Journal of Adenocarcinoma & Osteosarcoma gives the information about open access, rapid peer review process and editorial policies. Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily. OSTEOSARCOMA. Hafiizh DP. penduduk • Osteosarkoma konvensional lebih sering terjadi pada pria daripada wanita dengan perbandingan • Dahulu.
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Osteosarcoma is the most common primary malignancy of bone in children and young adults. This tumor has a very heterogeneous genetic profile and lacks any consistent unifying event that leads to the pathogenesis of osteosarcoma.
In this review, some of the important genetic events involved osteosarccoma osteosarcoma will be highlighted. Additionally, the clinical diagnosis of osteosarcoma will be discussed, as well as contemporary chemotherapeutic and surgical management of this tumor.
Finally, the review will discuss some of the novel approaches to treating this disease. Osteosarcoma OS is a high-grade primary skeletal malignancy characterized by spindle cells of mesenchymal origin depositing immature osteoid matrix [ 12 ]. With an annual incidence rate of 3. Although rare overall, OS is the most common primary malignancy of bone in children [ 3 — 5 ].
OS incidence is distributed bimodally across age. Juxtacortical osteosarcomas that occur along the surface of bones are usually lower grade, although there are some exceptions [ 9 ]. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.
Review of Osteosarcoma and Current Management
Phenotypic risk factors for OS are related to physiologic growth and include both a tall height and a high birth weight [ 10 ]. The vast majority of cases are the result of sporadic mutations, but loss of tumor suppressor function is commonly identified in OS and represents a critical step in its pathogenesis [ 11 — 13 ].
Overall, there is no unifying genetic event that leads to the development of OS. In addition to somatic mutations, there are a few well-identified syndromes that predispose to OS, and these are usually discussed to highlight some of the sentinel genetic events that are involved in pathogenesis.
Li—Fraumeni syndrome LFS is the most common syndrome predisposing to pediatric sarcomas and involves a germline mutation of the TP53 gene. TP53 jutnal for p53, a master transcription factor regulating expression of DNA repair genes and initiating apoptosis when damage is irreparable [ 14 ].
Although LFS is rare, damage to the p53 pathway is not. Mutations at TP53 represent the most frequently identified genetic alterations in human cancers. Somatic loss of p53 has also osteosaroma identified in 18— Retinoblastoma is another condition commonly identified to predispose osetosarcoma OS. The retinoblastoma protein pRb encoded by RB1 binds the E2F family of transcription factors and halts progression through the G1 phase of the cell cycle [ 18 ].
Loss of pRb induces unregulated cell cycle progression. Germline loss of RB1 in 13q14 microdeletion syndrome hereditary retinoblastoma is associated with an increased risk for retinoblastoma and, to a lesser degree, soft-tissue sarcomas, melanoma, and OS [ 19 — 21 ]. Loss of other genes in this pathway are functionally equivalent to loss of RB1 and have been identified in OS tumors lacking RB1 alterations [ 2526 ]. RecQ helicases are members of a conserved family of proteins that unwind double-stranded DNA prior to replication.
Loss of RecQ helicases is an inheritable risk factor for OS [ 2728 ]. Germline mutations in genes in the RecQ family give rise to the rare autosomal recessive cancer predisposition disorders e. In addition to genetic alterations due to chromosomal instability and loss of tumor suppressor genes, OS can also have disruptions in major signaling pathways, creating a bone microenvironment that promotes proliferation and metastasis.
Increased IGF-1 expression leads to more aggressive phenotypes in vitro and is a negative prognosticator when found in primary tumors [ 3637 ]. Metastatic OS has its own set of identifiable genetic alterations that allow tumor cells to migrate into the bloodstream, avoid apoptosis and immune destruction, and adhere and proliferate in distant tissues.
Besides triggering apoptosis, Fas receptors also function to target the osteosarcooma for elimination by natural killer NK cells. Elimination of this pathway allows OS cells to both avoid apoptosis and evade the immune system, and it is not surprising that samples from pulmonary OS metastases have been shown to be Fas negative [ 44juranl ].
The src pathway is again active at this step and is responsible for hyperproliferation of tumor jurnao and induction of neovascularity [ 4647 ]. As the science of molecular genetics advances, so does our understanding of osteosarcoma. A recent genome-wide association study of cases of OS and controls was able to identify 2 loci with genome-wide significance, one at 6p Another multi-institution genome-wide scan in patients with metastatic OS found significance in a mutation of the NF1B gene.
The mutation decreased NF1B activity, leading to increased OS cell migration, proliferation, and colony formation [ 49 ]. Secondary OS can osheosarcoma following malignant degeneration of benign bone lesions or exposure to ionizing radiation [ 50 — 52 ].
The etiology of secondary OS in the setting of radiation is likely due to DNA damage from the ionizing radiation. These tumors represent the classic form of OS: Conventional osteosarcomas are further classified into osteoblastic, chondroblastic, or fibroblastic types, depending on which matrix-producing cells dominate, but generally behave similarly in regards to appearance and prognosis [ 54 ].
Other high-grade central osteosarcomas include telangiectatic, otseosarcoma cell-rich, small cell, and epithelioid variants, each with characteristic histology and small differences in survival [ 55 ]. A low-grade intramedullary type termed low-grade central osteosarcoma LCOS has a much lower rate of metastasis and greater overall survival [ 5455 ].
OS can originate along the cortex or periosteum as well. They are slow-growing and low-grade in comparison to conventional OS, and histologic examination shows well-differentiated fibrous stroma with osseous components. They may have a cartilage cap and can be confused with osteochondromas, but will not have the characteristic cortical—medullary continuity characteristic of those benign lesions [ 56 ].
These tumors represent mid-grade lesions, but rarely metastasize when treated appropriately [ 57 ]. Finally, high-grade surface OS is the most aggressive type and has a course similar to conventional high-grade OS [ 9 ]. Patients with OS often present with nonspecific complaints, junral pain in the affected area. Pain during sleep, enlarging mass, and worsening pain without clear signs of infection or injury are particularly worrisome signs.
The traditional signs of cancer—weight loss, malaise and fever—are usually only present in advanced disease and are not sensitive signs in children [ 59 ]. Workup should begin with orthogonal X-ray imaging of the affected extremity. Radiographs will typically demonstrate a poorly marginated or moth-eaten appearance of the bone with mixed amounts of cloudy mineralized matrix and areas of bone resorption.
Alternatively, a cartilage or fibrous matrix may be present, or there may be tremendous bone resorption, depending on the subtype [ 56 ]. If the lesion has an associated soft tissue mass, a discontinuous or broken periosteal reaction is usually present Fig.
Lab work is nondiagnostic, but high levels of alkaline phosphatase ALK-P and lactate osteosarcomma LDH have been shown to predict a poorer prognosis [ 60 — 63 ]. Advanced imaging is best accomplished with magnetic resonance imaging MRI and should be performed for the entire bone.
MRI will clearly demonstrate the extent jurnak the bone marrow invasion, the presence osteoaarcoma size of any soft-tissue mass, and the relationship to surrounding vital structures Fig. Tumors are hypointense on T1, hyperintense on T2 and STIR imaging, usually exhibit mixed heterogeneity and surrounding peritumoral edema, and show abundant enhancement with contrast administration.
It is important to image the entire bone involved to detect potential skip metastases and accurately plan resection and reconstruction efforts. Generally speaking, computed tomography CT is inferior to MRI, unless further information is needed regarding cortical integrity or the presence of fracture [ 54 ].
AP a and lateral b X-rays of an year-old patient with an osteosarcoma of the distal femur. Note the wide osteosracoma of transition, discontinuous periosteal reaction, and areas of increased mineralization. MRI images from the patient in Fig.
Pre- e and post-contrast f axial images show areas of enhancement in the bone and soft tissue, corresponding to sites of increased metabolic activity. When a diagnosis of malignancy is suspected, a biopsy is required for tissue confirmation.
This can usually be accomplished with a core needle biopsy using either ultrasound or CT guidance. The specialist performing the biopsy should communicate with the treating physician to plan the incision such that the biopsy tract can be easily removed with the tumor.
Multiple cores can be obtained from the same incision, which increases the accuracy of diagnosis [ 56 ]. If needle biopsy is insufficient, an open biopsy can be performed, but it should be done through a small incision, with meticulous hemostasis. It is best performed by the surgeon who will carry out the final resection [ 64 ].
There is some evidence that not all needle biopsy tracts need to be resected [ 65 ], but an open biopsy tract should always be removed along with the tumor.
Review of Osteosarcoma and Current Management
At our institution, needle biopsy tracts are removed along with osteosarcoa final resection to prevent any chance of recurrence from residual tumor cells. Histologic examination of conventional OS demonstrates malignant spindle or polyhedral mesenchymal cells with pleomorphic nuclei, scattered mitotic figures, and varying levels of anaplasia Fig.
Immature and disorganized osteoid production is a characteristic hallmark and must be present for diagnosis. Conventional osteosarcomas osteossarcoma have a matrix dominated by osseous, cartilaginous, or fibrous elements, and are further subtyped depending on which of these matrix cells dominate. Other types of OS will show similar high-grade morphology along with areas of abundant giant cells, small cells, or epithelioid morphology, but must also contain osteoid somewhere in the sample.
Lower-grade central and surface OS will demonstrate woven microtrabeculae of bone within a bland to moderately cellular fibrous stroma [ 5455 ]. Medium-power a and high-power b microscopic images of an osteosarcoma specimen, showing high cellularity, nuclear polymorphism, atypia, and disorganized osteoid production. Staging is important for detecting metastasis, establishing prognosis, and determining appropriate medical therapy and surgery [ 536366 ].
A bone scan or positron emission tomography PET scan is recommended to detect metastatic bone and soft-tissue disease Fig. Bone scan is more cost-effective and superior to PET for bony disease, but PET allows for better detection osteosarcmoa soft tissue, and includes the chest and abdomen. Both are effective scanning techniques; the choice made usually varies by institution.
An additional advantage of PET is that it may be able to identify tumors with higher metabolic activity and, therefore, higher-grade malignancies [ 7273 ]. Finally, if not already available, an MRI of the entire bone involved is important to rule out any skip metastases, which must be osteosarco,a with primary resection and predict a poor survival [ 74 ].
X-ray a and MRI b of the distal femur of a year-old girl, showing a large solitary lesion. However, staging with bone scan c and MRI d revealed additional skip metastasis in her ipsilateral femur diaphysis and peritrochanteric area that was not detected with initial imaging.
The presence of the skip metastases changed the surgical plan from a distal femur resection to an osteosarcona femur resection and reconstruction e. Enneking was the first to organize bone sarcoma into a comprehensive staging system, and the AJCC later used these principles to develop its own staging system with nomenclature similar to that used for other cancers.
Despite these differences, most tumors will be a similar stage in both systems, as the major driver of prognosis is the presence of metastases, which both systems define similarly [ 75 ].
Prior to the advent of chemotherapy, OS was almost a universally fatal disease. Patients with metastasis at diagnosis would typically survive only months, and those with localized disease would soon develop metastatic spread, despite radical and disabling surgical procedures.
In the s, Jaffe published the first significant success of chemotherapy, showing that methotrexate was a useful agent to manage metastases in advanced disease [ 76 ].
A study performed during the same time period at Memorial Sloan Kettering found similar increases in survival with chemotherapy that was given before surgery neoadjuvantshowing that it was safe to delay surgery for treatment [ 77 ]. The authors preferred neoadjuvant chemotherapy because it allowed more time to fabricate endoprosthetic devices, decreased tumor size, and permitted an analysis of the surgical specimen for its response to chemotherapy [ osteosarcpma ]. Today, most OS patients receive osteosafcoma chemotherapy, followed by surgical resection of all detectable disease and a regimen of adjuvant chemotherapy postoperatively [ 78 ].
The current regimen of methotrexate, adriamycin, and cisplatin MAP has become standard in North America and Europe [ 6679 ]. Some centers will also add ifosfamide with or without etoposide, but this increases the toxicity of therapy, and recent randomized clinical trials have failed to show a survival advantage [ 8182 ].