Silent Persistence: Late Pulmonary Recurrence of Metastatic OsteosarcomaOz Mordechai1, Anat Ilivitzki2, Eugene Vlodavsky3,Myriam Ben-Arush1, Sergey Postovski4.1-Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa, Israel.2- Department of Pathology, Rambam Health Care Campus, 31096 Haifa, Israel.3- Department of Radiology, Rambam Health Care Campus, 31096 Haifa, Israel.4- Pediatric Oncology Unit, Emek General Hospital, IsraelCorresponding author: Oz Mordechai, o_mordechai@rambam.health.gov.ilTo the Editor,We report a case highlighting metastatic osteosarcoma’s biological complexity and clinical unpredictability. It features an exceptionally late pulmonary relapse in a pediatric patient after a prolonged remission, emphasizing the challenges of long-term disease surveillance and management.A 12-year-old boy was diagnosed with classical osteoblastic osteosarcoma of the right proximal humerus. He presented with localized pain, swelling, and reduced mobility. Imaging studies, including MRI and chest CT, revealed an aggressive primary tumor (Fig. 1A) and multiple bilateral pulmonary nodules (Fig. 1B) suggestive of metastatic disease. Bone scan was negative. Biopsy confirmed classic osteoblastic osteosarcoma (Fig. 1C).Treatment followed the P9754 protocol (Pilot 2 – Doxorubicin Intensification with Ifosfamide), including high-dose Methotrexate, Doxorubicin, Cisplatin, and Ifosfamide. A clinical and radiological response was notable. Following three cycles of neoadjuvant therapy, residual lung nodules persisted.Surgical resection of the tumor revealed 100% necrosis (Huvos Grade IV). Thoracotomy was performed at the end of chemotherapy, removing all palpable right lung nodules, all of which were necrotic. The left-sided nodules were not resected due to anticipated morbidity, and all disappeared during follow-up.The patient remained in clinical and radiologic remission for an extended period of 11 years before presenting with hemoptysis. Chest CT identified a solitary lesion in the left lower lobe (Fig. 2A). PET-CT was performed to exclude systemic spread, confirming isolated recurrence. Thoracoscopic resection confirmed histologic recurrence of osteoblastic osteosarcoma (Fig. 2B).Later, multiple new pulmonary nodules appeared. The patient demonstrated no clinical response to second-line chemotherapy with Ifosfamide and Etoposide. Treatment with tyrosine kinase inhibitors—initially pazopanib, followed by regorafenib—was attempted; however, the disease continued to progress. The patient died approximately 2.5 years after recurrence, nearly 14 years from initial diagnosis.Osteosarcoma is the most common pediatric bone malignancy, with a peak incidence during adolescence[1,2]. At diagnosis, 15–20% of patients have detectable metastases, most commonly in the lungs [1,2]. While most recurrences occur within three years, late relapses—those occurring beyond five years—are rare and poorly understood [3].Pulmonary metastases at diagnosis predict poor outcomes, with long-term survival in the range of 10–40% [3-8]. Prognostic factors include the number and laterality of metastases, resectability, and histologic response [3,8].Surgical resection remains the main curative approach for metastatic relapse [9-13]. The role of chemotherapy in recurrent disease, particularly late relapses, is controversial [11]. Regimens such as ifosfamide/etoposide [14,15] and gemcitabine/docetaxel [9,16] are commonly employed, although supporting evidence is limited to small, non-randomized studies. In this patient, these salvage therapies did not achieve disease control.Next-generation sequencing (NGS) was performed on primary and recurrent tumor samples to investigate the biology of this late relapse. Analysis identified 1,097 shared variants, including canonical osteosarcoma drivers (TP53, RB1, CDKN2A, APC). The primary tumor contained 272 unique variants, including 10 classified as pathogenic, while the recurrent tumor exhibited only 94 unique variants, none of which were pathogenic.This genomic profile suggests reactivation of a dormant subclone rather than accumulation of new mutations through continuous evolution. One plausible explanation is that a minor, therapy-resistant subpopulation presents at diagnosis, potentially with stem-like features, remained quiescent and evaded initial treatment. Over time, these dormant cells may have re-entered the cell cycle, ultimately leading to clinically detectable relapse.Such dormancy-based models challenge the traditional view of continuous tumor evolution and highlight the biological plasticity of osteosarcoma [17]. Understanding whether late-relapsing cells derive from a stable dormant clone or undergo further molecular adaptation could inform future strategies for surveillance, therapeutic targeting, and risk stratification.Despite improved understanding of molecular drivers, effective targeted therapies remain elusive. Several tyrosine kinase inhibitors have shown limited activity in relapsed osteosarcoma, and predictive biomarkers are lacking. In our case, pazopanib and regorafenib did not yield benefit.Ellegast et al.[18] reported a case of metastatic osteosarcoma relapsing 16 years after therapy. The recurrent tumor showed greater genomic complexity than the primary, suggesting evolution toward a more treatment-resistant phenotype. These findings support the need for alternative second-line regimens, though it remains uncertain whether such recurrent clones retain chemosensitivity.Despite improved understanding of molecular drivers, effective targeted therapies remain elusive. Several tyrosine kinase inhibitors [19-22] have shown limited activity in relapsed osteosarcoma, and predictive biomarkers are lacking. In our case, pazopanib and regorafenib did not yield benefit.This case illustrates the potential for exceptionally prolonged remission in metastatic osteosarcoma. While some studies have documented late relapses in non-metastatic patients [23-28], reports of such delayed recurrence in patients initially presenting with metastatic disease are exceedingly rare.This case further highlights the indispensable role of surgical resection in managing metastatic disease and the potential of integrated genomic analysis to elucidate the biology of relapse. Although rare, late recurrences pose distinct clinical challenges and expose limitations in current treatment strategies.Figures :
