XII Международная студенческая научная конференция Студенческий научный форум - 2020

BONE TUMORS: DEFINITION

Bone tumor is an inexact term, which can be used for both benign and malignant abnormal growths found in bone, but is most commonly used for primary tumors of bone, such as osteosarcoma (or osteoma). It is less exactly applied to secondary or metastatic tumors found in bone.

CLASSIFICATION

Bone tumors may be classified as "primary tumors" which originate in the bone, and "secondary tumors" which originate elsewhere.

PRIMARY TUMORS

Primary tumors of bone can be divided into benign tumors and cancers. Common benign bone tumors may be neoplastic, developmental, traumatic, infectious, or inflammatory in etiology. Examples of benign bone tumors include osteoma, osteochondroma, aneurysmal bone cyst, and fibrous dysplasia.

Malignant primary bone tumors include osteosarcoma, chondrosarcoma, Ewing's sarcoma, and other sarcoma types. Multiple myeloma is a hematologic cancer, which also frequently presents as one or more bone tumors.

SECONDARY TUMORS

Secondary bone tumors include metastatic tumors, which have spread from other organs, such as the breast, lung, and prostate. Metastatic tumors more frequently involve the axial skeleton than the appendicular skeleton. Tumors that originate in the soft tissues may also secondarily involve bones through direct invasion.

CHARACTERISTICS OF BONE CANCER OCCURRENCE

Bone cancer is not a common cancer compared to many other types of cancer. The principal malignant tumors of bone are:

a) osteosarcomas that occur mostly in the leg bones of children and young adults; this form is more frequent among girls under 15 and boys over 15; its incidence is higher among nonwhites than whites; b) chondrosarcomas that usually afflict people over 40 years of age; this is a slow-growing tumor that often starts in the pelvic bones;

c) Ewing's sarcoma, a cancer that impacts mainly children and teenagers; this form infiltrates large bones such as those of the thigh, upper arm, shin or pelvis; two times as many males are affected as females; a fast-growing tumor, its incidence is almost 9-fold higher among whites than blacks.

EPIDEMIOLGY

According to the U.S. Surveillance, Epidemiology and End Results Program, osteosarcomas contribute 36% of all types of bone cancer, followed by chondrosarcomas and Ewing's sarcomas with around 30% and 16% respectively. The incidence of osteosarcoma appears to be more frequent in two periods of life, during adolescence and old age.

Regarding the geographical distribution of incidence and according to the Unit of Descriptive Epidemiology of the International Agency for Research on Cancer (IARC), only a few countries in Africa have reliable statistics on bone cancer. Among them, Mali has the highest standardized rate among males (1.4 per 100,000), while Algeria exhibits the highest rate among females (1.2 per 100,000), with a male/female ratio ranging from 0.75 to 1.55(3).

In the Americas, Chinese males in Hawaii have the highest incidence rate of bone cancer (6.4 per 100,000). Actually, this is the highest rate in the world. Among females, Paraguay has the highest incidence rate in the region (1.6 per 100,000). The highest male-female ration (9.0) in the world is found among Japanese Americans in Los Angeles, California. In the United States, Filipino males and Japanese females have the lowest incidence rates for bone cancer. Canada has a moderate frequency rate of bone cancer within the America. In Canada, Quebec seems to have the highest and New Brunswick, the lower rate of bone cancer patients.

In Europe, Poland (Wilesia) has the highest incidence rate of this disease in both males and females, with 2.4 and 1.5 per 10,000 respectively, while Italy shows the lowest rates for males and females. Both France and Sweden have the highest male/female ratio.

In Australia, the incidence rate of this disease ranges from 0.3 per 100,000 in Tasmanian males to 2.0 in Maori males. In females, except for Maoris (1.2 per 100,000), most regions have an age standardized rate below 1.0 per 100,000. In general, this continents has the highest male/female ratio (around 1.6), indicating a higher incidence rate of bone cancer among males.

In Asia, the Philippines (Manila) has the highest rate of males while Thailand (Khon Kaen) has the highest frequency in females. It is interesting that Singapore Indians have the lowest male/female ratio of bone cancer in the world (0.5), while Israeli on-Jews show the second highest worldwide male/female ratio (4.0).

In brief, among males, Chinese in Hawaii have the highest incidence rate of bone cancer, while Khon Kaen of Thailand has the highest rate among women in the world.

With regard to the mortality rate from bone cancer, we compared existing statistics on different continents for two time periods (1984-86 and 1994-96). In general, the mortality rate of the world's population decreased in males from 1.01 to 0.91. In females, the rate in 1984-86 was 0.78, which fell to 0.63 in 1994-96.

The mortality rates from bone cancer rose significantly among both males (from 0.47 to 0.80) and females (from 0.41 to 1.04) in Africa, indicating a 7% increase among males and an increment of more than 15% among females for a period of 10 years. Although the number of cases is small, it still indicates a significant elevation of mortality from bone cancer. In the Americas, a 0.3% increase in male and a 0.4% rise in female mortality from bone cancer have been reported. Interestingly, this disease shows a higher frequency among Asian males compared to the rate 10 years ago; the rate has remained unchanged among females. The two continents of Europe and Oceania have seen a sharp and significant decrease of the mortality rate. For example, in Europe, the rate fell by around 2.4% in males and by 1.8% in females. In Oceania, these declines were 2.4% in males and 2.9% in females.

The rate reduction could be mostly due to better and advanced treatment of bone cancer as well as disease prevention through public education and awareness in avoiding known risk factors. In general, it seems that the mortality rates from bone cancer are decreasing.

ETIOLOGICAL FACTORS FOR BONE CANCER

Bone cancer comprises around 5% of all cancers among children in developed countries, particularly in North America and Europe. There is little information about risk factors for bone cancer in adults, while some data are available on the etiology of this disease among children. Therefore, in this section, we will review the existing evidence of risk factors for bone cancer in children.

Genetics:

The possible role of genetics in the etiology of bone cancer was suggest in a cohort of 850 children with bone cancer in England. In a meta-analysis of five studies, twin cases developed osteosarcoma as well as retinoblastoma, while no twins with Ewing's sarcoma or non-specified bone cancer showed a affected co-twin. In general, family aggregation of osteosarcoma is rare. Recently Longhi et al reported four cases of osteosarcoma in two siblings and in a father and son. These patients had no other tumors in their family history and had negative p53 mutations.

It seems that the frequency of certain types of cancer, such as melanoma and brain tumors (OR=1.9) or stomach cancer (OR=2.0), is higher among the first-degree relatives of cases of Ewing’s sarcoma of bone and soft tissues.

In a multicenter study of osteosarcoma in the United States and Canada, 3% of subjects exhibited germ-line p53 mutations. In another case-control investigation in Spain, a significantly higher proportion of children with osteosarcoma had HLA-Al1 and HLA-B7 antigens. Such a high frequency ofHLA-A11 antigen was also found in Japan in 1990(11), while the possible role of HLA-B7 reported by Barona et al'o was not confirmed by any other authors.

Socio-demographics:

Holly et al. observed that regular intake of mixed vitamin supplements during childhood decreases the risk of bone tumors (RR=0.4; 95%CI 0.1-1.4), but another group reported no association between vitamin or mineral supplements and bone tumors. Hartley et al examined the possible role of breast-feeding in bone cancer prevention. They concluded that there was no association. Several other studies found no association between bone tumors and maternal or paternal smoking during pregnancy, while another case-control investigation of Ewing's sarcoma showed that both paternal and maternal smoking during pregnancy increased the risk of this disease in children. The relative risk was 2.0 from maternal smoking and 3.7 from paternal exposure. It should be mentioned here that if both parents were smokers, the risk was more than 7-fold higher compared with non-smoker parents.

Holly et al. observed no association between maternal smoking during pregnancy and the risk of osteosarcoma. No association was reported for maternal alcohol intake during pregnancy and bone cancer in general, Ewing's sarcoma or osteosarcoma. Winn et al discerned no correlation between maternal coffee consumption during pregnancy and the risk of Ewing's sarcoma.

Ionizing radiation:

In a follow-up study of 220 children with tuberculosis treated by radium-224, around 16% developed bone cancer, particularly osteosarcoma. In a case-control study, no association was found between osteosarcoma and postnatal exposure to diagnostic ionizing radiation.

Maternal reproductive history:

There appears to be no association between maternal age, number of previous pregnancies as well as difficulty of becoming pregnant and bone cancer. Mothers who use medications for nausea and vomiting during pregnancy have a significantly higher risk of having children with Ewing's sarcoma.

Two case-control studies observed no association between maternal estrogen use in the year before or during pregnancy and the risk of osteosarcoma in children up to age 24 years.

Medical History:

Schumacher et al. reported an excess of rib abnormalities among Ewing's sarcoma patients, but not in osteosarcoma cases. A case-control study in the United States found a high rate of hernias and heart conditions among Ewing's sarcoma subjects. The high frequency of hernias occurred early in life. This finding was not confirmed by another case-control investigation in California or by a comparison of England and Canada.

Other factors:

In a large cohort of male, world-class Finnish athletes, with 30 to 60 years of follow-up, no cancer sites showed a significant excess, but there was a significantly higher risk of sarcoma of the bone and soft tissue. It was suggested that the history of injuries during their active sports period might have been the major cause of the high frequency of bone and soft tissue sarcoma.

TYPES OF BONE TUMORS

OSTEOMA

Osteoma is a benign bony outgrowth of membranous bones. They are found mostly on skull and facial bones. Large osteomas may develop on the clavicle, pelvis, and tubular bones (parosteal osteomas). Soft tissue osteomas may occur in the head, eye, and tongue, or in the extremities. Osteomas are slow growing lesions that are normally completely asymptomatic. They only present if their location within the head and neck region is causing problems with breathing, vision, or hearing.

The highest incidence is in the sixth decade. Some authors report that osteomas occur more often in women than men (3:1). Multiple osteomas are associated with Gardner's syndrome. The etiology of osteomas is unclear. They may be related to osteoblastomas or may simply be a developmental anomaly. The fact they are often found in the auditory canals of swimmers and divers who frequent cold water suggests that in some cases they are some type of inflammatory reaction.

The radiological appearance of osteomas depends on their location. Central osteomas are well-delineated sclerotic lesions with smooth borders, without surface irregularities or satellite lesions. Dr. Enneking describes the lesion as having the appearance of "one-half of a billiard ball" attached to the underlying bone. The adjacent cortex is not involved or weakened. Peripheral osteomas are radiopaque lesions with expansive borders that may be sessile or pedunculated. Osteomas need to be differentiated from enostosis that also appear as densely sclerotic well-defined lesions on x-ray.

Bone scan will show increased uptake during the active phase of growth, which will diminish to background levels as the lesion becomes progressively less active.

There are two types of osteomas microscopically. Compact or "ivory" osteomas are made of mature lamellar bone. They have no Haversian canals and no fibrous component. Trabecular osteomas are composed of cancellous trabecular bone with marrow surrounded by a cortical bone margin. Trabecular osteomas can be found centrally (endosteal) or peripherally (subperiosteal).

Treatment of osteomas is only necessary if they are symptomatic. Large osteomas should be evaluated to rule out other diagnoses.

OSTEOCHONDROMA

Osteochondroma, or osteocartilaginous exostosis, is the most common skeletal neoplasm. The cartilage capped subperiosteal bone projection accounts for 20-50% of benign bone tumors and 10-15% of all bone tumors. Osteochondromas occur most frequently in the first two decades of life with a ratio of male to female of 1.5 to 1. Osteochondromas are found most often in long bones, especially the distal femur and proximal tibia, with 40% of the tumors occurring around the knee. 2

Osteochondromas are most likely caused by either a congenital defect or trauma of the perichondrium, which results in the herniation of a fragment of the epiphyseal growth plate through the periosteal bone cuff. Osteochondromas can either be flattened (sessile) or stalk-like (exostosis) and appear in a juxta-epiphyseal location. The lesions occur only in bones that develop from cartilage (endochondral ossification). Osteochondromas are also the result of radiation therapy in children. After the close of the growth plate in late adolescence there is normally further growth of the osteochondroma. Clinically, osteochondromas present with pain due to mechanical irritation or a painless mass. A fracture can occur through the stalk of the lesion, which also causes pain.

Hereditary multiple osteochondromatosis is an autosomal dominant condition that can lead to both sessile and pedunculated lesions. The lesions may occur on different bones or on the same bone, and symptoms present in the first decade of life. The risk of malignant transformation to chondrosarcoma in hereditary multiple osteochondromatosis is unknown, but may be 25-30% compared to approximately 1% for a solitary osteochondromas.3 The risk of malignant degeneration increases as the number and size of the osteochondromas increases. In general, a sessile lesion is more likely to degenerate into sarcoma than an exostosis.

Plain films are normally enough to diagnose osteochondromas. Sessile lesions cover a wide area and as a result cause metaphyseal widening or a "trumpet shaped deformity" on x-ray. Lesions with stalks are often found more distally and are common over the posterior femoral metaphysis. CT is helpful in determining if the marrow and cortices of the lesion are continuous with the bone. The relationship of the lesion to other structures and the thickness of the cartilage cap are best delineated with MRI.

On gross examination, an osteochondroma is an irregular bony mass with a bluish gray cap of cartilage. Opaque yellow cartilage has calcification within the matrix. The base of the lesion has a rim of cortical bone and central cancellous bone. Occasionally, a bursae develops over an osteochondroma. Normally, the cartilage cap ranges from 1-6 mm thick. Over 2 cm of cartilage or renewed growth of a dormant lesion is signs of possible malignant transformation. Under the microscope, an osteochondroma has endochondral ossification on the basal surface of hyaline cartilage so it resembles a normal growth plate with rows of chondrocytes. The cartilage is more disorganized than normal, has binucleate chondrocytes in lacunae, and is covered with a thin layer of periosteum. There is no treatment necessary for asymptomatic osteochondromas. If the lesion is causing pain or neurologic symptoms due to compression, it should be excised at the base. As long as the entire cartilage cap is removed, there should be no recurrence. Patients with many especially large osteochondromas should have regular screening exams and radiographs to detect malignant transformation early.

ANEURYSMAL BONE CYST

Aneurysmal bone cyst (ABC) is a solitary, expansible and erosive lesion of bone. It is found most commonly during the second decade and the ratio of female to male is 2:1. ABC's can be found in any bone in the body. The most common location is the metaphysis of the lower extremity long bones, more so than the upper extremity. The vertebral bodies or arches of the spine also may be involved. Approximately one-half of lesions in flat bones occur in the pelvis. One theory of the etiology of primary ABCs is that these lesions are secondary to increased venous pressure that leads to hemorrhage which causes osteolysis. This osteolysis can in turn promote more hemorrhage causing amplification of the cyst.

More often, ABC's are thought to be a reactive process secondary to trauma or vascular disturbance. ABC's can be secondary to an underlying lesion such as non-ossifying fibroma, chondroblastoma, osteoblastoma, UBC's, chondromyxoid fibroma and fibrous dysplasia. This association is so strong that the lesion should be examined microscopically in several places to eliminate the possibility of a primary lesion. In one report (Kransdorf, Amer J Roentgenol 1995 Mar;164(3):573-80) the authors state that the original lesion can be identified in one-third of cases. The most common precursor lesion was giant cell tumor, (19-39%) of cases, followed by osteoblastoma, angioma, and chondroblastoma. Less common precursor lesions were fibrous dysplasia, non-ossifying fibroma, chondromyxoid fibroma, unicameral bone cyst, fibrous histiocytoma, eosinophilic granuloma, and osteosarcoma. A translocation involving the 16q22 and 17p13 chromosomes has been identified in the solid variant and extra osseous forms of aneurysmal bone cyst.

The clinical presentation of an ABC is swelling, tenderness and pain. Occasionally there is limited range of motion due to joint obstruction. Spinal lesions can cause neurological symptoms secondary to cord compression. Pathological fractures are rare due to the eccentric location of the lesion. Depending on the location, the differential includes UBC, chondromyxoid fibroma, giant cell tumor, osteoblastoma and the highly malignant telangiectatic osteosarcoma.

On plain film, an ABC is normally placed eccentrically in the metaphysis and appears osteolytic. The periosteum is elevated and the cortex is eroded to a thin margin.The expansile nature of the lesion is often reflected by a"blow-out" or "soap bubble" appearance. CT scan can also help delineate lesions in the pelvis or spine where plain film imaging may be inadequate. CT scan can narrow the differential diagnosis of ABC by demonstrating multiple fluid-fluid levels within the cystic spaces. MRI can also confirm the multiple fluid-fluid levels and the non-homogeneity of the lesion. ABC appears on both T1 and T2 MRI with a low signal rim encircling the cystic lesion. A careful search for radiological signs of the precursor lesion, if any, is recommended. Some lesions may have a flocculent chondroid matrix that may be a clue to their pathogenesis.

On gross examination, an ABC is like a blood-filled sponge with a thin periosteal membrane. Soft, fibrous walls separate spaces filled with friable blood clot. Microscopically, the ABC has cystic spaces filled with blood. The fibrous septa have immature woven bone trabeculae as well as I macrophages filled with hemosiderin, fibroblasts, capillaries and giant cells.

The treatment approach will vary depending of the location and aggressiveness of the lesion. A slow growing, indolent ABC has been observed to regress spontaneously. Selective embolectomy of nutrient vessels and percutaneous injection of a fibrosing agent are newer treatment modalities. Herve Deramond used percutaneous injection of methyl methacrylate successfully for an aggressive ABC lesion in the second cervical vertebra.

Most lesions can be treated with curettage and application of a high-speed burr. Local recurrence rates vary widely, with one recent report having 4 recurrences in 40 patients (Gibbs JBJS Am 1999 Dec; 81(12):1671-8). Recurrence was statistically related to young age and open growth plates, and may be less likely following wide excision than following intraregional treatment by curettage. If a recurrence is detected, a thorough examination of the original radiographs and pathology specimens should be performed to insure that the primary lesion, if any, is discovered, since this may radically alter the treatment plan. Once the precise diagnosis is known, local recurrences may be retreated by appropriate methods. Wide resection and limb-sparing reconstructions are necessary to prevent progressively destructive recurrence. Curettage and bone graft can be complicated by profuse bleeding from the lesion. If bleeding is a concern, preoperative selective embolization can be used. Radiation has been used in some cases where operative treatment is not possible, but this adds the additional risk of malignancy.

FIBROUS DYSPLASIA

Fibrous dysplasia is an uncommon, benign disorder characterized by a tumor-like proliferation of fibro-osseous tissue. The cause of fibrous dysplasia is unknown. Most cases of fibrous dysplasia display no particular pattern of inheritance. Fibrous dysplasia can present as an autosomal dominant disorder affecting the mandible and maxilla bones in children in their teenage years.

The tissue in the tumor is immature, woven bone that cannot differentiate in to mature, lamellar bone. This may be due to a mutation in a cell surface protein. There may be a relationship between the c-fos proto-oncogene and the development of fibrous dysplasia. This is a somatic mutation, rather than in the germline. The abnormality is limited to the tissues within the lesions. The cells have an increased number of hormone receptors, which may explain why these lesions become more active during pregnancy. This author has seen patients who have increased pain in their fibrous dysplasia lesions linked to their monthly menstrual cycle.

This tumor is normally a monostatic (solitary) tumor that arises during periods of bone growth in older children and adolescents and slowly enlarges. Monostatic fibrous dysplasia accounts for 75 to 80% of cases. Polyostotic fibrous dysplasia may occur as multiple lesions in adjacent bones. It accounts for 7% of benign bone tumors. Fibrous dysplasia can occur anywhere but is usually found in the proximal femur, tibia, humerus, ribs, and craniofacial bones in decreasing order of incidence. Skeletal deformities can occur because of repeated pathological fractures through affected bone.

Polyostotic cases can affect multiple adjacent bones or multiple extremities. The combination of polyostotic fibrous dysplasia, precocious puberty, and cafe au lait spots is called Albright's syndrome.

The association of fibrous dysplasia and soft tissue tumors has been given the name Mazabraud's syndrome. Other endocrine abnormalities including hyperthyroidism, Cushing's disease, thyromegaly, hypophosphatemia, and hyperprolactinemia have been associated with fibrous dysplasia.

Most patients are diagnosed with fibrous dysplasia in the first three decades of life. Cases of polyostotic fibrous dysplasia are typically diagnosed in the first decade of life. Females and males are equally affected.

Monostotic fibrous dysplasia may be completely asymptomatic and is often an incidental finding on x-ray. Pain and swelling at the site of the lesion can also be present. Female patients may have increased symptoms during pregnancy. Unfortunately, this tumor can also present as a pathological fracture that is followed by a nonunion or malunion.

Radiographically, fibrous dysplasia appears as a well-circumscribed lesion in a long bone with a ground glass or hazy appearance of the matrix. There is a narrow zone of transition and no periosteal reaction or soft tissue mass. The lesions are normally located in the metaphysis or diaphysis. There is sometimes focal thinning of the overlying cortex, called "scalloping from within". The radiological appearance can also be cystic, pagetoid, or dense and sclerotic. Repeated fractures through lesions in the proximal femur can result in the formation of a so-called shepherd's crook deformity.

T-99 bone scan uptake may be normal or increased. Bone scans are not helpful in diagnosing these lesions but can be useful in identifying asymptomatic lesions. MRI scans are CT scans can be helpful in delineating the extent of the lesion and identifying possible pathological fractures. MRI can identify sarcomatous change within the lesion or CT scans.

On gross appearance, the tumor is a solid white or tan mass. The cut surface is gritty or sandy because of the fine bone spicules it contains. Microscopically, fibrous dysplasia appears as irregular foci of woven bone arising from a cellular fibrous stroma. The stroma has a whorled appearance and is highly vascular. The short, irregular bone segments or trabeculae are not rimmed by osteoblasts. These irregular trabeculae have been described as "Chinese letters" or "alphabet soup". No lamellar bone is found within a fibrous dysplasia lesion.

A biopsy may be needed to confirm the diagnosis, but surgery is not necessary for an asymptomatic lesion unless there is a risk for pathological fracture. Lesions whose behavior is latent (see more about that here) do not need any evaluation or treatment unless there is a risk of pathologic fracture (more about that here).

Surgery with curettage of the lesion can be associated with high rates of local recurrence. Cortical grafting or implant fixation can stabilize painful long bone lesions. Cortical strut grafts are preferred to a morselized cortical cancellous graft, which can become replaced with the same immature fibrous lamellar bone that comprised the lesion. Curettage and bone grafting alone is best suited to lesions in non-weight bearing bones.

Lesions within the proximal femur are a particular challenge because they present in the young patients, and complications of treatment or from the tumor can lead to significant damage to the affected hip joint and long-term disability. These lesions should be evaluated carefully for risk of pathological fracture. It is the author's opinion that rigid, intramedullary fixation with the strongest possible device (a steel or titanium cephalomedullary nail) is the best method for treatment of proximal femoral lesions.

Curettage and bone grafting of proximal femoral lesions cannot be counted on to provide long-term healing, since the bone graft seems to be reabsorbed by the lesion in some cases. Persistent nonunion, malunion and refracture through lesions in the femoral neck has been frequently observed. Orthopedic surgeons are counseled to consult with an orthopedic oncologist for optimal management of these difficult lesions.

The authors feel that patients with symptomatic or large lesions from fibrous dysplasia should be placed on bisphosphate medicines long-term. These medicines have proven effective in reducing symptoms and increasing cortical thickness. The author uses Fosamax 35 mg weekly for children and 70 mg weekly for adults. Any patient with fibrous dysplasia who has had surgical stabilization should be placed on Fosamax post-operative. Review the indications and dosage for Fosamax before prescribing. The use of Fosamax in children is not routine and should be managed carefully and conjunction with an experienced pediatrician. Large, symptomatic or critical lesions can be managed with intravenous bisphosphonate medicines, including zolendronic acid.

CHONDROSARCOMA

Chondrosarcoma is a malignant tumor that produces cartilage matrix. Primary chondrosarcoma is very uncommon, arises centrally in the bone, and is found in children. Secondary chondrosarcoma arises from benign cartilage defects such as osteochondroma or enchondroma. Chondrosarcoma can also be classified as intramedullary, which generally arise from enchondromas, and surface which arise from osteochondromas. Chondrosarcoma occurs in the fifth or sixth decades and has a male to female ratio of 1.5 to 1. It is most common in the femur, humerus, ribs and on the surface of the pelvis. Patients with Ollier's disease (multiple enchondromatosis) or Maffucci's syndrome (multiple enchondromas and hemangiomas) are at much higher risk of chondrosarcoma than the normal population and often present in the third and fourth decade.

The presentation of chondrosarcoma depends on the grade of the tumor. A high-grade, fast growing tumor can present with excruciating pain. A low grade, more indolent tumor is more likely to present as an older patient complaining of hip pain and swelling. Pelvic tumors present with urinary frequency or obstruction or may masquerade as "groin muscle pulls".

On plain radiographs, chondrosarcoma is a fusiform, lucent defect with scalloping of the inner cortex and periosteal reaction. Extension into the soft tissue may be present as well as punctate or stippled calcification of the cartilage matrix. CT is helpful in defining the integrity of the cortex and distribution of calcification. MRI is invaluable in surgical planning as it demonstrates the intraosseous and soft tissue involvement of the tumor. MRI is also helpful in evaluating possible malignant degeneration of osteochondromas by allowing accurate measurements of the cartilage cap, which should be less than 2 cm thick.

On gross examination, chondrosarcoma is a grayish-white, lobulated mass. It may have focal calcification, mucoid I degeneration, or necrosis. Histologically, chondrosarcoma is differentiated from benign cartilage growths by enlarged plump nuclei, multiple cells per lacunae, nucleated cells, and hyperchromic nuclear pleomorphism. Chondrosarcoma is graded from 1 (low) to 3 (high). Low-grade chondrosarcoma is very close in appearance to enchondromas and osteochondromas and has occasional binucleated cells. High grade chondrosarcomas have increased cellularity, atypia and mitoses. There is an inverse relationship between histologic grade and prognosis with higher grades having a worse prognosis and early metastases.

There are three additional types of chondrosarcoma. Mesenchymal chondrosarcoma is a rare variant with a bimorphic histologic picture of low-grade cartilaginous cells and hyper cellular small, uniform, and undifferentiated cells that resemble Ewing's sarcoma. Mesenchymal chondrosarcoma has a predilection for the spine, ribs and jaw and it presents in the third decade. It is more common in females and can grow exceptionally large. It is very likely to metastasize to lungs, Lymph nodes and other bones. Clear cell chondrosarcoma is a malignant cartilage tumor that may be the adult variant of chondroblastoma. It is a rare, low-grade tumor with an improved prognosis over other chondrosarcomas. Like chondroblastoma, it is found in the epiphysis of the femur and humerus. Histologically, soft tissue invasion is rare. Clear cell chondrosarcoma has clear cells with vacuolated cytoplasm. The cartilage matrix has significantly calcified trabeculae and giant cells. Dedifferentiated chondrosarcoma is the most malignant form of chondrosarcoma. This tumor is a mix of low-grade chondrosarcoma and high-grade spindle cell sarcoma where the spindle cells are no longer identifiable as having a cartilage origin. The dedifferentiated portion of the lesion may have histological features of malignant fibrous histiocytoma, osteosarcoma, or undifferentiated sarcoma. This biphasic quality is evident on x-ray with areas of endosteal scalloping and cortical thickening are contrasted with areas of cortical destruction and soft tissue invasion. Dedifferentiated chondrosarcoma has a 5-year survival of 10%.

Treatment of chondrosarcoma is wide surgical excision. There is a very limited role for chemotherapy or radiation. Biopsies must be planned with future tumor excision in mind. Patients with adequately resected low-grade chondrosarcomas have an excellent survival rate. The survival of patients with high-grade tumors depends on the location, size and stage of the tumor.

EWING’S SARCOMA

Ewing's sarcoma is a highly malignant tumor that is a type of peripheral primitive neuroectodermal tumor (PNET). Ewing's sarcoma is found in the lower extremity more than the upper extremity, but any long tubular bone may be affected. The most common sites are the metaphysis and diaphysis of the femur followed by the tibia and humerus. Ewing's sarcoma is most common in the first and second decade but may affect persons from age 2 to 80. This tumor preferentially affects whites more than blacks and Asians. The ratio of male to female is 3:2.

The clinical presentation of Ewing's sarcoma includes pain and swelling of weeks or months duration. Erythema and warmth of the local area are sometimes seen. Osteomyelitis is often the initial diagnosis based on intermittent fevers, leukocytosis, anemia and an increased ESR.

Radiologically, Ewing's sarcoma is often associated with a lamellated or "onion skin" periosteal reaction. This appearance is caused by and splitting and thickening of the cortex by tumor cells. The lesion is usually lytic and central. Endosteal scalloping is often present. The "onion-skin" appearance is often followed with a "moth-eaten" or mottled appearance and extension into soft tissue. . Bone marrow infiltration is not obvious on plain x-ray. While Ewing's sarcoma is usually lytic, it may present as a sclerotic lesion with bone expansion. CT is helpful in defining bone destruction. MRI is essential to elucidate the soft tissue involvement because with TI-weighted images the tumor has low intensity compared to the normal high intensity of bone marrow. On: 12-weighted images the tumor is hyper intense compared to muscle. Ewing's sarcoma has increased uptake on bone scan.

Grossly, the tumor is gray to white in color and poorly demarcated. The consistency is soft, gray, and sometimes semi-liquid especially after breaking through the cortex. Areas of hemorrhage and necrosis are common. The destruction is often greater on gross appearance than was visible on radiographs. Under the microscope, Ewing's sarcoma consists of densely packed uniform small cells in sheets. The cells have scant cytoplasm without distinct borders. The cells are two to three times as big as lymphocytes and have a single oval or round nucleus without prominent nucleoli. The tumor spreads through Haversian canals, which cause the appearance of permeative margins on x-ray. Glycogen is present within the cells causing a positive reaction to periodic acid-schiff (PAS) stain. Most Ewing's sarcomas are positive with HBA-71 or 0-13 stain which is an antibody to the protein product of myc 2. The microscopic differential includes lymphoma and metastatic neuroblastoma that must be excluded by reticulin stain and urine vanillyl mandelic acid and homovanillic acid respectively. Rhabdomyosarcoma is ruled out if the specimen stains negatively with desmin, myoglobin and actin stains. A neural origin is supported by electron microscope findings of pseudorosettes. The common finding in Ewing’s sarcoma and primitive neuroectodermal tumors of choline acetyltransferase and the translocation further support this (11:22) (q24; ql2). It is thought that Ewing's sarcoma with its few organelles is the poorly differentiated end of the spectrum of PNET. Neuroepithelioma is an example of well-differentiated PNET and has neurosecretory granules and neuritic processes.

Treatment for Ewing's sarcoma includes surgery, radiation and multi-drug chemotherapy. Radiation or chemotherapy with vincristine, dactinomycin and cyclophophamide (VAC) are used preoperatively. Adjuvant chemotherapy follows surgery and decreases recurrences. The tumor metastasizes to lungs and lymph nodes. Poor prognostic signs include increased age, increased ESR and leukocytosis at presentation.

MULTIPLE MYELOMA

Multiple myeloma is a malignant tumor of plasma cells that causes widespread osteolytic bone damage. Multiple myeloma is the most common primary tumor of bone and is found in the spine, skull, ribs, sternum and pelvis but may affect any bone with hematopoietic red marrow. The average patient age is over fifty years old and men are affected twice as often as women are.

The presenting symptom of multiple myeloma is usually pain. The patient may have a normocytic, normochromic anemia secondary to marrow failure and an increased ESR. Hypercalcemia may cause confusion, weakness and lethargy. Other symptoms may include cachexia, spinal cord compression and renal insufficiency. Bacterial infections are common because of a lack of normal immunoglobulin production. Monoclonal immunoglobulin is found on serum electrophoresis. Light chain subunits of immunoglobulin are called BenceJones proteins and are present in urine.

The radiological appearance of multiple myeloma is characterized by irregular lytic defects of different sizes. These lytic areas are often described as "punched out" and have no periosteal reaction. Erosion begins intramedullary and progresses through the cortex. MRI is useful for delineating spinal lesions. Bone scan can fail to have increased uptake in 25% of patients suggesting a plain film skeletal survey should always be done.

On gross examination, the marrow space has been replaced by a diffuse gelatinous red brown tissue. Tumor nodules of approximately 1 cm in size may be present.

Microscopically, multiple myeloma is composed of sheets of plasma cells. The degree of cytologic atypia of these cells has no prognostic value. The osteolytic lesions are caused by increased osteoclastic resorption that is stimulated by cytokines released by-the plasma cells.

Treatment of multiple myeloma consists of palliative chemotherapy or bone marrow transplant. Only patients with complete remission of their disease experience any bony healing. Bisphosphonates are used to inhibit resorption of bone and subsequent hypercalcemia. Untreated, a patient with bony lesions will only survive an average of 6-12 months. The cause of death is usually infection or a hemorrhage.

OSTEOSARCOMA

Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. There is a preference for the metaphyseal region of tubular long bones. 50% of cases occur around the knee. It is a malignant connective (soft) tissue tumor whose neoplastic cells present osteoblastic differentiation and form tumoral bone.

Osteogenic Sarcoma is the 6th leading cancer in children under age 15. Osteogenic Sarcoma affects 400 children under age 20 and 500 adults (most between the ages of 15-30) every year in the USA. Approximately 1/3 of the 900 will die each year, or about 300 a year. A second peak in incidence occurs in the elderly, usually associated with an underlying bone pathology such as Paget's disease, medullary infarct, or prior irradiation. Although about 90% of patients are able to have limb-salvage surgery, complications, such as infection, prosthetic loosening and non-union, or local tumor recurrence may cause the need for further surgery or amputation.

The tumor may be localized at the end of the long bones. Most often, it affects the upper end of tibia or humerus, or lower end of femur. The tumor is solid, hard, irregular ("fir-tree" or "sun-burst" appearance on X-ray examination) due to the tumor spicules of calcified bone radiating in right angles. These right angles form what is known as Codman's triangle. Surrounding tissues are infiltrated.

Microscopically: The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumor. Tumor cells are very pleomorphic (anaplastic), some are giant, numerous atypical mitoses. These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular) - tumor bone. Tumor cells are included in the osteoid matrix. Depending on the features of the tumor cells present (whether they resemble bone cells, cartilage cells or fibroblast cells), the tumor can be sub classified. Presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favors the bloodstream metastasizing

The causes of osteosarcoma are not known. Questions remain about whether radium, or fluoride, in drinking water can act as "environmental triggers" for increasing the incidence of the disease. A low selenium or Vitamin D3 level or a high level of inflammation, as measured by interleukin-6, interleukin-8, or Nf-kB, Tumor Necrosis Factor Alpha may have a significant role as tumor suppressors and tumor initiators respectively. Recent studies show that an increased level of c-Fos can lead to osteosarcoma. Many patients first complain of pain that may be worse at night, and may have been occurring for some time. If the tumor is large, it can appear as a swelling. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture).

Patients with osteosarcoma are best managed by a medical oncologist and an orthopedic oncologist experienced in managing sarcomas. Current standard treatment is to use neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The percentage of tumor cell necrosis (cell death) seen in the tumor after surgery gives an idea of the prognosis and also lets the oncologist know if the chemotherapy regime should be altered after surgery.

REFERENCES

Eggli, KD et al., Ewing's Sarcoma, Radiologic Clinics of North America, 31(2):325-337, March 1994.

Bulloughs, Peter, Orthopaedic Pathology (third edition), Times Mirror International Publishers Limited, London, 1997.

Fletcher, Christopher, Diagnostic Histopathology of Tumors, Churchill Livingstone: New York, 1990.

Huvos, Andrew, Bone Tumors: Diagnosis Treatment and Prognosis, W.B.Saunders, Co., 1991.

Bertoni at al, Am J Clin pathol., 1988;90 377-384

Clarke et al, Am J Surg Pathol., 1985;9:806-815

Macdonald, Arch Pathol Lab Med. 2002;126:599-601

Khandpur et al, Aus J Dermatol., 2003;44:190

Bullough, Peter, Orthopaedic Pathologv (third edition), Times Mirror International Publishers Limited, London, 1997.

Huvos, Andrew. Bone Tumors: Diagnosis. Treatment and Prognosis, W.B. Saunders, 1991.

Conway, W., MD, PhD, and C. Hayes, MD. Miscellaneous Lesions of Bone.

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