Case Report
An 11-year old male presented after injuring his left tibia and had an abnormality on X-ray which prompted a follow-up MRI. MRI demonstrated a left tibial bony lesion, suspicious for a malignancy. Patient underwent core needle biopsy of his left tibia and pathology revealed a low grade osteosarcoma. Patient underwent surgical excision of his left tibia with allograft reconstruction. Pathology now confirmed the presence of a high-grade osteosarcoma. Patient received chemotherapy per Children’s Oncology Group’s AOST0331 protocol9. He completed the planned therapy regimen without any major complications.
He was followed up regularly every 3 months for physical exam, surveillance labs, and imaging studies that did not demonstrate any acute disease. Several months after completing therapy, his younger brother was diagnosed with high grade osteosarcoma of left ilium. Our patient was then evaluated via genetic testing that revealed a TP53 mutation, specifically TP53, c.818G>A (p.Arg273His), consistent with LFS. His mother, younger brother, and another half-brother tested positive for the same TP53 mutation. Patient underwent surveillance as per LFS Education and Early Detection Program (LEAD)10 . The program included annual brain and whole body MRI’s, annual blood and urine tests to evaluate adrenal gland function, tumor markers for common LFS associated tumors, and physical exams every 6 months10. The inclusion of whole body MRI and brain MRI is particularly essential as LFS has a high incidence of asymptomatic tumors11. Following LEAD guidelines, our patient was evaluated with MRI of brain and whole Body which showed no evidence of new tumors or other abnormalities.
He underwent a brain MRI as part of his surveillance scans (13 month interval since previous surveillance scan) that showed a well-circumscribed mass in the left lateral cerebellum measuring 1.5 X 1.1 X 0.6 cm (Fig. 1). He was clinically asymptomatic, had no abnormalities on physical exam, and had no evidence of lesions at other body sites. The patient underwent surgical resection of his cerebellar lesion. Neuropathological evaluation showed densely cellular highly mitotic neoplasm with large pleomorphic nuclei and apoptotic cells without the presence of any cerebellar tissue (Fig. 2). Next Generation Sequencing identified the following genomic alterations; SMO copy number loss, DDX3X copy number loss, TP53 mutation p.R273H, TP53 copy number loss, and MYCYN copy number gain. Testing revealed that the tumor was positive for YAP-1 and GAB-1. These results are consistent with Sonic Hedgehog (SHH)-activated large cell anaplastic medulloblastoma arising in a patient with germline TP53 mutation. Patient’s medulloblastoma was located in the lateral cerebellum and most SHH tumors are known to be mainly located in the cerebellar periphery12. Medulloblastomas identification is enhanced via diffusion MR because they are hypercellular tumors that result in decreased Apparent Diffusion Coefficient (ADC) values13. Overall, SHH-activated and TP53-mutant medulloblastomas are rare and associated with a dismal prognosis14.
Patient and his mother decided to forego any systemic chemotherapy due to the poor prognosis of secondary anaplastic medulloblastoma. Repeat MRI of brain 3 months post craniotomy showed evidence of recurrent neoplasm along the superior aspect of the left cerebellar hemisphere that measured 3.2 X 3.4 X 1.3 cm. Patient was placed on hospice as the family decided to forego any further intervention and he died at home on July 23, 2018.
Shortly after, his mother died from recurrent high grade pleomorphic sarcoma of pelvis. Patient’s younger brother, who was diagnosed with osteosarcoma developed recurrent pulmonary metastatic disease of his osteosarcoma. He succumbed to his illness while under Hospice care at home. Patient’s half-brother is undergoing serial evaluations according to LEAD program and remains cancer-free.