” (75) is the treatment of choice for chondromyxoid fibromas, which provides “satisfactory functional results with a low recurrence rate”. (75) The “En-bloc excision procedures report the lowest rate of recurrence”, (75) but result in a functional deficit and cosmetic concerns. Curettage alone shows a recurrence rate of up to 80%. (75) Recurrences, usually occur 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.(16)

6. Malignant tumoral lesions

6.1. Osteosarcoma

Osteosarcomas are malignant neoplasms, which are “composed of proliferating cells that focally produce osteoid”. (16,76)

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” (16) like variants. (16,77)

“Other variants include small cell osteosarcoma, telangiectatic osteosarcoma, low-grade intramedullary, intracortical, surface (parosteal, periosteal and high-grade surface), and multifocal osteosarcoma.” (16,77)

6.1.1. Conventional osteosarcoma

Conventional Osteosarcoma is the most common type representing 80% of all osteosarcoma cases. (77) 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”. (16,29) “An association with prior radiation therapy and possibly with metallic or other orthopedic implants” (16) have been reported, as well as familial osteosarcomas, which are associated with different chromosomal mutations. (16)

Over 85% of the patients who present with “conventional de novo osteosarcoma, are below the age of 30 years”. (16) “Peak incidence is in the second decade of life.” (77) 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. (16,29,78)

“In secondary osteosarcomas, the incidence of flat bone and diaphyseal involvement is much higher.” (16,29) The occurrence in “the distal appendicular skeleton, such as the hands and feet is very low.” (16,29)

Surgical Pathology: “Osteosarcomas are often large lesions, generally over 5 cm. The conventional osteosarcomas are intramedullary and centred in the metaphysis.” (16)

“Grossly, the vast majority of osteosarcomas demonstrate penetration of the cortex, with an extraosseous soft tissue extension”, (16) and their appearance is variable depending “on the predominant differentiation, and is frequently” (16) multifaceted. (16,29)

“Areas of lobular cartilaginous growth and gritty bone may be found within the same mass”, (16) as well as “foci of haemorrhage and necrosis” (16) are commonly encountered. “Large blood-filled areas may represent a telangiectatic component. The periosteal reaction is frequently visible as spicules or lamellae of the bone.” (16) Spread to the joints and along intra-articular ligaments may occur. (16,29)

Distant foci, which are termed skip lesions or skip metastases may be found “within the marrow cavity of the same bone”, (16) and are associated with important potential causes of recurrences. (16,29)

“Microscopically, osteosarcomas are high-grade, anaplastic tumors and frequently show distinct osteoid production.” (16) Usually, the more peripheral areas of the tumor are less ossified, while the central areas are more ossified. (16,29) “Osteoblastic, chondroblastic, and fibroblastic differentiation is commonly” (16) combined. Even though there is no, or only small amounts of osteoid produced, some osteosarcomas may “produce heavily ossified metastases, although the primary tumor has little or no bone production.” (16)

“The neoplastic cells of the osteosarcoma may be plasmacytoid, epitheloid, spindled, or oval”, (16) with a “marked nuclear pleomorphism” (16) and hyperchromatism, “a high mitotic rate, and atypical mitotic forms”. (16,79)

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”, (16) and “some osteosarcomas can resemble osteoblastomas”. (16)

The “giant cell rich type, characterized by a proliferation of bland giant cells” (16) 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”, (16) so no “incorrect interpretation of this lesion as a GCT will result”. (16) Usually, “these tumors are metaphyseal (like conventional osteosarcomas) rather than epiphyseal (like other GCTs).” (16) “A tumor that appears to be a giant cell tumor histologically but arises in a skeletally immature person” (79) should be sampled widely to rule out osteosarcoma, especially “if it is accompanied by a visible periosteal reaction”. (79)

“Rarely, an osteosarcoma that resembles a chondroblastoma is seen.” (16) In case the chondroblastoma-like osteosarcoma “is epiphyseal and well circumscribed, it is a very difficult diagnosis”, (79) and it must be made histologically. (79) “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.” (16) Furthermore, its “bone formation, atypical mitotic activity, and infiltration of adjacent intertrabecular spaces” (79) may help distinguish it from chondroblastomas. (16,79)

Management: Untreated osteosarcomas, will lead to lung or widespread metastases, and are uniformly fatal. (16,76,80)

The current treatment of choice includes chemotherapy before and after surgery. (76) Necrosis after “neoadjuvant chemotherapy is used by many” (16) physicians “as a prognostic marker, and to tailor the postoperative chemotherapy regime”. (16) “The goal for a positive treatment with neoadjuvant chemotherapy is to achieve at least 90% necrosis on the surgically resected tumor.” (16,80–82)

6.1.2. Telangiectatic osteosarcoma

Telangiectatic osteosarcoma (TO) is a rare subtype of osteosarcoma and considered a high-grade malignant neoplasm. (83,84)

Patients usually present with local pain, a soft tissue mass, or pathological fractures. (85)

The tumor has a male predominance, and occurs in patients between 15 and 20 years, with a median age of 17.5 years. (85)

“The most common location at presentation is the metaphyses of long bones”, (85) with the distal femur being the most frequently affected. (83,85)

Surgical pathology: Macroscopically, “the tumor may appear as a blood clot, be a hemorrhagic-necrotic mass or be multicystic with blood-filled spaces or ABC-like”. (16,83) “When the blood is washed away, the cyst demonstrates many thin fibrous septa, giving it a “honeycomb” or sponge-like appearance.” (83,85)

Microscopically, “two variants are described”, (14) the “hemorrhagic-necrotic” (14) and the “ABC-like variant”, (14) “corresponding to the gross appearances.” (14,16)

“In the hemorrhagic-necrotic variant”, (16) widely separated “malignant cells are present”, (16) “in a background of blood and necrotic debris”. (16) “In some cases a delicate lacelike osteoid matrix is identified between the malignant cells.” (85)

In the ABC-like variant, necrosis is sparse or absent. Malignant cells can be seen within wall of the cyst, as well as benign giant cells, and some osteoid. (16,83) The “multinucleated giant cells” (85) in combination “with the atypical stromal cells is a common microscopic feature. In addition, foci of hemosiderin-laden macrophages are common”. (83,85)

Management: The extend of surgical resection of the tumor “depends on the location, size, and response to” (85) 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. (84–87)

6.2. Conventional Chondrosarcoma

Conventional Chondrosarcomas are malignant tumors, “in which neoplastic cells differentiate to form chondroid”, (14) instead of osteoid. If these tumors 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”, (88) they “are referred to as secondary”. (16,89–91)

Depending on their location, chondrosarcomas are subdivided into central, peripheral and periosteal subgroups. (29,90)

“Less than 2% of chondrosarcomas occur in patients less than 20 years of age”, (16) primary chondrosarcomas occur in patients between 50 and 60 years, and secondary osteosarcomas occur in patients between 40 and 50 years. (16)

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. (16) The symptoms are usually of long duration, and tumors which are located in the skull base, may cause neurological symptoms. (89)

“Chondrosarcomas are often centred around the trunk and the proximal limbs”, (16) whereof “two-thirds of chondrosarcomas occur in the limb girdles, femora, and humeri”. (16,89,92)

Surgical Pathology: High-grade (grade 2 and 3) (91,93) chondrosarcomas “are composed of cellular cartilage showing extension into soft tissues and/or permeation of bone with entrapment of preexisting trabeculae. There may be widespread mitotic activity, multinucleation of chondrocytes, and necrosis”. (16,29,94)

Low-grade chondrosarcomas (grade 1) (91,93) “can be difficult to diagnose”, (16) because they resemble benign, yet “cellular cartilage lesions such as chondromas”. (16) The best way to differentiate is to look at the location of the tumor. “Cartilagenous tumors of the sternum are almost always malignant regardless of the histologic appearance”, (14) whereas “chondromas of the hands and feet, perosteal chondromas, enchondromas of Ollier’s disease and Maffucci’s syndrome, synovial chondromatosis, and soft tissue chondromas of the hands and feet are most often benign, in spite of sometimes alarming cellularity”. (14,16,29)

Grossly, chondrosarcomas are large tumors, usually grater than 4 cm in size. (94) We can see a lobular architecture with a hyaline quality and “foci of hemorrhage, necrosis, and cystic (liquifactive or myxoid) change”. (16) “The matrix of chondrosarcomas can vary in consistency from firm hyaline cartilage to thin mucus-like” (16) (myxoid) cartilage, the latter being “very suggestive of chondrosarcoma”. (16) The areas of matrix mineralization “have a distinctive ring-and arc-like pattern”, (94) which “reflects enchondral ossification around lobules of well-formed hyaline cartilage”. (16,29,89,94)

“Microscopically, chondrosarcomas are frequently lobular, except at the very periphery”, (16) where the “lobules are completely coalescent”. (16) “Necrotic foci can later calcify”. (16) Myxoid change, which is frequent, “is a “bubbly” transformation of cartilage that can lead to cystification or liquefaction” (16) and should be taken seriously because it suggests malignancy, in case of a marked myxoid change or necrosis. (16,29,94)

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”. (16) “Chondrosarcomas also tend to be more cellular”, (16) 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”. (16,29,94)

“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” (16) and “can be hyaline or myxoid”. (16) In case of chondrosarcomas developing on osteochondromas, “wide fibrous septae are seen in some cases”, (16) 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 the adjacent soft tissues in such instances.” (16) “Calcification can be present”, (16) and is often seen “around the lobules of cartilage”. (16,29,94)

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. (16,88,90,95) Resected patients should undergo lifelong surveillance, due to the possibility of late local and systemic recurrence.(92)

6.3. Ewing sarcoma

Ewing sarcoma, also called Ewing tumour, “is a primary osseous neoplasm composed of small round cells, with no matrix production”. (16,29) “It is considered to be one of the less differentiated tumors from the group of neoplasms with neuroectodermal differentiation. Tissue culture studies in the presence of differentiation agents like cAMP, have showed that the tumour develops neural features”. (16,96,97) Ewing sarcoma tends to affect patients in the first two decades of life. (16) Highest incidence of frequency is between 10 and 20 years. There is predilection for the male sex. (29,98) Most 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. (16,29,99) The lungs are the most common site for metastases, followed by bone and bone marrow. (99) 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. (16,29)

Surgical Pathology: Macroscopically, “the tumor may be firm, glistening, or more friable, mimicking pus. Hemorrhage 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” (16) and with a rare, scarce, or variable, yet not anomalous “number of mitotic figures”. (16) In areas of necrosis, perivascular cuffing may be evident. The immunohistochemical stain, Mic 2 (CD 99) brings into evidence the “protein expression of a pseudoautosomal gene located on the X- and the Y-chromosomes”, (16) and demonstrates “membranous positivity in the large majority” (16) of Ewing’s sarcoma. “Ewing tumours show a characteristic t(11;22) chromosomal translocation”. (16,29,100–103)

Management: Progress in treatment has led to a 70-80% survival rate, excluding patients with metastases present at the time of the diagnosis. (99) The primary modality of treatment is surgery, together with chemotherapy, with or without neo-adjuvant and adjuvant radiation. (16,103)

Part 2 – PRACTICAL PART

INTRODUCTION

We started this thesis with the goal to analyse the children’s bone pathology (tumoral and non-tumoral) reflected in the database of the Pathology Laboratory of the Children Hospital Cluj-Napoca.

In this try, we want to see if are there any particularities of this bone pathology in children from Cluj area, compared with literature data.

MATERIAL AND METHOD

For this goal, we extracted from the Laboratory Data Base, the bone biopsies from the last 20 years (2000-2019) and analysed them.

These bone biopsies are coming from the Orthopedic Infantile Surgery Clinic of the Children Hospital.

The extracted data was introduced in Excel and classified in:

Non-tumoral lesions:

Metabolic diseases of the bone

Bone matrix diseases

Osteogeneses Imperfecta

Abnormal mineralization of the bone

Rickets and osteomalacia

Abnormal bone resorption

Hyperparathyroidism

Paget disease of the bone

Osteoporosis

Osteopetrosis

Traumatic bone lesions

Fractures

Bone infarctions

Aseptic necrosis of the femoral had

Ossificans myositis

Reactive periostitis

Bone Infections

Acute osteomyelitis

Chronic osteomyelitis

Bone tuberculosis

Pseudo-tumoral lesions

Solitary bone cyst

Aneurismal bone cyst

Bone cyst ganglioma

Metaphyseal fibrous defect

Fibrous dysplasia of bone

Osteo-fibrous dysplasia of the bone

Langerhans granulomatosis

Tumoral lesions

Benign

Osteochondroma

Chondroma

Osteoid osteoma

Malignant

Osteosarcoma

Chondrosarcoma

Ewing sarcoma

Other

RESULTS

Between the years 2000 and 2019 (May), 343 bone biopsies representing 0.72% from a total of 47.000 biopsies were performed, in the Children Hospital in Cluj-Napoca.

59.6% of these bone biopsies were performed in male children and 40.4% in female children.

Fig.1: Gender distribution of bone biopsy infantile cases

These children were aged between 0 and 18 years.

43% (148 cases) of these were with a non-tumoral pathology and the rest of 57% (195 cases) were with a tumoral pathology.

Fig.2: Tumoral and non-tumoral bone pathology is almost equal in children.

Fig.3: The pathological classification of the 148 non-tumoral cases

Fig.4: Repartition of our 195 cases of tumoral bone biopsy in benign and malignant cases.

Non-tumoral bone pathology

In figure 3, the distribution of our 148 non-tumoral cases on pathological classes of non-tumoral lesions, is represented.

Malformations, Metabolic Bone disorders and traumatic bone lesions are exceptionally the subject of a bone biopsy, despite the fact that they are relatively frequent in the children’s orthopedic clinical pathology, and were not present in the last 20 years in our data base.

Inflammations (32%) and pseudo-tumoral lesions (68%) are the non-tumoral bone pathology in our experience.

Inflammations

In our non-tumoral study group we encountered:

44 cases with osteomyelitis

5 acute osteomyelitis

39 chronic osteomyelitis

3 cases with proliferative periostitis

65% of these 47 inflammatory cases were boys, 35% were girls, the difference being statistically significant (P<0.05).

This difference is due to the fact that male children are more frequently the subject of bone trauma, which is the main cause of these inflammations.

The age of these children was between 0 and 18 years, but the most frequent age group affected by inflammations were children aged between 7 and 15.

Localization of this inflammations were:

Not specified – 38.2%

Femur – 29.2%

Tibia and peroneus – 17%

Humerus – 3.2%

Foot short bones – 3.2%

Hand short bones – 2.4%

Pelvis – 2.4%

Jaws – 0.8%

Clavicula – 0.8%

Scapula – 0.8%

Ribs – 0.8%

As we can see, the most frequent location of osteomyelitis in children are the long bones of the leg, which is in concordance with literature data.

This preferential location, sustains the traumatic theory for the cause of osteomyelitis.

Fig.5: Acute osteomyelitis

Pseudo-tumoral bone lesions

Solitary bone cyst

We encountered in our database, 18 cases with solitary simple bone cysts, 13 being boys and 5 being girls, between 5 and 17 years old.

This significant male incidence of this lesion, is not mentioned in the literature, and is eventually related to a possible traumatic etiology of these lesions.

The humerus was the main location of this lesion, followed by the femoral bone, in concordance with literature.

Fig.6: Solitary bone cyst localization and Rx image from one of our cases.

Aneurismal bone cyst

We encountered in our study group, 45 cases with this diagnosis, making it the second most frequent non-tumoral single bone lesion in children.

30 were boys and 15 were girls, aged between 5 and 17, with a maximum incidence between 7 and 16 years. This male preponderance is again, not mentioned in the literature, and might, as well, be related to a possible traumatic etiology of the lesion.

The humerus and femoral bone are again the main location of this lesion, as it was for the simple cyst, another lesion with male predominance and possible traumatic etiology.

Fig.7: Aneurismal bone cyst localization and Rx

Fig.8: Microscopic aspect of aneurismal bone cyst

Metaphyseal fibrous defect (non-ossifying bone fibroma)

We have encountered 10 such cases in our database. With 6 girls and 4 boys, this is the first entity from this group, without male predominance, and probably, without traumatic etiology.

Aged between 8 and 17, these lesions were located exclusively in the long bones of the leg, as it is also mentioned in the literature.

Fig.9: Localization and microscopic aspect of non-ossifying fibroma

Fibrous- and osteofibrous dysplasia of the bone

We encountered 17 cases with fibrous dysplasia of the bone (monostotic form) and 1 case with osteofibrous dysplasia of the bone.

Gender distribution was almost equal (10 boys and 8 girls), aged between 5 and 16 years, being again a non-traumatic derivate lesion.

The main location was in the long tubular bones of the limbs, as it is mentioned in the literature.

Fig.10: Localization and microscopic aspect of fibrous dysplasia of the bone

Eosinophilic granuloma (Langerhans granulomatosis)

We encountered 11 cases with eosinophilic granuloma of the bone. Gender distribution was 4 boys and 7 girls, between 1 and 15 years old, being again a non-traumatic derivate lesion.

Main location was in the femoral bone, as it is mentioned in the literature.

Fig.10: Localization and microscopic aspect of eosinophilic granuloma of the bone

Tumoral bone lesions

Benign tumoral lesions

We encountered 162 benign tumors of the bone in our data base. The list of this tumors is presented below.

Osteochondromas (exostosis) – 100 cases

Osteoid osteoma – 6 cases

Chondromas – 37 cases

Sacro-coccygeal teratoma – 4 cases

Osteoma – 11 cases

Chondroblastoma – 1 case

Chondromyxoid fibroma – 3 cases

Osteochondromas

Being the most frequent tumor of the bone, we encountered it in 58 boys (58%) and 42 girls (42%) aged between 1 and 19.

In only 5 of these cases, the lesion was multiple, the rest, being unique.

The main location was at the level of the metaphysis of the long bones (femoral bone mostly), but also at the level of the short bones of the hand and foot.

Fig.11: Localization and Rx of exostosis

Fig.12: Localization and Rx of chondromas

Chondromas

On the second place regarding bone tumors, chondromas are affecting equally both genders (19 boys and 18 girls), between the ages 2 and 19 years.

Only 1 case from this series was with multiple lesions, and was included in the Ollier Disease category.

Localization was mostly in the short bones of hand and foot, however it was also encountered in long bones.

Fig.13: Microscopic image from the only case with chondroblastoma

Chondroblastoma

We only had 1 such case, a 4 year old boy, with the tumor located in the humerus.

Chondromyxoid fibroma

We had 3 such cases (2 girls and 1 boy) aged between 7 and 17 years. 2 of them were located in the tibia and 1 in peroneally.

Osteoid osteoma

With only 6 cases, it seems to be a more rare entity than expected, in comparison to the literature.

2 cases were boys and 4 cases were girls, aged between 5 and 15.

4 cases were located in the short bones of the foot (metatarsi, calcaneus and phalanx) and 2 cases on the long bones (tibia and humerus).

Osteoma

Being a rare tumor for the childhood period, we only encountered 11 cases. All were boys, aged between 11 and 16 years.

2 cases were located in the neurocranium, 8 in short bones of hand and foot and 1 in the sacral area.

Malignant bone tumors

We encountered 33 cases with malignant tumors of bones.

Osteosarcoma – 20 cases

Chondrosarcoma – 2 cases

Ewing sarcoma – 11 cases

Osteosarcoma

This was the most frequent tumor, in our study group, from this class. 9 cases were boys and 11 were girls, with age between 5 and 17.

Fig. 14: Gender distribution of osteosarcoma cases reveals nonsignificant gender predisposition.

Histological subtypes of our osteosarcoma cases were:

Conventional osteosarcoma – 9 cases – 45%

Telangiectatic osteosarcoma – 9 cases – 45%

Giant cell osteosarcoma – 1 case – 5%

Small cell osteosarcoma – 1 case – 5%

Fig.15: Conventional osteosarcoma. Typical HE image with atypical cells producing osteoid matrix.

Fig.16: Conventional osteosarcoma. Comparing the HE (left), Trichrome Masson stain (right) puts the new osteoid formation in even better evidence.

Fig 17: Necrosis and hemorrhage are common in conventional osteosarcomas. Hemorrhagic areas can particularly induce confusions with the telangiectatic form.

Fig.18: Giant cell osteosarcoma is considered to be a form of conventional osteoblastic osteosarcoma.

Fig.19: Small cell osteosarcoma is also a form of conventional osteosarcoma but the differential diagnosis with a bone lymphoma has to be taken into consideration. Immunohistochemistry is sometimes necessary in this situation, the small cells being vimentin positive (in our image) and LCA negative.

Fig. 20: Telangiectatic osteosarcoma have vascular spaces and solid areas. HE x40

Fig.21: Osteoid formation appears between vascular spaces.

Fig.22: Large multinucleated osteoclast-like cells are present in the solid area, like in aneurysmal bone cysts, making the differential diagnosis sometimes very difficult.

A differential comparation between classic osteosarcoma (with giant and small cell forms) and telangiectatic osteosarcoma, reveal the same gender and age distribution for both.

Fig.23: Differential annual distribution of these 2 forms of osteosarcoma indicates tendency in decrease of multiannual incidence for classic osteosarcoma and increase for telangiectatic osteosarcoma, but without statistical significance.

Fig.24: The differential analysis of distribution, didn’t come with significant differences between conventional and telangiectatic osteosarcoma.

After the year 2000, proof was provided by the literature, that aneurismal bone cysts are containing some genetic mutations, transforming the concept of them being a pseudo-tumoral lesion, into the concept of being a premalignant lesion for the telangiectatic form of osteosarcoma.

Ewing sarcoma

We encountered 11 cases with this diagnosis, all of them with positive immunohistochemical markers (CD99+++ and PAS positive) but no genetic confirmation.

8 cases were boys and 3 were girls, which is a significant male predilection for this cancer (2x higher in comparison to literature reports), aged between 5 and 18 years.

Fig.25: The significant male incidence of Ewing sarcoma.

Localization of this tumors was:

Long bones – 3 cases

Short and wide bones – 3 cases

Extra-skeletal (soft tissue) – 5 cases

This localization distribution indicates an almost equal chance for a Ewing sarcoma to be skeletal or in the soft tissue.

Fig.26: HE aspect of Ewing sarcoma. A small, round, blue cell tumor.

Fig.27: PAS stain is characteristically positive in this tumor

Fig.28: The immunohistochemical profile is very important for diagnosis, the tumor being characteristically intense CD99 positive. Rhabdomyosarcoma is the main differential diagnosis with this immuno-profile and in some cases with DES+, only the genetic test for t(11,21) make differential possible.

Chondrosarcoma

We only encountered 2 such cases in the last 20 years, a 5 year old girl with humeral chondrosarcoma, and a 9 year old boy, with extra-skeletal, soft tissue, chondrosarcoma.

DISSCUSIONS

Bone biopsy represents less than 1% from the general work volume of a Pathology Laboratory in a Children Hospital.

Bone pathology which involves bone biopsies affect more frequently boys, of all ages (0-18 years) especially because they are more exposed to bone trauma during their playing habits.

Tumoral pathology is the most frequent (57%) cause of a bone biopsy but non-tumoral pathologies almost equal the tumoral pathologies in their need for bone biopsy, especially because of pseudo-tumoral lesions.

Inflammations of the bone, represent 31.7% of non-tumoral pathologies, and 13.7% of all bone biopsies, in our study group, being represented mostly by osteomyelitis.

Osteomyelitis, affects significantly more frequent, boys, due to the fact that this pathology is related to trauma exposure, and is mostly located in the long bones.

The pseudo-tumoral lesions, represent 70.6% of non-tumoral pathologies and 29.6% of all bone biopsies.

Aneurysmal bone cysts (ABC), represent the main pseudo-tumoral lesions, representing alone, 44.55% of pseudo-tumoral lesions and 13.19% of all bone biopsies.

Of unknown etiology, is considered to result from local bone, hemodynamic disturbances, being as a primary lesion the result of a arterio-venous shunt, or secondary to the nearby presence of tumoral mass. Recently a mutation was described (a TRE17/USP6 translocation) (100) in this pseudo-tumoral lesion, generating the opinion that this lesion maybe a premalignant condition for the telangiectatic osteosarcoma.

In our study group, boys were significantly more frequently affected by ABCs, while telangiectatic osteosarcoma had a non-significant more frequent incidence in girls.

This suggests that, trauma (potentially by inducing a secondary arterio-venous shunt), is a potential etiology for ABCs (male significant predominance), but girls are more susceptible to develop the genetic mutations for a malignant transformation of the diseases.

Solitary bone cysts, also have a significant male predominance, indicating again, a possible consequence for traumatic etiology.

Tumoral lesions of the bone, represent 57% of all bone biopsies, fortunately 83% of them are benign tumors.

By far the most frequent tumor and most frequent cause for bone surgical biopsy, are osteochondromas. They represent 51.2% of tumoral bone lesions, and 29.3% of all bone biopsies, being the most frequent single lesion that requires bone biopsy.

Affecting almost equally both genders, this tumor, has a small, but present risk for malignization. Despite the fact that in some locations (feet and hand) they can be described as “bizarre parosteal osteochondromatous proliferation – Nora’s lesions” the risk for malignization of this bizarre osteochondromas remain low.

Chondromas are the second most frequent bone tumors, representing 18.97% of all tumors and 10.8% of all bone biopsies.

Again, they have a low risk for malignization with the exception of Ollier syndrome (1 case in our study group).

Osteosarcomas are the most frequent malignant bone tumors in children. They represent 10.25% of tumoral bone pathology and 5.8% of all bone biopsies in children.

Conventional and telangiectatic osteosarcomas, seem to have different etiologies, the second one being considered more aggressive and with a tendency to increase in frequency, in the last 20 years.

Despite a female preponderance, this is not a significant one.

Ewing sarcoma is the second malignant bone tumor, but in our experience, 5 from 11 cases were located in the soft tissue, being extra-skeletal.

Chondrosarcomas seem to be in a decreasing incidence in the last 20 years, our only 2 cases, being both encountered before the year 2010.

CONCLUSIONS

Bone biopsies represent less than 1% from the general work volume of a Pathology Laboratory in a Children Hospital.

Inflammations of the bone, represent 31.7% of non-tumoral pathologies, and 13.7% of all bone biopsies, in our study group, being represented mostly by osteomyelitis.

The pseudo-tumoral lesions, represent 70.6% of non-tumoral pathologies and 29.6% of all bone biopsies.

Aneurysmal bone cysts (ABCs), represent the main pseudo-tumoral lesion, representing alone, 44.55% of pseudo-tumoral lesions and 13.19% of all bone biopsies.

Tumoral lesions of the bone, represent 57% of all bone biopsies, fortunately 83% of them are benign tumors.

Osteochondromas represent 51.2% of tumoral bone lesions, and 29.3% of all bone biopsies, being the most frequent single lesion that requires bone biopsy.

Chondromas are the second most frequent bone tumor, representing 18.97% of all tumors and 10.8% of all bone biopsies.

Osteosarcomas are the most frequent malignant bone tumor in children. They represent 10.25% of tumoral bone pathology and 5.8% of all bone biopsies in children.

Ewing sarcoma is the second malignant bone tumor, but in our experience, 5 from 11 cases were located in the soft tissue, being extra-skeletal.

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