An 18 year old white male presented with a 6 month history of discomfort and swelling in his left knee. An X-ray and MRI of the left knee revealed a large, partly mineralized tumour in the medial tibial diaphysis. In his past history, the patient had been diagnosed at birth with coarctation of the aorta and primary lymphoedema. Balloon dilatation angioplasty was successfully performed on day 13 of life. Subsequent cardiac medical management included nifedipine between the ages of 4 and 9; this was later switched to atenolol because of lymphoedema. His phenotype was consistent with a variant of Irons–Bianchi syndrome or ‘‘Milroy-like’’ lymphoedema. Further details of his medical history and treatment are described elsewhere []. Genetic testing to date has proven negative for pathogenic variants, including the “Red Cell gene panel” and the 23 genes in the “Rasopathy panel” although heterozygous variations of uncertain clinical significance were identified in the FAT4 gene (c.8290A > C and c.12070C > T). He had also received topical bleomycin and acitretin for persistent plantar viral warts. The patient had no family history of congenital syndromes, but there was a strong family history of cancer including renal cell carcinoma, skin cancer, bowel cancer and breast cancer in second-degree relatives. Plain radiographs demonstrated a poorly defined, permeative, radiolucent lesion, centred in the proximal tibial meta-diaphysis. A pathological fracture was present. There was postero-medial cortical destruction with adjacent areas of ossification. There was evidence of low density in the medial soft tissue mass, raising the possibility of a fatty matrix. Magnetic resonance imaging (MRI) showed that the tumour filled the medullary cavity of the proximal tibial metaphysis; it had an ill-defined margin and crossed the physis extending to the subarticular surface but there was no intra-articular extension. Extensive medial cortical destruction was associated with an almost circumferential spiculated soft tissue mass which had displaced the calf musculature and popliteal neurovascular bundle. The tumour breached the deep fascia and the interosseous membrane. The lesion was of heterogeneous isointense signal on T1- and high signal on T2-weighted images. Areas of high T1 signal suppressed on fat saturation sequences, supporting a partly fatty matrix. A pathological fracture was clearly seen extending transversely across the proximal tibia. Positron emission tomography with fluorodeoxyglucose (FDG) integrated with computed tomography (PET/CT) confirmed an ill-defined proximal tibial lesion with medial cortical destruction and a large soft tissue mass containing areas of fat attenuation and ossification. The tumour showed marked FDG uptake with a standardised uptake value (SUV) of 17.1 and a band of relative photopaenia in the region of the undisplaced transverse pathological fracture. A further focus of markedly increased FDG uptake with an SUV of 13.5 was seen in a lateral distal femoral lesion which was presumed to represent a metastasis. Eight small bilateral pulmonary nodules (maximum 4 mm) were also noted on the PET/CT scan consistent with lung metastases. There was no lymphadenopathy, and no fat or other soft tissue lesion was noted. Histology of a biopsy of the tibial mass revealed a proliferation of malignant cells that had vacuolated cytoplasm and large atypical pleomorphic nuclei. There were vacuolated tumour giant cells and numerous small lipoblast-like cells with a single cytoplasmic fat vacuole and hyperchromatic nuclei as well as brown fat-like cells with multiple small fat vacuoles. There were frequent mitotic figures, many of which were atypical. No evidence of osteoid formation was seen. There was infiltration of cancellous bone and evidence of lymphovascular invasion. Immunohistological analysis showed that the malignant cells strongly expressed FABP4/aP2 [, ], a marker of adipocyte differentiation and UCP1 [–], a marker of brown adipose tissue; there was no expression of S100, desmin, smooth muscle/muscle actin, myogenin, CD34, CD31, CD30, CD45, cytokeratin, epithelial membrane antigen, CD99 or CD117. Cytogenetic analysis showed that there was no evidence of MDM2 or CDK4 amplification. The morphological and immunohistochemical features were thought to be most in keeping with a diagnosis of primary pleomorphic liposarcoma of bone. The patient was treated with two cycles of neoadjuvant multi-agent chemotherapy, comprising methotrexate, doxorubicin and cisplatin (MAP), as per the closed European American Osteosarcoma (EURAMOS) trial. His baseline pre-treatment 2D transthoracic echocardiogram was within normal limits with an ejection fraction of 70%. The patient tolerated the chemotherapy well with clinical improvement after 2 cycles of chemotherapy as evidenced by a significant reduction in his analgesia use. The preoperative MRI showed an interval reduction of the large primary left tibial lesion but an increase in size and interval of the right distal femoral lesion. The preoperative PET scan demonstrated a discordant excellent metabolic response to neoadjuvant chemotherapy within both the primary tumour and the metastatic lesions. The FDG uptake was significantly reduced in the primary tumour of the tibia from 17.1 to 2.7 and the focus in the femur and right tibia showed only background activity. The majority of the bilateral pulmonary nodules had also resolved. The patient underwent an uncomplicated surgical resection of the primary tumour in the proximal tibia and the lesion in the distal femur with reconstruction using a linked distal femur and proximal tibial endoprosthesis (Stanmore Implants, UK). At operation, the left proximal tibial tumour was noted to be yellow and necrotic; it filled the medullary cavity and had spread through the bone cortex into covering soft tissues. A second yellow nodule was present in the left distal femur. Histologically, the resected tibia contained only a small amount of residual viable tumor that was similar morphologically and immunohistochemically to that seen in the biopsy. There was extensive (> 95%) tumor necrosis as a consequence of neoadjuvant chemotherapy. Post-operative adjuvant chemotherapy was considered appropriate in this case because of the excellent response to chemotherapy. As routine cardiac assessment demonstrated an asymptomatic significant reduction in ejection fraction (70–53%), adjuvant chemotherapy was changed to 5 cycles of ifosfamide and etoposide, because of the previously reported activity of ifosfamide in liposarcoma []. 12 months after surgical excision of the tibial and femoral lesions, the patient is well with no evidence of metastasis or recurrence on clinical and radiological (including PET scan) follow up.