Brain Metastasis in Pediatric Patients with Osteosarcoma

Abstract

Background: Brain metastases in pediatric osteosarcoma are infrequent but associated with a dire prognosis.

Methods: This retrospective study examined six pediatric patients at Johns Hopkins Hospital who developed brain metastases from osteosarcoma between April 2015 and November 2023.

Results: Median survival post-brain metastasis was 2.5 months. The patients underwent various treatments, including chemotherapy, surgery, and radiation. Despite these interventions, outcomes were uniformly fatal. Notably, one patient survived over 13 months post-brain metastasis with a treatment regimen of cabozantinib and nivolumab along with surgical resection and radiation, highlighting the potential efficacy of multimodal treatment regimens. This case demonstrated changes in the immune microenvironment, hinting at an anti-tumoral response, although no histologic response was observed.

Conclusions: These findings emphasize the critical need for vigilant clinical monitoring, especially in patients with new neurological symptoms. The study highlights the diagnostic challenges and the rapid progression of brain metastases, underscoring the necessity for further research. Prospective studies and clinical trials focusing on novel therapeutic strategies are essential to improve outcomes. Disease biology studies examining tumor features across primary, pulmonary, and brain metastatic sites may offer insights into the mechanisms of metastasis and potential therapeutic targets, providing a foundation for better management of this devastating complication.

Keywords: brain metastasis; osteosarcoma; pediatric oncology.

Figure 1

The clinical courses and genomic characteristics of six patients with osteosarcoma brain metastases. (A) Swimmer’s plot depicts the treatment course and clinical histories; (B) the mutational landscape of primary osteosarcoma following neoadjuvant chemotherapy and, when available, lung and brain metastases. Clinical sequencing results were derived from the Johns Hopkins NGS Solid Tumor Panel and Foundation One Heme assay. I/E, ifosfamide/etoposide; MAP, methotrexate, cisplatin, and doxorubicin; MTP, muramyl tripeptide.

Figure 2

Representative axial T1 MRI imaging initial brain metastases of (A) Patient 1; (B) Patient 2; (C) Patient 3; (D) Patient 4; (E) Patient 5; and (F) Patient 6.

Figure 3

Histology, immunohistochemistry (IHC), and flow cytometry of brain metastases in Patient 5 pre- and post-immunotherapy (IT). (A,B) Histologic sections 100x of pre (A) and post (B) are morphologically similar and display high-grade conventional osteosarcoma, showing sheets of mitotically active tumor cells producing osteoid and chondroid matrix, respectively. Significant histologic response to therapy is not identified. (C,D) Pre- and post-immunotherapy photomicrographs showing anti-CD8 IHC stains at 4× magnification. (E,F) Pre- and post-immunotherapy photomicrographs displaying anti-PD-L1 IHC stains at 4× magnification; (G) Stacked bar chart showing the proportion of the different subsets of freshly isolated tumor-infiltrating immune cells characterized via multiparameter flow cytometry from tumor specimens obtained pre- (pre-IT) and post- (post-IT) immunotherapy. B cells: B lymphocytes; CTL: cytotoxic T cells; TH: helper T cells; Treg: regulatory T cells. (H) Stacked bar chart depicting the proportion of intra-tumoral memory T cell compartments according to defined phenotypes assessed by multiparameter flow cytometry pre-IT and post-IT. CM: central memory T cells, Naïve: naïve T cells; EM: effector memory T cells; TEMRA: terminally differentiated effector memory T cells re-expressing CD45RA.