Patho sheet.bone # 3 - Reham Kelano

Bone tumors
Primary bone tumors are considerably less common than are metastatic lesions
The most common originating sites or bone metastases, in descending order of frequency are:
-Prostate
-breast
-lung
-kidney
-G.I
- Thyroid
Metastases may be destructive (osteolytic) or associated with reactive new bone formation (osteoblastic)
Certain condition is associated with an increased risk of bone neoplasm:
• Paget disease
• Chronic osteomyelitis
• Exposure to radiation
A few cases are associated with hereditary tumor syndromes
Gardner syndrome osteoma
Familial retinoblastoma osteosarcoma
The cause of the vast majority of bone tumors remains unknown
Bone-forming tumors
These neoplasms are characterized by the production of osteoid by tumor cells. This type of intrinsic osteoid formation must be distinguished from bone formation in osteoblastic metastases, in which osteoid id produced by reactive osteoblasts rather than by neoplastic cells.
Osteoma
Benign lesion of bone that in many cases represent developmental aberration or reactive growths rather than true neoplasm.
They are most commonly encountered in the head and neck, including paranasal sinuses, but may occur in other sites as well.
They present as localized, solitary, hard, exophytic growths attached to the surface of bone multiple osteomas are a feature of Gardner syndrome.
Histologically: osteomas are composed of bland mixture of woven an lamellar bone.
Although they may cause local mechanical problems and cosmetic deformity, they are not invasive and do not undergo malignant transformation
Osteoid osteoma and osteoblastoma :
Are benign neoplasms that have very similar histologic features . They are distinguished primarily by their size , site of origin and certain radiographic features.
Osteoid osteoma arises most often in the proximal femur and tibia during the second to third decade of life . They occur more commonly in males than in females (2:1)
By definition they are less than 2cm in greatest dimension , whereas obteoblastomas are larger.
Local pain is an almost universal complaint in patients with osteoid osteoma and can usually be relieved by aspirin.
Osteoblastoma arise most often in the vertebral column , although they may occur in other sites as well .
They occur most often during the second to third decades and affect males more often than females.
They may also cause pain which is difficult to localize and not responsive to aspirin .
Local excision is the treatment of choice for most lesions and incompletely resected lesions may recur.
Morphology:
Radiographically ,these neoplasms present as well circumscribed lesions which usually involve the cortex. The central area of the tumor termed the nidus is radiolucent but may become mineralized and sclerotic.
A rim of sclerotic bone is present at the edge of both types of tumors that is more conspicuous in osteoid osteomas.
Microscopically both neoplasms are composed of interlacing trabecular of woven bone surrounded by osteoblasts. The intervening stroma is made up of loose vascular connective tissue and contains a variable numbers of giant cells.

Osteogenic sarcoma :
Are malignant mesenchymal neoplasms in which the neoplastic cells produce osteoid. Excluding multiple myeloma, osteosarcoma is the most common primary malignant tumor of bone.
Although once they were universally fatal, recent therapeutic advances have dramatically improved the outlook for these neoplasms.
Osteosarcoma can be divided into primary forms which arise de novo and secondary forms which arise as a complication of a known underlying process, such as Paget disease of bone or a history of radiation exposure.
Conventional osteosarcoma occurs most often during the second decade of life. Although they may arise anywhere in the body, the most common site of origin is the area around the knee, specifically the distal femur and proximal tibia.
Males are affected more often than females mutation in the TP53 tumor suppressor gene, are present in many sporadic osteosarcomas and overexpression
Of theMDM2 ontogeny is also noted in many cases. MDM2 protein binds to and inactivates the TP53 gene product.
Germ-line mutations in the retinoblastoma gene predispose patients to develop osteosarcoma as well as hereditary retinoblastoma.
Loss of heterozygosity at 3p, 13q, 17p and 18q has also been noted in these tumors.
Morphology:
The typical osteosarcoma present as a large ill-defined lesion in the metaphyseal region of the involved bone.
It characteristically destroys the cortex and frequently extends into the marrow cavity the tumor elevates the periostern to produce the so called cofman triangle on radiographs, which is formed by the angle between the elevated periosteom and the surface of involved bone. Invasion of the epiphyseal plate is uncommon microscopically; the hall mark of osteosarcoma is the formation of osteoid by malignant mesenchymal cells. This is seen in the form of islands of primitive bony trabeculae hugged by rim of malignant osteosarcoma.
Other mesenchymal elements particularly cartilage may be present, and giant cells sometimes mistaken for osteoclasts are often present.
Clinical features:
Osteosarcoma present as progressively enlarging, often painful masses that may come to attention because of a fracture of the affected bone.
Although the clinical and radiographic features may strongly suggest the diagnosis, histologic confirmation is necessary in all cases.
Conventional osteosarcomas are aggressive lesions that metastasize through the blood stream early in their course. The lungs are a common site of metastases.
Approximately 20% of patients have detectable pulmonary spread at the time of diagnosis.
Surgery combined with radiation therapy and chemotherapy has greatly improved the prognosis of these tumors.
Secondary osteosarcomas occur in an older age group. The most commonly develop in the setting of paget disease or previous radiation exposure and rarely in patients with fibrous dysplasia, bone infarcts or chronic osteomyelitis.
Secondary osteosarcomas are highly aggressive neoplasms which respond less favorably to current therapies.
Cartilaginous tumor:
Osteochondroma
Sometimes called exostosis, are benign tumor composed of mature bone and a cartilaginous cap.
They account for about one third of all benign tumor of bone.
They probably represent malformations rather than true neoplasms.
They tend to stop growing once the normal growth of the skeleton is completed.
They occur most be multiple in rare familial disorders termed multiple hereditary exostosis.
Most osteochndromas are asymptomatic but some might cause cosmetic deformation.
They usually arise from the metaphysis near the growth plate of long bone and presentation broad based bony excrescences firmly anchored to the cortex of adjacent bone.
A cap of hyaline cartilage is present which in young subject, contains a growth plate similar to that seen in normal epiphysis.
Most follow a benign course rare instance of sarcomatous transformation in patients with familial disease.
Chondroma (enchondroma):
Benign lesions composed of mature hyaline cartilage that occurs most often in small bones of the hands and feet.
They may occur at any age but most common in the third to fifth decade.
They may be solitary or multiple.
Several syndromes are associated with multiple chondromas: Ollier disease, Maffucci syndrome. They are well circumscribed lesions that arise within the medullary cavity of the bone.
Microscopically they are composed of mature hypo cellular hyaline cartilage population by bland chondrocytes.
Solitary chondromas are almost always innocuous, in contrast, chondrosarcomas develop in about one third of patients with multiple chondroma syndromes.
Chondrosarcoma:
Are multiband neoplasms populated by mesenchymal cells that produce a cartilaginous matrix.
Males are affected about twice as frequently as females.
Among malignant non hematopoietic tumors of bone they are second only to osteosarcoma in frequency .
Unlike cartilage forming osteosarcoma, the neoplastic cells of chondrosarcoma do not form osteoid.
Chondrosarcomas occur in older patients compared to osteosarcoma, with a peak incidence in the sixth decade.
They arise in central portions of the skeleton (shoulder, pelvis, proximal femur and ribs) although some occur in patients with multiple enchondromas or more rarely oseochondroma.
Morphology:
They arise within the medullary cavity of bone to form an expansile glistening mass that frequently erode the cortex.
Microscopically they range from well differentiated lesions with minimal atypia to highly pleomorphic chondrocytes with multinucleate cells and lacunae with two or chondrocytes.
10% of low grade chondrosarcoma transform into a high grade sarcoma referred to as dedifferentiated chondrosarcoma. The sarcomatous element may be an osteosarcoma or a fibrosarcoma.
Clinical features:
Chondrosarcomas present most often as progressively enlarging, sometimes painful masses involving the central portion of the skeleton.
Their rate of growth and ultimate behavior are closely correlated with histologic grade, with poorly differentiated lesions behaving in a more aggressive fashion than better- differentiated tumors.
Chondrosarcomas metastasize via the hematogenous route most often to the lungs.

Giant cell tumor bone:
Also known as osteoclastoma is a neoplasm that contains large numbers of osteoclast like giant cells admixed with mononuclear cells.
They account for about 20% of all benign tumors of bone.
Most cases arise in the epiphysis of long bones particularly the distal femur, proximal tibia, proximal humerus and distal radius.
They occur most commonly between the ages of 20 and 40 with a slight female preponderance.
Current opinions suggest that the giant cell component is likely a reactive cell population derived from macrophages and that only the accompanying mononuclear cells are neoplastic.
Morphology:
Giant cell tumor presents as radiolucent lesions involving the end of long bone.
They are almost always solitary, longstanding tumors that erode the cortex of bone.
They have a dark brown appearance grossly due to abundant vascularity.
Areas of necrosis and cystic changes are sometimes present.
Histologically they are composed of two major cell populations, large multinuclear cells.
Rarely malignancy may develop in a giant cell tumor and in these cases it is the mononuclear cells that develop anaplastic features.
Clinical features:
They usually present with local pain that might be mistaken for arthritis.
Biopsy is usually necessary to establish the diagnosis.
Multicentricity is exceedingly uncommon in giant cell tumor and when present should raise the suspicion of hyperparathyroidism.
Although histologically benign, recurrences are common often simple curettage.
Sarcomatous transformation is rare and may occur de novo or in previously benign tumor treated with radiation therapy.
On occasion a histologically benign giant cell tumor may metastasize to the lung.
Ewing sarcoma family of tumors
This family includes:
. Ewing sarcoma of bone
. Extra osseous EWS
. Primitive neuro ectodermal tumor (PNET)
. Neuro epithelioma
. Askins tumor
EWS and PNET are the most common and they account for 6% to 10% of all primary bone tumors.
Following osteosarcoma as the second most common form of bone tumors in children.
The features that unite the Ewing sarcoma family of tumors are a common neural origin and the presence of chromosomal translocations that result in the fusion of the EWS gene on 22q12 to a member of the ETS family of translocation factors, mainly FL1 on 11q24 and ERG on 21q22. The resulting novel Chimeric proteins cause transcriptional activation of several target genes that disregulate cell differentiation and proliferation.
At a practical level these translocations are of diagnostic importance, thus approximately 95% of patients with Ewing sarcoma have t (11, 22) or t (21, 22).
Ewing sarcoma occurs predominantly in children and adolescent with a peak incidence in the second decade.
It is highly aggressive nesplasm that must be differentiated from other “small blue cell” tumors.
Morphology:
It arises within the medullary cavity of affected bone to produce soft and expansile mass.
The femur, tibia and pelvis are favored sites it occurs most often in the diaphysis it usually extends beyond the medullary cavity into cortical bone and periosteum where it may produce lamellae of reactive bone in an onion skin pattern.
Microscopically it is composed of sheets of Primitiue cells with small uniform nuclei and scant cytoplasm.
The cytoplasm contains glycogen that can be demonstrated by PAS stain or electron microscopy.
Immunohistochemical studies are usually required to differentiate it from other small blue cell tumors. Ewing sarcoma cells regularly express a neural marker the MIC2 (CD99) antigen that is not entirely specific for Ewing sarcoma but is of diagnostic use when employed with other antibodies.
Clinical features:
Ewing sarcoma classically presents as pain, often accompanied by local inflammation and fever that suggests the diagnosis of an inflammatory lesion.
Biopsy is required for diagnosis.
Recent advances in treatment have significantly improved the outlook for patients with this sarcoma with a 5 year survival rate of close to 75%.
Fibrous Dysplasia:
Is an uncommon, benign, tumor like lesions of bone in which normal trabecular bone is replaced by proliferating fibrous tissue and disorderly islands of malformed bone.
It occurs in three forms:
- Monostotic
- Polyostotic
- Polyostotic with endocrine abnormalities
The pathogenesis of fibrous is unclear; it appears to be a developmental defect in bone formation.
Overexpression of FOS proto oncogene and somatic mutations in the gene coding for a stimulatory nucleotide binding protein have been described in the polyostotic forms.
Monostotic fibrous dysplasia is the most common form, accounting for 90%of cases.
It usually arises during adolescence and becomes quiescent often bone growth is complete.
The most common site of involvement is the ribs, femur, tibia, jaw and calvarium.
Although most cases are asymptomatic same cases may come to attention because of fractures or local deformity of bone.
Polyostotic fibrous dysplasia limited to bone account s for about 25% of cases, it appears at slightly earlier age and can continue to case problems which can cause significant deformity.
Polyostotic fibrous dysplasia associated with endocrine abnormality are the least common, responsible for about 3% of cases.
It occurs most often in females, affected individuals develop unilateral bone lesions, café-au-lait spots on the same side of the body and precocious puberty. (McCune-Albright Syndrome).
Other endocrine abnormalities may develop including hyperthyroidism and Cushing syndrome. More recently fibrous dysplasia has been described in association with neuro fibromatosis type 1.
Morphology:
The lesions of fibrous dysplasia are circumscribed and radiolucent. They are usually surrounded by a thin margin of sclerotic bone.
Histologically, foci of fibrous dysplasia contain proliferating fibroblasts and abundant collagen surrounding small erratically distributed islands of woven bone.
Clinical features:
Pathologic features and bone deformity may occur in any type of fibrous dysplasia but they are a greater problem in polyostotic disease.
Sarcomas are very rare complication of fibrous dysplasia usually encountered in patients with the polyostoic from secondary to radiation therapy.



That's all for today
Good Luck 
Reham Kilano
"Last lec for the Bone"