1. Introduction
Ewing sarcoma (ES) is an aggressive cancer of the bone and/or soft tissue and has peak incidence in the adolescent and young adult population. Behind osteosarcoma, it is the second most common bone cancer found in children, comprising 10-15% of all primary malignancies of the bone.[1] At initial diagnosis, metastatic status is the most important prognostic factor, with survival rates diverging for patients with localized disease compared to those presenting with metastatic disease.[2] Common sites of metastasis include the lungs and bone, with bone marrow (BM) metastasis less commonly reported. Among patients with metastatic disease, those with lung metastases alone have a better prognosis, with event-free survival (EFS) ranging from 29-52% while patients with bone/BM metastases have an EFS of 20% or lower.[2,3] Metastatic BM involvement has further been reported as an independent risk factor distinct from multiple bone metastasis.[2,4,5] In one large analysis, patients with both BM and bone metastasis had inferior 3-year OS and EFS (21% and 14%) compared to patients with bone metastasis but no BM metastasis (37% and 31%).[2] Accurate identification of metastatic pattern is important in determining treatment, monitoring response, and determining prognosis.
Staging usually includes imaging of the primary site plus evaluation of metastatic disease with a chest CT (computed tomography), [F-18]fluorodeoxyglucose positron emission tomography (FDG-PET) scan, and bone marrow biopsy and aspirate (BMBA). The current gold standard evaluation for detection of metastatic BM disease has been BMBA. For example, the Children’s Oncology Group required this procedure for enrollment on the last two protocols for patients with newly diagnosed disease. In adult patients with primary bone cancer, a BMBA is not routinely performed, and the current National Comprehensive Cancer Networks (NCCN) guidelines recommend an MRI of the spine and pelvis as an alternative to BMBA. [6] A BMBA procedure is invasive and carries a small risk of complications,[7] including risks of general anesthesia administration in young patients. The increased use of FDG-PET scan, a non-invasive technique allowing for whole-body staging, has prompted investigators to ask if this modality may replace BMBA for detection of BM metastasis,[8-12] with several cohort studies directly comparing FDG-PET to BMBA in detection of BM metastasis. [13-18] Other studies have evaluated the use of FDG-PET/CT scan in ES and rhabdomyosarcoma and demonstrated FDG-PET scan to have a high sensitivity and specificity for detection of bone metastases when compared to bone scan and MRI.[17,19-22] FDG-PET scans have been shown to be superior to bone scans to detect asymptomatic metastasis in ES patients.[15]
To provide clarity on the incidence of metastatic BM disease in ES and the best strategy to diagnose BM disease at presentation in these patients, we pooled available evidence in this systematic review. First, we describe the incidence of metastatic BM disease with and without the presence of additional metastatic disease in the presentation of newly diagnosed ES as well as clinical associations with BM metastatic disease. Second, we report the available sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FDG-PET scans for diagnosis of metastatic BM disease in newly diagnosed ES patients.