Current therapeutic approaches of bone sarcomas

Introduction

Bone sarcomas include a variety of primary, nonepithelial, malignant neoplasms with metastatic potential originating from bone cells or their precursors. Some are purely osteolytic, while others produce a calcified matrix (e.g., osteosarcoma), a cartilaginous matrix (e.g., chondrosarcoma), or a mixed osteolytic/osteoblastic matrix [ ]. Bone sarcoma genesis can be explained by a conjunction between a minimum of one oncogenic event and an adequate microenvironment leading to the emergence of cancer, followed by its growth and potential migration to distant organs. Oncogenic events at the gene expression level such as mutation, duplication, and translocation occurring during mesenchymal stem cells differentiation increase the risk of their transformation to cancerous cells and result in the emergence of malignant osteoblastic or chondroblastic malignant cells [ , ].

The three main bone sarcomas in descending order of frequency are osteosarcoma, Ewing's sarcoma, and chondrosarcoma [ ]. Most bone sarcomas occur in children and young adults and develop in the extremities, especially the distal femur, or the pelvis [ , ]. The differential diagnosis is related to age. Before 5 years of age, a destructive bone lesion is most commonly metastatic neuroblastoma or eosinophilic granuloma; above 5 years, it is often a primary bone sarcoma; after 40 years of age, it tends to be metastasis or myeloma [ ]. Moreover, specific events for bone tumors include prior benign/malignant lesions, family history, and previous radiotherapy. A recent injury is reported in up to 60% of patients and should not rule out a malignant tumor [ , ].

Bone sarcomas most commonly metastasize to the lungs; radiographs or computed tomography of the chest assess the lungs for metastasis. A technetium bone scan examines for other similar bone lesions (metachronous lesions) or metastatic bone disease. Laboratory tests and tumor markers are not helpful in the staging of bone sarcomas [ , ]. Biopsy is the gold standard for the diagnosis [ ]. The principles of the biopsy are (1) minimal contamination of normal tissues; (2) core needle biopsy, preferably imaging guided is preferable to open biopsy; (3) adequate sampling of representative areas for histology must be assured; (4) samples should always be sent for microbiological culture for a potential differential diagnosis; (5) samples must be interpreted by an experienced pathologist; and (6) the request form should contain sufficient details for the site of the tumor and the patient's details and history [ , ]. In aggressive and malignant bone tumors, the biopsy tract must be considered to be contaminated with tumor and must be removed en bloc with the resection specimen, including the possible channels through which drains have been placed to avoid local recurrences. Biopsy tracts should be clearly marked by means of a small incision or ink tattoo to ensure that the location can be recognized at the time of the definitive procedure. Samples should be quickly submitted for pathological assessment, ideally within half an hour; upon arrival, and before formalin fixation, tumor imprints (touch preps) can be taken (useful for tumor-specific translocation by FISH), and tissue/cell suspensions should be kept frozen in cryomolds [ ].

After biopsy and histological diagnosis, treatment proceeds. Current treatments for bone sarcomas include limb-salvage surgery with wide-margin resection or amputation, with or without adjuvant treatments including chemotherapy and radiation therapy according to the tumor's histology. Patients with locally or distally advance sarcomas may benefit from palliative treatments [ , ].

Surgery

Surgery is the primary therapeutic approach; input from vascular and plastic surgeons and urologists is often necessary based on the location and extend of the tumor. For some bone sarcomas, such as osteosarcoma and Ewing's sarcoma, neoadjuvant chemotherapy, prior to surgical treatment, aims to treat the potential micrometastatic disease, reduce the soft-tissue mass about the bone tumor and/or mature the mass, allow for easier resection, and improve the survival of the patients. In patients with high-grade tumors, those with metastases at presentation or local recurrence, and poor responders to first line treatment, a carefully planned approach with target treatments or early amputation is paramount [ ]. Whether preoperative radiation therapy is performed after the initiation of chemotherapy is generally determined by a discussion between the surgeon, the medical, and the radiation oncologist about the feasibility of a negative margin with surgery and the inherent functional loss with resection. There are particular concerns about radiation in younger patients, who have a relatively high rate of postradiation sarcoma [ , ].

An absolute indication for amputation is tumor involvement of the major neurovascular structures. Additionally, amputation should be considered when curative surgery is possible and limb-salvaging resection is unlikely to obtain a negative margin or a functionally viable extremity. The choice of the amputation incision and technique depends on the presence of a biopsy incision and the location of tumor's soft-tissue mass. If neurovascular structures are not encased (i.e., not more than 50% surrounded in the case of arteries or motor nerves), these structures are spared. If arteries are encased, arterial resection with reverse interpositional vein graft, synthetic graft, or vein allograft allows for bypass of the vessel and leaves the encased structure with the resection specimen for en bloc resection [ ]. Pathological fractures in patients with primary bone sarcomas should not be considered an absolute indication for amputation. Limb-salvage surgery of selected patients with a pathological fracture, particularly one that unites following chemotherapy, does not appear to increase the risk of local recurrence or death. Patients should be treated by neoadjuvant chemotherapy, and their tumors should then be resected with safe surgical margins. The response of the tumor to chemotherapy is predictive of fracture union and improved overall survival and local disease control. The extent of fracture displacement may not portend a poorer prognosis and the type of fracture stabilization may not significantly affect the outcome. Pathological fractures in chemoresistant primary bonesarcomas are a relative contraindication for limb-salvage surgery. Multicenter studies are necessary to obtain statistically significant data that will assist in the treatment of this patient population [ , ].

The tumor with the biopsy scar surrounded by a cuff of healthy tissue must be removed en bloc [ , ]. It has been postulated that margins of less than 1 cm may be associated with a very low rate of recurrence, although no well-controlled study has proven this [ , ]. Intralesional surgery should be avoided because it will lead to a high risk of local recurrence regardless of whether the patient receives perioperative radiation therapy or chemotherapy. If intralesional surgery has been performed, re-excision of the tumor bed is recommended [ ]. For low-grade chondrosarcomas of the extremities, intralesional surgery is acceptable as it has been reported to have a low rate of recurrence [ ].

Megaprosthetic or allograft reconstruction is performed after bone sarcoma resection. Allograft prosthesis composites are valuable options in certain tumor locations such as the proximal humerus and the proximal tibia for optimal soft-tissue reattachment to the allograft. In the femur, modular megaprostheses are used preferably [ ]. Biological reconstruction techniques include allografts or autografts such as vascularized fibula, particularly for intercalary bridging of diaphyseal defects [ ]. In growing children, reconstruction after bone sarcoma resection is challenging, particularly in terms of addressing leg length inequality. In general, allograft reconstruction is performed, unless the resection involves the joint. In that case, an expandable prosthesis [ ] or rotationplasty should be considered. In selected cases, preservation of the epiphyseal portion of the bone and the joint surface may be achieved by physeal distraction; however, this applies only to patients in whom the epiphysis is still open [ , ]. Limited pelvic resections with or without reconstruction are associated with the best outcome for the patient, provided tumor-free margins have been obtained. Extended pelvic resections with or without sacral invasion and/or salvage of the leg are difficult and fraught with complications [ , , ].

Extracorporeal irradiation and reimplantation of the host bone has been reported as an oncologically safe and inexpensive technique for limb salvage in diaphyseal bone sarcomas, with good functional results [ ]. Extracorporeal irradiated autograft may be supplemented with a vascularized fibular graft for biological augmentation of the intercalary reconstruction after wide resection of malignant bone tumors of the femur [ ].