Bone Sarcoma

Overview

The most frequent primary pediatric bone cancer is osteosarcoma, which arises from primitive bone-forming (osteoid generating) mesenchymal cells. It can be classified as primary (no underlying bone pathology) or secondary (underlying pathology that has undergone malignant degeneration/conversion), accounting for around 20% of all primary bone tumors.

Osteosarcoma manifests itself in a highly heterogeneous manner, allowing it to be subdivided into various subgroups based on the degree of differentiation, location within the bone, and histological variance. The imaging appearance, demographics, and biological activity of these sarcomas are widely variable when compared to other bone tumors.

Treatment choices and survivorship have dramatically improved in recent years thanks to the relentless efforts of several medical, surgical, and scientific specialists. 

Epidemiology of Bone Sarcoma

The age distribution of osteosarcoma is bimodal. The initial peak occurs between the ages of 10 and 14 years, coinciding to the pubertal growth surge. This subtype accounts for the great majority of primary osteosarcomas. The incidence rate of osteosarcoma in children aged 0 to 14 years is four cases per million persons, regardless of ethnicity or gender. For children aged 0 to 19, this rate climbs to five cases per million persons per year.

The next noticeable peak occurs in individuals above the age of 65, when the occurrence of osteosarcoma is more likely to be secondary malignancy caused by malignant degeneration of Paget disease, sites of bone infarction, and so on. The patient's age has been observed to connect with survival; older people have the lowest survival rate. Death rates from osteosarcoma have been continuously declining at a rate of about 1.3 % each year. Regardless of gender, the 5-year overall survival rate is around 68 %.

Osteosarcoma is the seventh most prevalent juvenile malignancy, accounting for around 2.4 % of all pediatric tumors. The most prevalent cancer is leukemia (30%), followed by central nervous system malignancies (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), and retinoblastoma (2.8 %).

With an incidence rate of 6.8 cases per million persons, blacks are the ethnic group most likely to be impacted by osteosarcoma. Hispanics come in second, with an incidence rate of 6.5 cases per million people. This cancer affects white people at a rate of 4.6 cases per million persons each year.

The incidence of osteosarcoma has previously been reported to be greater in men than in females, with 5.4 cases per million males and 4 cases per million females, respectively.

Pathophysiologic and radiological features of Osteosarcoma

Osteosarcomas are more prevalent in bone growth sites, possibly because proliferation renders osteoblastic cells in this location more likely to acquire mutations that might lead to cell transformation (the RB gene and p53 gene are commonly involved).

The tumor might be located at the end of a long bone (commonly in the metaphysis). It usually affects the proximal end of the tibia or humerus, or the distal end of the femur. In 60% of instances, osteosarcoma affects the region around the knee, 15% at the hip, 10% at the shoulder, and 8% in the jaw. Because of the tumor spicules of calcified bone radiating at right angles, the tumor appears solid, hard, and irregular ("fir-tree," "moth-eaten," or "sun-burst" look on X-ray inspection). These right angles combine to produce a Codman triangle, which is typical but not diagnostic of osteosarcoma. The surrounding tissues have been invaded.

The presence of osteoid (bone formation) within the tumor is a hallmark microscopic feature of osteosarcoma. Tumor cells are very pleomorphic (anaplastic), with many unusual mitoses. These cells create osteoid—tumor bone, which is characterized by irregular trabeculae (amorphous, eosinophilic/pink) with or without core calcification (hematoxylinophilic/blue, granular).

The osteoid matrix contains tumor cells. The tumor can be characterized based on the characteristics of the tumor cells (whether they resemble bone cells, cartilage cells, or fibroblast cells). Multinucleated osteoclast-like large cells can be seen in osteosarcomas. 

What are the causes of Bone Sarcoma?

Several research organizations are looking into cancer stem cells and their ability to produce tumors, as well as the genes and proteins that induce distinct phenotypes:

• Radiotherapy for unrelated conditions may be a rare cause.
• A small supernumerary marker chromosome or a giant rod chromosome is present in the tumor cells of low grade OS including low grade central OS and paraosteal OS carry various potentially pro-cancerous genes, and are thought to contribute to the development of these OS.
• Familial cases where the deletion of chromosome 13q14 inactivates the retinoblastoma gene is associated with a high risk of osteosarcoma development.
• Bone dysplasias, including Paget's disease of bone, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses, increase the risk of osteosarcoma.
• Li–Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma development.
• Rothmund–Thomson syndrome (i.e. autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataracts) is associated with increased risk of this disease.
• Large doses of Sr-90, nicknamed bone seeker, increases the risk of bone cancer and leukemia in animals and is presumed to do so in people.

There is no convincing link between water fluoridation and cancer or cancer fatalities, both in general and especially for bone cancer and osteosarcoma. A series of studies revealed that the content of fluoride in water had no relationship with osteosarcoma. The views about the link between fluoride exposure and osteosarcoma derive from a 1990 research of the US National Toxicology program, which found inconclusive evidence of a link between fluoride and osteosarcoma in male.

Actually, fluoride is naturally present in water sources, but many communities have chosen to add extra fluoride to the point where it can minimize tooth decay. Fluoride is also renowned for its potential to stimulate the production of new bone. However, additional study indicates that fluoridated water poses no risk of osteosarcoma in humans. The majority of the research entailed tracking the number of osteosarcoma patient cases in certain localities with varying fluoride concentrations in drinking water.

As a consequence, the median fluoride concentrations in osteosarcoma patients' and tumor controls' bone samples are not substantially different. Fluoride concentrations in bones, as well as fluoride exposures in osteosarcoma patients, have been shown to be no different from healthy persons. 

Signs and symptoms of Bone Sarcoma

Osteosarcoma symptoms may be persistent for a long period, perhaps weeks or months, before patients seek medical attention. The most frequent presenting symptom is bone pain, which worsens with exercise. Parents are frequently anxious that their child has sprained an ankle, developed arthritis, or is experiencing growing pains. A history of traumatic musculoskeletal injury may or may not be present.

Except for the telangiectatic variety of osteosarcoma, which is linked with pathologic fractures, pathologic fractures are not a common feature of osteosarcoma. As a result of the discomfort, you may walk with a limp. Depending on the size and location of the tumor, a swelling or lump may or may not be recorded. Systemic symptoms, such as those found in lymphoma (fever, night sweats, and so on), are quite uncommon.

Respiratory symptoms are uncommon, but when they do occur, they suggest severe lung involvement. Additional symptoms are uncommon since metastases to other places are exceedingly uncommon.

Physical examination findings are typically focused around the location of the primary tumor and may include:

• A palpable mass may be tender and warm with or without an overlying pulsation or bruit, though these signs are nonspecific.
• Joint involvement with decreased range of motion.
• Local or regional lymphadenopathy (unusual).
• Respiratory findings with metastatic forms.

How Osteosarcoma is diagnosed?

National Comprehensive Cancer Network's 2020 Guidelines for Initial Evaluation of Osteosarcoma (Version 1.2020):

Clinical History and Physical Exam

Laboratory Analysis of Lactate Dehydrogenase (LDH) and Alkaline Phosphatase (ALP) Levels: 

In the first workup, biochemical markers such as serum alkaline phosphatase (ALP) and lactate dehydrogenases (LDH) are evaluated because they give evidence for diagnosis and prognosis. Because of the increased osteoblastic activity associated with osteosarcoma, ALP levels will be elevated. Extremely high levels have been associated to a large tumor burden and are often regarded as a poor prognostic indication. It is also critical to assess biomarker levels later in the treatment process, since levels may drop with successful therapy or rise with residual illness or relapse.

Diagnostic imaging of Primary Tumor Site:

• Radiographs: While MRI is the gold standard for diagnosing osteosarcoma, radiographs are typically the first study acquired when a possible bone mass is found during a physical exam. A conventional radiograph of osteosarcoma may show the following features: medullary and cortical bone destruction, permeative or moth-eaten cortex, "Sunburst" configuration (due to aggressive periostitis), "Codman triangle" configuration (due to elevation of the periosteum away from the bone), ill-defined "fluffy" or "cloud-like" osseous lesion, soft-tissue mass, calcification of osteoid.

• Magnetic Resonance Imaging: after identifying a suspicious lesion on a radiograph, MRI may be necessary for further characterization. MRI is an indispensable tool for defining the extent of a tumor inside and outside the bone. The entirety of the involved bone, as well as one joint above and one joint below the tumor, should be included in the study so that “skip” lesions are not missed. 

MRI can accurately and precisely delineate the degree of tumor in the adjacent soft tissues, joint involvement, whether or not the tumor crosses the physis, proximity to the nearest neurovascular bundle. Nearly every aspect of treatment is assessable with MRI, from pre-surgical assessment for limb-sparing resection to the degree of chemotherapy response in the form of tumor necrosis, shrinkage, and improved capsulation. Traditional sequences acquired in MRI of osteosarcoma may demonstrate the following:

T1 Weighted Images

1. Non-ossified soft tissue component: intermediate signal intensity
2. Osteoid components: low signal intensity
3. Peritumoral edema: intermediate signal intensity
4. Scattered foci of hemorrhage: variable signal intensity based on chronicity

T2 Weighted Images

1. Non-ossified soft tissue component: high signal intensity
2. Osteoid components: low signal intensity
3. Peritumoral edema: high signal intensity

• Computed Tomography (CT): CT is generally used to aid with biopsy planning and disease staging. Unless the osseous lesion in issue is primarily lytic, CT may not add considerably to direct evaluation of the tumor following radiography and MRI. Small quantities of mineralized material may be undetectable on plain film and MRI in the event of lytic lesions. CT of the chest, on the other hand, is the modality of choice for assessing metastases.

Nuclear Imaging:

• Positron Emission Tomography: PET imaging is a type of nuclear medicine imaging that detects highly metabolic lesions. It is a vital tool for evaluating tumor size and screening for subtle abnormalities if a suspicious mass is identified on first diagnostic imaging. PET is useful later in the therapy course for detecting recurrence.

• Radionuclide Bone Scan: Technetium 99 methylenediphosphonate (Tc99 MDP) bone scan is an effective and readily available imaging modality for detecting bony metastasis. It is a less expensive but less specific alternative to PET imaging.

Biopsy of Osteosarcoma:

A biopsy is required when the physical exam, laboratory analysis, and diagnostic imaging establish the existence of a lesion compatible with osteosarcoma. To minimize recurrence owing to probable seeding of this tract with cancer cells, the final surgical treatment must involve excision of the biopsy tract, which should be tattooed for easy identification. The surgeon who does the biopsy should ideally be the same person who performs the resection, so that they are familiar with the course and scope of the biopsy.

Because of its high rate of accuracy, an open approach to biopsy was traditionally thought to be the best alternative. In recent years, however, research has found that an open technique is associated with an increased risk of problems such as infection, poor wound healing, and tumor cell seeding of the location.

As a result, core biopsy has largely replaced the conventional open technique, not only because of the reduced danger of tumor cell contamination of the surgical bed, but also because of cheaper cost and shorter recovery time. It is especially important for patients who have the possibility for limb-sparing surgeries, in which as much local tissue as feasible should be spared as safely as possible.

Importantly, recent research has demonstrated that fine-needle aspiration is ineffective for biopsy since it does not provide an enough tissue sample for reliable diagnosis. Following the biopsy, pathologists should study tissue samples in fresh or frozen format for conclusive diagnosis, grading, and histological subtyping, all of which will influence medical and surgical treatment approach. 

Treatment of Osteosarcoma

The treatment of choice for osteosarcoma is a total radical surgical en bloc excision of the tumour. Although around 90% of patients can have limb-salvage surgery, problems such as infection, prosthesis loosening and non-union, or local tumor recurrence may need further surgery or amputation.

Mifamurtide is given to a patient after surgery to remove a tumor, and it is used with chemotherapy to destroy any residual cancer cells, lowering the chance of recurrence. In addition, when the tumor has been removed, rotationplasty is a possibility.

Patients with osteosarcoma benefit from the expertise of a medical oncologist and an orthopedic oncologist who have experience treating sarcomas. The current standard of care is neoadjuvant chemotherapy (chemotherapy administered before to surgery), followed by surgical resection. The proportion of tumor cell necrosis (cell death) found in the tumor after surgery indicates the prognosis and also informs the oncologist about whether the chemotherapy regimen should be changed following surgery.

When possible, limb-salvage orthopedic surgery (or amputation in some cases) is combined with a combination of high-dose methotrexate with leucovorin rescue, intra-arterial cisplatin, adriamycin, ifosfamide with mesna, BCD (bleomycin, cyclophosphamide, dactinomycin), etoposide, and muramyl tripeptide. Rotationplasty is an option. If the rate of necrosis is low, ifosfamide can be administered as an adjuvant therapy.

Despite the efficacy of treatment for osteosarcoma, it has one of the lowest pediatric cancer survival rates. The best documented 10-year survival rate is 92%; the treatment utilized is an intensive intra-arterial regimen that tailors therapy based on arteriographic response. In certain studies, three-year event-free survival varies from 50 to 75 percent, while five-year survival ranges from 60 to 85 percent. Overall, 65–70% of patients treated five years ago are still living today. These are typical survival rates that vary substantially based on the individual necrosis rate.

Filgrastim and pegfilgrastim improve white blood cell and neutrophil levels. Anemia can be treated with blood transfusions and epoetin alfa. Computational study of a panel of osteosarcoma cell lines revealed novel common and specific treatment targets (proteomic and genetic) in osteosarcoma, whereas phenotypes revealed a greater relevance for tumor microenvironments. 

Prognosis of Osteosarcoma

Prognosis is separated into three groups:

Stage I: osteosarcoma is rare and includes parosteal osteosarcoma or low-grade central osteosarcoma. It has an excellent prognosis (>90%) with wide resection.

Stage II: The prognosis is determined by the location of the tumor (proximal tibia, femur, pelvis, and so on), the size of the tumor mass, and the degree of necrosis caused by neoadjuvant chemotherapy. Other pathological characteristics, such as the degree of p-glycoprotein, whether the tumor is cxcr4-positive, or Her2-positive, are also essential, as these are linked to distant lung metastases.

Patients with metastatic osteosarcoma have a better prognosis when they have a longer time to metastasis (greater than 12 months to 4 months), fewer metastases, and are resectable. It is preferable to have fewer metastases rather than a longer latency to metastasis. Those who have been treated for a longer period of time (more than 24 months) and have fewer nodules (two or less) have the best prognosis, with a two-year survival rate after metastases of 50%, a five-year survival rate of 40%, and a 10-year survival rate of 20%. The prognosis is poorer if metastases are both local and regional.

Stage III: The resectability of the main tumor and lung nodules, the degree of necrosis of the underlying tumor, and perhaps the number of metastases determine the prognosis of osteosarcoma with lung metastases. The overall survival rate is around 30%.

An unknown number of juvenile cancer fatalities are caused by malignant neoplasms of the bones and joints. Osteosarcoma mortality rates have been dropping at a rate of roughly 1.3% each year.

Conclusion

Malignant bone tumors are characterized as either primary (arising from abnormal bone or cartilage cells) or secondary (arising from normal bone or cartilage cells) (bone metastases of other tumors). The cancer cells in these tumors resemble early types of bone cells, which ordinarily aid in the formation of new bone tissue, but the bone tissue in an osteosarcoma is weaker than that in normal bones. 

The majority of osteosarcomas occur in children, adolescents, and young adults. Although teenagers are the most usually afflicted age group, osteosarcoma may occur at any age.

Osteosarcomas are the most frequent primary bone tumors. This tumor differs in terms of primary location, radiological features, and the age of the patient at which it often arises. Pain that intensifies at night or with physical exercise is frequent, and it is generally accompanied by edema.

Chemotherapy, radiation treatment, and/or ultimate surgical excision may be necessary depending on the type and stage of the tumor. Bone tumors can also develop as a result of metastasis from other primary malignancies. Metastases are most typically found in the spine and pelvis and are usually caused by lung, breast, or prostate cancer.

Treatment focuses on the underlying cancer, as well as pain management and fracture prevention due to metastases.