1. Concept

Malignant bone tumors, also known as "bone cancer", refer to malignant tumors that grow in bones and accessory tissues. Bone malignancies are classified into primary and secondary.

Primary malignant tumor of bone: malignant tumor growing from bone or its affiliated tissues, generally including osteosarcoma, chondrosarcoma, Ewing sarcoma.

Secondary bone malignant tumor: malignant tumor that transfers from other tissues or organs in the body to bone through blood circulation and lymphatic system, mainly including bone metastatic malignant tumor.

Bone malignant tumors accounted for only 0.2% of all malignant tumors.

According to the WHO classification of bone tumors (2020), bone malignant tumors are mainly divided into the following categories.^[1]

1）Cartilaginous tumors: tumors originating from cartilage can be divided into benign and malignant tumors.

2）Osteogenic tumors: tumors originating from bone tissue are called osteogenic tumors.

3）Fibrogenic neoplasms: desmoplastic fibroma, fibrosarcoma.

4）Vascular tumor of bone: Abnormal proliferation and accumulation of blood vessels in bone.

5）Tumors rich in osteoclast giant cells: giant cell lesion of the small bones, giant cell tumor of bone, malignant giant cell tumor of bone.

6）Chordal tumors: chordoma, chordoma, chondroid chordoma, poorly differentiated chordoma, and degenerative chordoma.

7）Other mesenchymal neoplasms of bone: chest wall cartilage mesenchymal malaria, lipoma, hibernoma.

8）Hematopoietic tumors of bone: plasmacytoma of bone, T-cell lymphoma, etc.

According to the classification of bone tumor subtypes, the proportion of osteosarcoma and osteoblastoma in the adolescent group was higher than that in the adult group, while the proportion of chondrosarcoma, chordoma, giant cell tumor of bone, malignant giant cell tumor of bone and undifferentiated sarcoma was lower than that in the adult group Group. Statistical analysis revealed significant associations between adolescent patients and osteosarcoma and between adult patients and chondrosarcoma ^[4].

Different age groups suffer from different types of bone tumors

2．Cause

Age: Adolescents aged 10-20 are at high risk of primary bone malignancies.

Genetic factors: People with a family history of genetic diseases such as neurofibroma, retinoblastoma, and tuberous sclerosis have an increased risk of primary bone malignancies.

Other diseases: Having eczematoid carcinoma or certain benign lesions of the bone, such as chronic osteomyelitis, may increase the risk.

3 .Diagnostic tests^[2]

MALIGNANT TUMOR OF BONE

Age<40 years old: Invasive and symptomatic osteopathic changes have a significant risk of becoming malignant primary bone tumors.

Age ≥ 40 years: CT scan of the chest, abdomen and pelvis should be  performed and compared.

All patients with suspected osteosarcoma should be fully staged prior to biopsy.

Standard staging workup for suspected primary bone cancer should include chest imaging (chest radiograph or chest CT), appropriate imaging of the primary site (MRI and/or CT), and bone scan or PET/CT.

Lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) tests should be performed before starting treatment.

4．Treatment of Bone Malignancies

Surgical treatment: Surgery for bone tumors usually requires extensive resection of the tumor. Surgical treatment should be the first choice for lesions that have surgical indications and can be surgically resected.

Chemotherapy: For some malignant bone tumors, especially osteosarcoma patients, surgery alone is usually not enough. These cancers sometimes have distant metastases, usually from the lungs. For such patients, chemotherapy may increase survival.

Radiation therapy: For malignant bone tumors, radiation therapy is most commonly used for those with tumors that cannot be removed surgically. Radiation therapy may also be given before surgery to shrink tumors, or after surgery to destroy remaining cancer cells.

Targeted therapy: Targeted drugs inhibit cancer cells to achieve therapeutic purposes. Currently, the most widely used targeted drugs mainly include epidermal growth factor receptor inhibitors, angiogenesis inhibitors, and inhibitors related to tumor signaling pathways.

Vascular embolization therapy: It can be used to reduce intraoperative bleeding, and palliative embolization therapy can also be used for unresectable bone malignant tumors.

Other treatments: Hyperthermia-chemotherapy can play a superimposed role of hyperthermia and chemotherapy.

5． Molecular detection of bone malignancies

The complexity and heterogeneity of bone tumors increase the difficulty of diagnosis and treatment. With the development of molecular genetic technology, the molecular characteristics of bone tumors have been studied, and some bone tumors can be analyzed with the help of genomic mutations. In a study of the clinical characteristics of 357 patients with bone tumors, a total of 2,780 clinically relevant genomic variants were identified, with an average of 10 genomic variants per sample (range, 0 to 33). Among these genomic variations, gene amplification was the most common mutation type (57%), followed by deletion/insertion mutations (24.9%), gene homozygous deletions (6.2%), truncating mutations (6%), gene fusions/ Rearrangement (5.9%).

The most frequently mutated genes with a mutation frequency of more than 10% were TP53 (37.4%), NCOR1 (15.7%), VEGFA (13.7%), RB1, CCND3, CDKN2A, GID4, TERT, CCNE1, and MAP2K4.

Gene mutation map of 357 Chinese patients with bone tumors^[4]

A total of 145 potential target mutations were identified in 122 (34.2%) of these patients with bone tumors, including 81 osteosarcomas, 17 chondrosarcomas, 6 chordomas, 3 undifferentiated sarcomas, and 2 undifferentiated pleomorphic sarcoma, 1 fibrosarcoma, 1 low-grade fibromyxoid sarcoma, 1 osteoblastoma, and 10 bone tumors of unspecified subtype.

Potentially targeted mutations in patients with bone tumors ^[4]

The most frequently mutated genes in the adult patient group included TP53, TERT, CDKN2A, CDK4, MDM2, and GLI1, and the adolescent group showed significant associations with NCOR1, VEGFA, CCND3, GID4, CCNE1, RB1, MAP2K4.

Different age groups have different mutated genes ^[4]

The expert consensus in China recommends the use of NGS methods for polygenic testing in patients with bone tumors who cannot be clearly diagnosed by routine pathological examination or who need targeted therapy, in order to find opportunities for clinical benefit.

Chinese expert consensus on next-generation sequencing of bone and soft tissue tumors

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The NGS method is the detection method recommended by Chinese experts ^[3]

Bone tumors widely occur in children and adolescents, and still face the problems of difficult treatment and high mortality. Due to the rarity of bone tumors and the small number of patients, the molecular mechanisms of bone tumors remain unclear. Although genome sequencing studies of bone tumors are ongoing, small sample sizes and limited bone tumor subtypes remain major limitations of the study. Understanding the molecular characteristics of bone tumors is helpful for differential diagnosis, and is of great significance for guiding the treatment of patients, improving the prognosis of patients. NGS studies have been extensively carried out in osteosarcoma in Western countries. Previous studies have shown that TP53, RB1 and CCND3 are commonly found in osteosarcoma. The studies described above identified a mutational signature in patients with bone tumors, pointing to differences in germline and somatic mutations between adolescent and adult patients. Relevant research results support that NGS technology can effectively assist the diagnosis of bone tumors and provide a basis for precise treatment of bone tumors.

Reference

[1] WHO classification of bone tumors (2020)

[2] NCCN Guidelines for Diagnosis and Treatment of Bone Cancer 2021

[3] Chinese expert consensus on next-generation sequencing of bone and soft tissue tumors (2021 edition)

[4] Xianbiao Xie, Yiying Bian, Haomiao Li, Junqiang Yin, Lantian Tian, Renbing Jiang, Ziliang Zeng et al A Comprehensive Understanding of the Genomic Bone Tumor Landscape: A Multicenter Prospective Study.Front. 08 June 2022doi:10.3389/fonc.2022.835004

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