Mini literature review on bone tumors of childhood: a

comparative review of the types

Done by: Shahd Ahmed Abdou, Zeinab Ali, Hagar Newigy, Aya Elahmady
AlRazi Group
ABSTRACT
The most common malignant bone tumors in children are Osteosarcoma (OS) and the

Ewing sarcoma family of tumors (ESFT) alongside with Osteochondroma,

Enchondroma, Osteoid osteoma, Osteoblastoma and many more. Improvements in

survival have been seen in most pediatric malignancies except the treatment and

prognosis for pediatric bone tumors; it has stayed the same for the past 3 decades. This

review and update of bone tumors in childhood and a comparison of their different

types, pediatric malignant bone tumors will provide a general overview of

Osteosarcoma and Ewing sarcoma in terms of: epidemiology, etiology, clinical

presentation, pathogenesis, diagnosis, treatment, current challenges, and emerging

drug targets.

1. INTRODUCTION
Osteosarcoma occurs most often in children and young adults between the ages of 10-20 and it

often happens during a growth spurt, more frequently in boys. It is a bone cancer and it can

spread to other organs making the lungs its first destination.

Epidemiology

Osteosarcoma is one of the most common types of cancer found in children and adolescents. A

research published in the Mayo Clinic proc stated that it occurs in 4.4 per million in children and

adolescents , and it is most likely to get an osteosarcoma in your 20’s. SEER*Stat software was

used to examine the incidence and survival rates for 5016 osteosarcoma patients from the

Surveillance, Epidemiology, and End Results (SEER) program (1975-2017) according to age (0-

9, 10-24, 25-59, and >60 years old, race/ethnicity, histologic subtype, stage, and tumor location.

Results show that primary osteosarcoma incidence was comparable across the sexes for cases 0
to 9 years old, increased considerably over the course of the research (P <.05), and the 5-year

relative survival increased consistently over time. African Americans had the greatest incidence

of all instances of advanced age put together, and their incidence increased significantly over the

course of the research (P< .05). Axial tumors, metastatic disease, older patients, males, American

Indian/Alaska Native cases, and cases of osteosarcoma that developed later all had lower overall

survival rates during the past few decades. Since the 2000s, the incidence of future osteosarcoma

has increased thrice in cases involving patients aged 0 to 24. Another type of bone tumor is

Ewing sarcoma, which occurs 2.9 per million in children. Another point worth noting is that

more than half of soft tissue sarcomas in children are rhabdomyosarcomas, which have an annual

incidence of 4.5 cases per million children and adolescents.

1.1 Aetiology and pathogenesis:

Malignant bone tumors are the hallmark of osteosarcoma, which mainly affects children and

teenagers. Although the precise etiology of osteosarcoma remains unclear, genetic and

environmental factors are thought to have a role. Osteosarcoma has been linked to genetic

modifications such as RB1 gene abnormalities and TP53 mutations. Osteosarcoma may also

develop as a result of environmental conditions, such as exposure to radiation or certain

chemicals. It is believed that mesenchymal stem cells or osteoblast progenitor cells, which

undergo malignant transformation and give rise to the tumor, are the source of osteosarcoma.

Research has been done on the function of ferroptosis-related genes (FRGs) in the pathogenesis

and outcome of osteosarcoma. In these patients, molecular subgroups with various FRG

expression patterns were found using nonnegative matrix factorization (NMF) clustering. A

multivariate Cox regression analysis and the least absolute shrinkage and selection operator

(LASSO) algorithm were used to build a predictive model for osteosarcoma based on FRG
expression. According to the study, a ferroptosis-related gene signature is linked to immunity

and reliably indicates the prognosis for osteosarcoma patients. Because of the genetic complexity

of this uncommon tumor, patient categorization and the development of prognostic biomarkers

have proven difficult, and the prognosis of adolescents and young adults with osteosarcoma has

not improved in decades. To get past the genetic complexity and pinpoint possible explanations,

transcriptomic studies using RNA sequencing (RNA-seq) of osteosarcoma diagnostic biopsies

have been carried out. In order to gain insight into the immune infiltrate and tumor

microenvironment transcriptional programs in pediatric osteosarcoma, the RNA-seq study

discovered stable independent components that recapitulate the tumor and microenvironment cell

composition. Overall, deregulation of ferroptosis-related genes plays a role in the etiology of

osteosarcoma and may affect the immune system and patient prognosis. The causes of

osteosarcoma remain unclear. Among the possible risk factors are: Genetic susceptibility:

Osteosarcoma risk is increased by some genetic disorders, such as LiFraumeni syndrome and

hereditary retinoblastoma. Radiation exposure: Receiving radiation treatment for malignancies in

the past may make osteosarcoma more likely to occur. Age and gender: Children and teenagers

are the main populations affected by osteosarcoma, with a greater incidence rate in men. Bone

illnesses: An increased incidence of osteosarcoma has been linked to certain bone conditions,

including Paget's disease and hereditary multiple exostoses. Environmental factors: While

additional research is required to establish a definitive correlation, certain studies suggest a

probable association between exposure to specific chemicals like beryllium and the development

of osteosarcoma. The second most common type of cancer in children and adolescents is

Ewing’s sarcoma. The pathophysiology of the cell of origin in Ewing's Sarcoma is unknown, but

it is thought to be of neuroectodermal origin. Mutations are found in 85-95% of cases, leading to

the formation of a fusion protein called EWS-FLI1. This fusion protein can be identified with

PCR/FISH and is useful in differentiating Ewing's sarcoma from other round cell lesions. Less

common translocations, including t(21:22) with fusion protein EWS-ERG, comprise the

remaining 10-15% of cases. Some associated conditions inculde: lungs (50%), bone (25%), and

bone marrow (20%) being the most common sites of metastasis. Secondary malignant neoplasms

can occur as a result of treatment with chemotherapy and radiation. These can include

hematologic secondary malignancies such as acute myeloid leukemia and myelodysplastic

syndrome, as well as solid secondary tumors like sarcoma and carcinoma. Ewing's Sarcoma is

also associated with the presence of distant macrometastases, which can contribute to the

development of secondary malignant neoplasms. Additionally, Ewing's Sarcoma has been found

to have an association with certain genetic mutations, such as the t(11:22) translocation and the

formation of fusion proteins like EWS-FLI1. However, further research is needed to fully

understand the etiology and pathogenesis of Ewing's sarcoma and to develop targeted therapies

based on these mechanisms.

1.2 Clinical Presentation

The most presented symptoms of bone tumor/osteosarcoma in children are pain

(usually associated with trauma) which is often recurring and occurs even at rest and

becomes more severe with time as well as swelling and presence of palpable mass or

enlarging soft tissue masses (which their location and demographics could give

important clues to the histology) alongside with pathologic fractures. Other systemic

signs could be unexplained weight loss with poor appetite, fatigue, anorexia, fevers,

night sweats, especially in cases of lymphoma.

1.3 Diagnosis

1. Medical history along with physical examination: get a detailed history from gender,

age, site of the pain, which bone is affected, time of onset of the pain and a family history for

cancers.

2. Radiography findings: look for osteolytic also known as bone-destructing, osteoblastic

or bone- forming lesions that affect the bone density. The radiologist should trace the

location of this lesion either in the diaphysis, epiphysis, metaphysis or the periosteum part of

the bone.

Clinical imaging can be:

· CT-scan: it is used to check for any distant metastasis into another organs and as a guide

in the biopsy diagnostic procedure.

· MRI: it is not really useful in diagnosis of bone tumors, but it provides a great value of

information about the prognosis and the response of a patient to a particular therapy in

addition to knowing if the surrounding structures from nerves, blood vessels and soft tissues

are affected.

3. Elevated biomarkers in the serum such as: lactate dehydrogenase, C-reactive proteins and

fibroblast growth factor-1 and -2 (FGF-1 and FGF-2),alkaline phosphatase levels .

4. The final diagnostic procedure that should be done to confirm the accuracy of having a

bone malignancy is: taking a biopsy which is said to be the gold standard method.

Biopsy is classified into two types:

Open (incisional) biopsy: it is the gold-standard method to use compared to percutaneous

biopsy. However, the patient can be prone to infections in their soft tissues and incisional wound.

Moreover, this type of biopsy is one of the most expensive diagnostic procedures to perform.

Percutaneous biopsy- It can either be:

Fine needle biopsy or Core needle biopsy (CNB), both are minimally-invasive, affordable biopsy

techniques. Core needle biospy is more preferable as it has

higher sensitivity than fine needle one and reduces the risk of

obtaining false negative results. Also, CNB method aids in

getting a decent amount of tissues that is enough to be

analysed under the microscopic examination as well as

reaching specific grade of the tumor and its degree of

differentiation.

● This figure shows a fluoroscopy-guided core-needle biopsy

2. Treatment

Bone tumor treatment differs from one patient to another according to the size , site, stage and

grading .However , the most common methods of therapy are Surgery , Chemotherapy , and

Radio therapy. Prior to surgery, chemotherapy may be administered to reduce the tumor and

destroy bone cancer cells. Additionally, it could carry on following surgery to prevent it from
recurring .

Following surgery, another type of chemotherapy termed mifamurtide, a biological therapy, has

been established for the treatment of non-metastatic osteosarcoma. This is administered in

addition to traditional chemotherapy and has increased survival. Surgery is typically the main

osteosarcoma treatment, but the degree of the surgery will again depend on the location and size

of the tumor. If the damaged limb must be amputated in specific circumstances, a specialized

center will create an artificial limb. It is frequently possible to do limb-saving surgery (including

a prosthetic or bone graft).In fact , Radiotherapy is used alongside of surgery.

It is also inevitable to mention that drug-resistance interactions can arise while treating the

malignant tumor. Therefore, a combinational therapy introducing several drugs to the treatment

needs to be done. In addition, it was found that Tyrosine Kinase Inhibitors (TKIs) are essential to

inhibit the action of tyrosine kinase by blocking the cell growth pathways and induce apoptosis

to the tumor cells.

3. CONCLUSION
In conclusion, further studies should be done in order to target drug-resistance to bone tumors
and improve the prognosis of the patients as well as enhancing their survival rates through more
investigations on tyrosine kinase inhibitors.

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