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Pleomorphic liposarcoma of bone: a rare primary malignant bone tumour

Pleomorphic liposarcoma of bone: a rare primary malignant bone tumour Background: Liposarcoma is an extremely rare primary bone sarcoma. Case presentation: We report a case of primary pleomorphic liposarcoma that arose in an 18 year old male in the metaphysis of the left tibia. Plain radiographs showed a partly sclerotic lesion and MR imaging a heterogeneous tumour predominantly isointense on T1- and high-signal on T2-weighted sequences with focal areas of increased T1 signal that suppressed with fat saturation. PET/CT showed marked FDG uptake (SUV = 17.1) in the primary tumour as well as a metastasis in the right distal femur and multiple small pulmonary metastases. Histologically, the tumour was a pleomorphic liposarcoma containing large tumour cells with vacuolated cytoplasm and hyperchromatic pleomor- phic nuclei as well as numerous lipoblasts and scattered brown fat-like cells. Tumour cells strongly expressed FABP4/ aP2, a marker of adipocyte differentiation, and UCP1, a marker of brown fat, but not S100. The case was treated with neoadjuvant MAP chemotherapy, resulting in extensive (> 95%) necrosis in the primary tumour and almost complete resolution of the femoral and pulmonary metastases. Conclusions: Pleomorphic liposarcoma can present as a sclerotic primary malignant bone tumour; markers of adipose differentiation are useful in histological diagnosis and neoadjuvant MAP chemotherapy results in significant tumor necrosis. Keywords: Liposarcoma, Bone, Malignant, Primary tumour there is considerable uncertainty regarding the histologi- Background cal diagnosis and optimum treatment of this rare tumour. Liposarcoma is an extremely rare primary malignant We report the clinical, radiological (including MRI and bone tumour defined in the 2005 AFIP Fascicle as “A PET/CT) and pathological findings in a case of primary malignant tumor with differentiation towards adipo - pleomorphic liposarcoma that arose in the proximal cytes” [1]. Catto and Stevens [2], reviewing the world tibia of an 18  year old male. We also review the litera- literature in 1963, could find only 15 cases of primary ture regarding primary liposarcoma of bone and reassess bone liposarcoma; they noted that most reported cases diagnostic criteria and treatment options in the light of were pleomorphic sarcomas and considered only one our findings. case, that reported by Dawson in 1955 [3], as completely convincing. In 1982 Addison and Payne accepted only six Case presentation examples of this tumour in previously published reports An 18 year old white male presented with a 6 month his- [4]. Subsequently, other cases have been reported, but tory of discomfort and swelling in his left knee. An X-ray and MRI of the left knee revealed a large, partly miner- alized tumour in the medial tibial diaphysis. In his past *Correspondence: nick.athanasou@ndorms.ox.ac.uk history, the patient had been diagnosed at birth with Nuffield Department of Orthopaedics, Rheumatology coarctation of the aorta and primary lymphoedema. Bal- and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University loon dilatation angioplasty was successfully performed of Oxford, Oxford OX3 7HE, UK Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 2 of 9 on day 13 of life. Subsequent cardiac medical manage- Magnetic resonance imaging (MRI) showed that the ment included nifedipine between the ages of 4 and 9; tumour filled the medullary cavity of the proximal tibial this was later switched to atenolol because of lymphoe- metaphysis; it had an ill-defined margin and crossed the dema. His phenotype was consistent with a variant of physis extending to the subarticular surface but there was Irons–Bianchi syndrome or ‘‘Milroy-like’’ lymphoedema. no intra-articular extension (Fig.  2). Extensive medial Further details of his medical history and treatment cortical destruction was associated with an almost cir- are described elsewhere [5]. Genetic testing to date has cumferential spiculated soft tissue mass which had dis- proven negative for pathogenic variants, including the placed the calf musculature and popliteal neurovascular “Red Cell gene panel” and the 23 genes in the “Rasopa- bundle. The tumour breached the deep fascia and the thy panel” although heterozygous variations of uncertain interosseous membrane. The lesion was of heterogeneous clinical significance were identified in the FAT4 gene isointense signal on T1- and high signal on T2-weighted (c.8290A  >  C and c.12070C  >  T). He had also received images. Areas of high T1 signal suppressed on fat satura- topical bleomycin and acitretin for persistent plantar tion sequences, supporting a partly fatty matrix. A patho- viral warts. The patient had no family history of congeni - logical fracture was clearly seen extending transversely tal syndromes, but there was a strong family history of across the proximal tibia. cancer including renal cell carcinoma, skin cancer, bowel Positron emission tomography with fluorodeoxy - cancer and breast cancer in second-degree relatives. glucose (FDG) integrated with computed tomography (PET/CT) confirmed an ill-defined proximal tibial lesion Radiological findings with medial cortical destruction and a large soft tissue Plain radiographs demonstrated a poorly defined, per - mass containing areas of fat attenuation and ossification meative, radiolucent lesion, centred in the proximal tib- (Fig.  3a). The tumour showed marked FDG uptake with ial meta-diaphysis. A pathological fracture was present a standardised uptake value (SUV) of 17.1 and a band (Fig. 1). of relative photopaenia in the region of the undisplaced There was postero-medial cortical destruction with transverse pathological fracture. A further focus of mark- adjacent areas of ossification. There was evidence of low edly increased FDG uptake with an SUV of 13.5 was seen density in the medial soft tissue mass, raising the possi- in a lateral distal femoral lesion which was presumed to bility of a fatty matrix. represent a metastasis (Fig. 3b). Eight small bilateral pul- monary 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. Histological findings Histology of a biopsy of the tibial mass revealed a prolif- eration of malignant cells that had vacuolated cytoplasm and large atypical pleomorphic nuclei (Fig. 4). There were vacuolated tumour giant cells and numerous small lipo- blast-like cells with a single cytoplasmic fat vacuole and hyperchromatic nuclei as well as brown fat-like cells with multiple small fat vacuoles (Fig.  4a, b). There were fre - quent mitotic figures, many of which were atypical. No evidence of osteoid formation was seen. There was infil - tration of cancellous bone and evidence of lymphovas- cular invasion. Immunohistological analysis showed that the malignant cells strongly expressed FABP4/aP2 [6, 7], a marker of adipocyte differentiation and UCP1 [8–10], a marker of brown adipose tissue (Fig. 4c, d); there was no expression of S100, desmin, smooth muscle/muscle actin, Fig. 1 a AP and lateral b plain radiographs demonstrate an ill- myogenin, CD34, CD31, CD30, CD45, cytokeratin, epi- defined radiolucent lesion in the proximal tibial metadiaphysis (black thelial membrane antigen, CD99 or CD117. Cytogenetic arrows) with posteromedial cortical destruction and adjacent ossifica- analysis showed that there was no evidence of MDM2 or tion (black arrowheads). A medial soft tissue mass with low density CDK4 amplification. The morphological and immunohis - raises the possibility of a fatty matrix (white arrow). A pathological fracture is present (white arrowhead) tochemical features were thought to be most in keeping Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 3 of 9 Fig. 2 Magnetic Resonance Imaging (MRI) of the proximal tibial lesion. a Coronal STIR, b coronal T1-, c axial T1-, d axial T2-weighted and, e axial pro- ton density with fat saturation. The images demonstrate an ill-defined proximal tibial medullary based lesion extending to the subarticular surface. There is extensive cortical destruction with an almost circumferential soft tissue mass, which has a spiculated appearance (black arrows) displacing the posterior muscles and popliteal neurovascular bundle. Tumour breaches the deep fascia anteriorly to extend into the subcutaneous tissues and penetrates the interosseous membrane to extend around the anterolateral tibial cortex. Heterogeneous partly high T1 signal suppresses with fat saturation sequences supporting a partly fatty matrix (white arrowheads). The pathological fracture is clearly seen extending transversely across the proximal tibia (white arrows) with a diagnosis of primary pleomorphic liposarcoma of clinical improvement after 2 cycles of chemotherapy as bone. evidenced by a significant reduction in his analgesia use. The preoperative MRI showed an interval reduction of Oncological and surgical treatment the large primary left tibial lesion but an increase in size The patient was treated with two cycles of neoadjuvant and interval of the right distal femoral lesion. The pre - multi-agent chemotherapy, comprising methotrex- operative PET scan demonstrated a discordant excellent ate, doxorubicin and cisplatin (MAP), as per the closed metabolic response to neoadjuvant chemotherapy within European American Osteosarcoma (EURAMOS) trial. both the primary tumour and the metastatic lesions. The His baseline pre-treatment 2D transthoracic echocardio- FDG uptake was significantly reduced in the primary gram was within normal limits with an ejection fraction tumour of the tibia from 17.1 to 2.7 and the focus in the of 70%. The patient tolerated the chemotherapy well with femur and right tibia showed only background activity. Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 4 of 9 Post-operative adjuvant chemotherapy was considered appropriate in this case because of the excellent response to chemotherapy. As routine cardiac assessment demon- strated 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 liposar- coma [11]. 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. Discussion Although liposarcoma is a relatively common malignant soft tissue tumour, it has only rarely been reported in bone (Table  1). In most of these reports, the tumour was simply described as a primary bone sarcoma containing numerous vacuolated pleomorphic tumour cells with the tumour considered to represent a liposarcoma mainly on cytomorphological grounds [2–4, 12–29]. Several of these reports have been questioned on the basis of histological Fig. 3 Axial CT and PET/CT imaging of the proximal tibial lesion. a interpretation and uncertainty as to whether the lesion Axial CT imaging shows medial cortical destruction and a large soft was entirely located within bone. In more recent reports, tissue mass containing areas of fat attenuation (white arrowheads) five such tumours have been specifically designated as and ossification (black arrows). b A coronal fused PET/CT image pleomorphic liposarcomas [30–34]. In the majority of shows there is marked FDG uptake in the proximal tibial tumour as reported cases, liposarcoma of bone has been noted to well as in a lateral distal femoral metastasis (white arrow). No other lipomatous lesion or tumour is present develop in major long tubular bones including femur, tibia and humerus with most cases located in the lower limb. The tumour has been reported to occur over a wide age range (13–69 years), with an average age of 38 years; only The majority of the bilateral pulmonary nodules had also six of the cases previously reported occurred in patients resolved. under the age of 25 years. In our case, the tumour arose in The patient underwent an uncomplicated surgical the proximal tibia of an 18 year old male. resection of the primary tumour in the proximal tibia and In most previous reports, plain radiographs of primary the lesion in the distal femur with reconstruction using liposarcoma of bone have shown an ill-defined osteolytic a linked distal femur and proximal tibial endoprosthe- lesion, but sclerotic areas have also been noted [4, 21, sis (Stanmore Implants, UK) (Fig.  5). At operation, the 22, 25, 32]. In this case, the tumour contained spiculated left proximal tibial tumour was noted to be yellow and areas of ossification with evidence of cortical destruction necrotic; it filled the medullary cavity and had spread and a soft tissue mass. These features suggested osteoid/ through the bone cortex into covering soft tissues. A sec- bone formation and the favored radiological diagno- ond yellow nodule was present in the left distal femur. sis pre-biopsy was osteosarcoma. MRI showed that the Histologically, the resected tibia contained only a small lesion was of heterogeneous isointense signal on T1- and amount of residual viable tumor that was similar mor- high signal on T2-weighted sequences respectively. Areas phologically and immunohistochemically to that seen in of high T1 signal suppressed with fat saturation, support- the biopsy. There was extensive (> 95%) tumor necrosis as ing a partly fatty matrix. Heterogeneous hyper-intensity a consequence of neoadjuvant chemotherapy. Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 5 of 9 Fig. 4 Histological analysis of the proximal tibial lesion shows primary pleomorphic liposarcoma of bone. a The tumor infiltrates cancellous bone and is composed of numerous lipoblasts and large pleomorphic cells, which have vacuolated cytoplasm and atypical nuclei. b Lipoblasts and brown fat-like cells are seen within the tumour. Immunohistochemistry shows the tumor cells express FABP4/aP2 (c) and UCP1 (d) on T1 and T2-weighted images has been described expressed FABP4/aP2, a marker of adipose differentia - in previous case reports [32, 34]. Haemorrhage could tion [6], and UCP1, a marker of brown fat cells [8–10]. account for high T1 and T2 signal areas but, in our case FABP4/aP2 has consistently been shown to be expressed methaemoglobin did not suppress with fat saturation. in soft tissue tumours of adipose differentiation and is Our case showed typical histological features of pleo- useful in distinguishing primary pleomorphic liposar- morphic liposarcoma. There were numerous small and coma from other soft tissue pleomorphic sarcomas [6]. large lipoblasts as well as many large tumour cells with FABP4/aP2 is also expressed by brown and white fat vacuolated cytoplasm and highly pleomorphic nuclei; in cells in hibernoma of bone [7]. In our case, expression addition, there were many brown fat-like cells with atypi- of FABP4/aP2 was useful in confirming the morphologi - cal large hyperchromatic nuclei. Tumour cells strongly cal diagnosis of primary pleomorphic liposarcoma and Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 6 of 9 liposarcoma of bone. First, it must be proved that the tumour has arisen primarily within the bone i.e. that it is not a metastatic deposit and that it is not periosteal in origin, involving the cortex and marrow secondarily. In addition, a predominance of immature pleomorphic, often bizarre, uni-globular and multi-globular lipoblasts should be noted histologically. Our case meets these criteria, having arisen within the tibia and containing numerous vacuolated tumor cells including lipoblasts. It should be noted that the WHO definition of liposarcoma of bone does not exclude origin from the bone surface [37]; it specifies that the tumour is “a malignant neoplasm whose phenotype recapitulates fat and arises within or on the bone surface.” Based on the findings in the present case, we propose that immunophenotypic expression of markers of adipocyte differentiation (i.e. FABP4/aP2 and UCP1) could usefully be added to the list of criteria for the diagnosis of primary liposarcoma of bone. Outcome following surgery alone of primary lipo- sarcoma of bone is relatively poor, and there is little data on the use of adjuvant or neoadjuvant chemother- apy or radiotherapy. A review of the literature shows Fig. 5 Post-resection AP plain radiograph demonstrates a Stanmore that 16 patients (55%) died after a mean of 13 (range, prosthesis with integral distal femur and modular proximal tibial component ½–36)  months, whereas 11 (38%) were alive at a mean follow-up of 28 (range 5–60) months (Table 1). Only five cases were treated with chemotherapy. In one case neo- adjuvant MAP chemotherapy resulted in 54% tumour excluding osteosarcoma and un-differentiated pleomor - necrosis; after surgery the treatment was switched to phic sarcoma, both of which are FABP4/aP2 negative [6]. ifosfamide and etoposide with no recurrence reported Expression of UCP1 was consistent with the finding of after 13  months follow-up [18]. Torigoe et  al. reported numerous brown fat–like cells within the tumour. UCP1 no effect of high dose ifosfamide; a change to cispl - was also expressed by lipoblasts in the tumour. Our case atin and doxorubicin resulted in liver toxicity and dete- did not show tumour cell expression of S100 or evidence rioration [32]. Macmull et  al. [28] found no effect with of MDM2/CDK4 amplification. Absence of S100 has doxorubicin, and when chemotherapy was changed to been noted in more than 50% of soft tissue pleomorphic ifosfamide and etoposide no relapse after 16 months fol- liposarcomas in which MDM2 and CDK4 amplification is low up. In a further two cases treated with chemotherapy, also typically absent [35]. there was no reported efficacy, both patients dying within Most previously reported intraosseous liposarco- 1.5  years of follow-up [19, 20]. There is now discussion mas have been noted to exhibit morphological fea- within the sarcoma community that rare high-grade pri- tures in keeping with the pleomorphic liposarcoma mary malignant bone tumours should have their chemo- subtype. However, other high-grade primary malignant therapy tailored according to their individual histological tumours containing liposarcomatous elements have been subtype [38, 39]. In our case neoadjuvant MAP treatment described in bone. These include a liposarcoma contain - resulted in an unexpectedly good tumour response after ing osteosarcomatous foci [25], a mesenchymoma of two cycles, with background FDG signal of the meta- bone showing liposarcomatous features [36] and a pri- static sites of disease and more than 95% necrosis in the mary dedifferentiated liposarcoma of the femur that pre - primary tumor noted after surgery. Pleomorphic liposar- sented as a malignant fibrous histiocytoma [29]. Downey coma of bone is rare tumour and there is no clinical trial et  al. [25] specified that several criteria must be met for data available to guide the optimal chemotherapeutic the acceptance of a diagnosis of a primary intraosseous Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 7 of 9 Table 1 Reported cases of primary liposarcoma of bone Authors (reference) Age/sex Site Subtype Treatment Metastasis Outcome (comment) Fender [12] 23/F Fibula? Unknown Decompression Intracranial Alive, 22 months follow-up (primary uncertain) Barnard [13] 30/F Humerus Unknown Amputation Lung Died after 2 months Rehbock et al. [14] 56/F Femur Unknown Stabilisation and radiation Bone, lymph nodes Died after 14 months (case not convincing) 60/M Iliac bone Unknown – – Died after 2 weeks (case not convincing) Duffy et al. [15] 49/M Femur Unknown Amputation, radiation – Alive, 60 months follow-up Dawson et al. [3] 28/F Femur Unknown Amputation Lung Died after 11 months Retz [16] 40/M Tibia Unknown Amputation – Alive 24 months follow-up Johnson et al. [17] 25/M Humerus Unknown Amputation Lung Died after 26 months 46/M Humerus Unknown – Lung Died after 18 months Catto et al. [2] 16/F Tibia Unknown Amputation Lung Alive, 9 months follow-up Goldman et al. [18] 33/M Ulna Unknown Amputation – Alive, 5 months follow-up Ross et al. [19] 15/M Fibula Unknown Resection, radiation Lung Died after 5 months Schwartz et al. [20] 49/M Tibia Unknown Amputation – Alive, 7 months follow-up Larsson et al. [21] 52/F Femur Unknown Radiation Lung Died after 5 months Schneider et al. [22] 69/M Fibula Unknown Amputation – Unknown, 24 months follow-up Pardo-Mindan et al. [23] 39/M Humerus Unknown Unknown Unknown Unknown Cremer et al. [24] 58/F Femur Unknown Amputation Lung Progression after 2,5 years with pulmonary metas- 37/F Ilium Unknown Radiation, methotrexate, cordotomy Cerebral tasis Died after 3 years of cerebral metastasis Downey et al. [25] 15/F Ischium Ilium Unknown Hemi-pelvectomy Lung Died after 2 months of pneumothorax, Pleomorphic liposarcoma with osteosarcomatous foci Addison et al. [4] 19/M Humerus Unknown Amputation, radiation, chemotherapy Lung Died after 10 months Kenan et al. [26] 57/M Scapula Myxoid Curettage – Alive, 36 months follow up Seo et al. [27] 69/M Temporal bone Well-differentiated Resection – Alive, 24 months follow-up Macmull et al. [28] 26/M Femur Well-differentiated 2 cycles of neoadjuvant MAP, resection, adjuvant – Alive, 16 months follow-up 4 cycles ifosfamide & etoposide. Zhang et al. [29] 26/M Femur De-differentiated Wide resection – Alive, 12 months follow-up Torok et al. [30] 34/M Femur Pleomorphic Wide resection, radiation, chemotherapy Lung Died after 16 months, cause unknown Hamlat et al. [31] 45/F Thoracic spine Pleomorphic Laminectomy T7-T8 and radiotherapy After 13 months 19 months follow-up, gradual deterioration of lung and rib disease Torigoe et al. [32] 38/F Humerus Pleomorphic Wide resection with endoprosthesis replace- Liver Died after 8 months of disease and liver failure ment. Initial high-dose ifosfamide without effect, followed by cisplatin and doxorubicin Lmejjati [33] 45/M Lumbar spine Pleomorphic Emergency decompression at L4/L5 and radio- None Died after 3 months of deterioration from disease therapy (45 Gy) Rasalkar [34] 13/M Femur Pleomorphic Neoadjuvant MAP 2 cycles (methotrexate, Lung No recurrence of local disease and complete adriamycin/cisplatin), Surgery, Adjuvant 1 response at 13 months follow-up cycle MAP and further chemotherapy with combinations of ifosfamide/etoposide and adriamycin/cisplatin Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 8 of 9 6. Bennet JH, Shousha S, Puddle B, Athanasou NA. Immunohistochemical approach. Treatment findings in our case provide some identification of tumours of adipocytic differentiation using an antibody support for the use for neoadjuvant MAP chemotherapy to aP2 protein. J Clin Pathol. 1995;48:950–4. to treat this rare tumour. 7. Vlychou M, Teh J, Whitwell D, Athanasou NA. 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Springer Journals
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2018 The Author(s)
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10.1186/s13569-018-0089-7
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Abstract

Background: Liposarcoma is an extremely rare primary bone sarcoma. Case presentation: We report a case of primary pleomorphic liposarcoma that arose in an 18 year old male in the metaphysis of the left tibia. Plain radiographs showed a partly sclerotic lesion and MR imaging a heterogeneous tumour predominantly isointense on T1- and high-signal on T2-weighted sequences with focal areas of increased T1 signal that suppressed with fat saturation. PET/CT showed marked FDG uptake (SUV = 17.1) in the primary tumour as well as a metastasis in the right distal femur and multiple small pulmonary metastases. Histologically, the tumour was a pleomorphic liposarcoma containing large tumour cells with vacuolated cytoplasm and hyperchromatic pleomor- phic nuclei as well as numerous lipoblasts and scattered brown fat-like cells. Tumour cells strongly expressed FABP4/ aP2, a marker of adipocyte differentiation, and UCP1, a marker of brown fat, but not S100. The case was treated with neoadjuvant MAP chemotherapy, resulting in extensive (> 95%) necrosis in the primary tumour and almost complete resolution of the femoral and pulmonary metastases. Conclusions: Pleomorphic liposarcoma can present as a sclerotic primary malignant bone tumour; markers of adipose differentiation are useful in histological diagnosis and neoadjuvant MAP chemotherapy results in significant tumor necrosis. Keywords: Liposarcoma, Bone, Malignant, Primary tumour there is considerable uncertainty regarding the histologi- Background cal diagnosis and optimum treatment of this rare tumour. Liposarcoma is an extremely rare primary malignant We report the clinical, radiological (including MRI and bone tumour defined in the 2005 AFIP Fascicle as “A PET/CT) and pathological findings in a case of primary malignant tumor with differentiation towards adipo - pleomorphic liposarcoma that arose in the proximal cytes” [1]. Catto and Stevens [2], reviewing the world tibia of an 18  year old male. We also review the litera- literature in 1963, could find only 15 cases of primary ture regarding primary liposarcoma of bone and reassess bone liposarcoma; they noted that most reported cases diagnostic criteria and treatment options in the light of were pleomorphic sarcomas and considered only one our findings. case, that reported by Dawson in 1955 [3], as completely convincing. In 1982 Addison and Payne accepted only six Case presentation examples of this tumour in previously published reports An 18 year old white male presented with a 6 month his- [4]. Subsequently, other cases have been reported, but tory of discomfort and swelling in his left knee. An X-ray and MRI of the left knee revealed a large, partly miner- alized tumour in the medial tibial diaphysis. In his past *Correspondence: nick.athanasou@ndorms.ox.ac.uk history, the patient had been diagnosed at birth with Nuffield Department of Orthopaedics, Rheumatology coarctation of the aorta and primary lymphoedema. Bal- and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University loon dilatation angioplasty was successfully performed of Oxford, Oxford OX3 7HE, UK Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 2 of 9 on day 13 of life. Subsequent cardiac medical manage- Magnetic resonance imaging (MRI) showed that the ment included nifedipine between the ages of 4 and 9; tumour filled the medullary cavity of the proximal tibial this was later switched to atenolol because of lymphoe- metaphysis; it had an ill-defined margin and crossed the dema. His phenotype was consistent with a variant of physis extending to the subarticular surface but there was Irons–Bianchi syndrome or ‘‘Milroy-like’’ lymphoedema. no intra-articular extension (Fig.  2). Extensive medial Further details of his medical history and treatment cortical destruction was associated with an almost cir- are described elsewhere [5]. Genetic testing to date has cumferential spiculated soft tissue mass which had dis- proven negative for pathogenic variants, including the placed the calf musculature and popliteal neurovascular “Red Cell gene panel” and the 23 genes in the “Rasopa- bundle. The tumour breached the deep fascia and the thy panel” although heterozygous variations of uncertain interosseous membrane. The lesion was of heterogeneous clinical significance were identified in the FAT4 gene isointense signal on T1- and high signal on T2-weighted (c.8290A  >  C and c.12070C  >  T). He had also received images. Areas of high T1 signal suppressed on fat satura- topical bleomycin and acitretin for persistent plantar tion sequences, supporting a partly fatty matrix. A patho- viral warts. The patient had no family history of congeni - logical fracture was clearly seen extending transversely tal syndromes, but there was a strong family history of across the proximal tibia. cancer including renal cell carcinoma, skin cancer, bowel Positron emission tomography with fluorodeoxy - cancer and breast cancer in second-degree relatives. glucose (FDG) integrated with computed tomography (PET/CT) confirmed an ill-defined proximal tibial lesion Radiological findings with medial cortical destruction and a large soft tissue Plain radiographs demonstrated a poorly defined, per - mass containing areas of fat attenuation and ossification meative, radiolucent lesion, centred in the proximal tib- (Fig.  3a). The tumour showed marked FDG uptake with ial meta-diaphysis. A pathological fracture was present a standardised uptake value (SUV) of 17.1 and a band (Fig. 1). of relative photopaenia in the region of the undisplaced There was postero-medial cortical destruction with transverse pathological fracture. A further focus of mark- adjacent areas of ossification. There was evidence of low edly increased FDG uptake with an SUV of 13.5 was seen density in the medial soft tissue mass, raising the possi- in a lateral distal femoral lesion which was presumed to bility of a fatty matrix. represent a metastasis (Fig. 3b). Eight small bilateral pul- monary 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. Histological findings Histology of a biopsy of the tibial mass revealed a prolif- eration of malignant cells that had vacuolated cytoplasm and large atypical pleomorphic nuclei (Fig. 4). There were vacuolated tumour giant cells and numerous small lipo- blast-like cells with a single cytoplasmic fat vacuole and hyperchromatic nuclei as well as brown fat-like cells with multiple small fat vacuoles (Fig.  4a, b). There were fre - quent mitotic figures, many of which were atypical. No evidence of osteoid formation was seen. There was infil - tration of cancellous bone and evidence of lymphovas- cular invasion. Immunohistological analysis showed that the malignant cells strongly expressed FABP4/aP2 [6, 7], a marker of adipocyte differentiation and UCP1 [8–10], a marker of brown adipose tissue (Fig. 4c, d); there was no expression of S100, desmin, smooth muscle/muscle actin, Fig. 1 a AP and lateral b plain radiographs demonstrate an ill- myogenin, CD34, CD31, CD30, CD45, cytokeratin, epi- defined radiolucent lesion in the proximal tibial metadiaphysis (black thelial membrane antigen, CD99 or CD117. Cytogenetic arrows) with posteromedial cortical destruction and adjacent ossifica- analysis showed that there was no evidence of MDM2 or tion (black arrowheads). A medial soft tissue mass with low density CDK4 amplification. The morphological and immunohis - raises the possibility of a fatty matrix (white arrow). A pathological fracture is present (white arrowhead) tochemical features were thought to be most in keeping Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 3 of 9 Fig. 2 Magnetic Resonance Imaging (MRI) of the proximal tibial lesion. a Coronal STIR, b coronal T1-, c axial T1-, d axial T2-weighted and, e axial pro- ton density with fat saturation. The images demonstrate an ill-defined proximal tibial medullary based lesion extending to the subarticular surface. There is extensive cortical destruction with an almost circumferential soft tissue mass, which has a spiculated appearance (black arrows) displacing the posterior muscles and popliteal neurovascular bundle. Tumour breaches the deep fascia anteriorly to extend into the subcutaneous tissues and penetrates the interosseous membrane to extend around the anterolateral tibial cortex. Heterogeneous partly high T1 signal suppresses with fat saturation sequences supporting a partly fatty matrix (white arrowheads). The pathological fracture is clearly seen extending transversely across the proximal tibia (white arrows) with a diagnosis of primary pleomorphic liposarcoma of clinical improvement after 2 cycles of chemotherapy as bone. evidenced by a significant reduction in his analgesia use. The preoperative MRI showed an interval reduction of Oncological and surgical treatment the large primary left tibial lesion but an increase in size The patient was treated with two cycles of neoadjuvant and interval of the right distal femoral lesion. The pre - multi-agent chemotherapy, comprising methotrex- operative PET scan demonstrated a discordant excellent ate, doxorubicin and cisplatin (MAP), as per the closed metabolic response to neoadjuvant chemotherapy within European American Osteosarcoma (EURAMOS) trial. both the primary tumour and the metastatic lesions. The His baseline pre-treatment 2D transthoracic echocardio- FDG uptake was significantly reduced in the primary gram was within normal limits with an ejection fraction tumour of the tibia from 17.1 to 2.7 and the focus in the of 70%. The patient tolerated the chemotherapy well with femur and right tibia showed only background activity. Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 4 of 9 Post-operative adjuvant chemotherapy was considered appropriate in this case because of the excellent response to chemotherapy. As routine cardiac assessment demon- strated 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 liposar- coma [11]. 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. Discussion Although liposarcoma is a relatively common malignant soft tissue tumour, it has only rarely been reported in bone (Table  1). In most of these reports, the tumour was simply described as a primary bone sarcoma containing numerous vacuolated pleomorphic tumour cells with the tumour considered to represent a liposarcoma mainly on cytomorphological grounds [2–4, 12–29]. Several of these reports have been questioned on the basis of histological Fig. 3 Axial CT and PET/CT imaging of the proximal tibial lesion. a interpretation and uncertainty as to whether the lesion Axial CT imaging shows medial cortical destruction and a large soft was entirely located within bone. In more recent reports, tissue mass containing areas of fat attenuation (white arrowheads) five such tumours have been specifically designated as and ossification (black arrows). b A coronal fused PET/CT image pleomorphic liposarcomas [30–34]. In the majority of shows there is marked FDG uptake in the proximal tibial tumour as reported cases, liposarcoma of bone has been noted to well as in a lateral distal femoral metastasis (white arrow). No other lipomatous lesion or tumour is present develop in major long tubular bones including femur, tibia and humerus with most cases located in the lower limb. The tumour has been reported to occur over a wide age range (13–69 years), with an average age of 38 years; only The majority of the bilateral pulmonary nodules had also six of the cases previously reported occurred in patients resolved. under the age of 25 years. In our case, the tumour arose in The patient underwent an uncomplicated surgical the proximal tibia of an 18 year old male. resection of the primary tumour in the proximal tibia and In most previous reports, plain radiographs of primary the lesion in the distal femur with reconstruction using liposarcoma of bone have shown an ill-defined osteolytic a linked distal femur and proximal tibial endoprosthe- lesion, but sclerotic areas have also been noted [4, 21, sis (Stanmore Implants, UK) (Fig.  5). At operation, the 22, 25, 32]. In this case, the tumour contained spiculated left proximal tibial tumour was noted to be yellow and areas of ossification with evidence of cortical destruction necrotic; it filled the medullary cavity and had spread and a soft tissue mass. These features suggested osteoid/ through the bone cortex into covering soft tissues. A sec- bone formation and the favored radiological diagno- ond yellow nodule was present in the left distal femur. sis pre-biopsy was osteosarcoma. MRI showed that the Histologically, the resected tibia contained only a small lesion was of heterogeneous isointense signal on T1- and amount of residual viable tumor that was similar mor- high signal on T2-weighted sequences respectively. Areas phologically and immunohistochemically to that seen in of high T1 signal suppressed with fat saturation, support- the biopsy. There was extensive (> 95%) tumor necrosis as ing a partly fatty matrix. Heterogeneous hyper-intensity a consequence of neoadjuvant chemotherapy. Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 5 of 9 Fig. 4 Histological analysis of the proximal tibial lesion shows primary pleomorphic liposarcoma of bone. a The tumor infiltrates cancellous bone and is composed of numerous lipoblasts and large pleomorphic cells, which have vacuolated cytoplasm and atypical nuclei. b Lipoblasts and brown fat-like cells are seen within the tumour. Immunohistochemistry shows the tumor cells express FABP4/aP2 (c) and UCP1 (d) on T1 and T2-weighted images has been described expressed FABP4/aP2, a marker of adipose differentia - in previous case reports [32, 34]. Haemorrhage could tion [6], and UCP1, a marker of brown fat cells [8–10]. account for high T1 and T2 signal areas but, in our case FABP4/aP2 has consistently been shown to be expressed methaemoglobin did not suppress with fat saturation. in soft tissue tumours of adipose differentiation and is Our case showed typical histological features of pleo- useful in distinguishing primary pleomorphic liposar- morphic liposarcoma. There were numerous small and coma from other soft tissue pleomorphic sarcomas [6]. large lipoblasts as well as many large tumour cells with FABP4/aP2 is also expressed by brown and white fat vacuolated cytoplasm and highly pleomorphic nuclei; in cells in hibernoma of bone [7]. In our case, expression addition, there were many brown fat-like cells with atypi- of FABP4/aP2 was useful in confirming the morphologi - cal large hyperchromatic nuclei. Tumour cells strongly cal diagnosis of primary pleomorphic liposarcoma and Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 6 of 9 liposarcoma of bone. First, it must be proved that the tumour has arisen primarily within the bone i.e. that it is not a metastatic deposit and that it is not periosteal in origin, involving the cortex and marrow secondarily. In addition, a predominance of immature pleomorphic, often bizarre, uni-globular and multi-globular lipoblasts should be noted histologically. Our case meets these criteria, having arisen within the tibia and containing numerous vacuolated tumor cells including lipoblasts. It should be noted that the WHO definition of liposarcoma of bone does not exclude origin from the bone surface [37]; it specifies that the tumour is “a malignant neoplasm whose phenotype recapitulates fat and arises within or on the bone surface.” Based on the findings in the present case, we propose that immunophenotypic expression of markers of adipocyte differentiation (i.e. FABP4/aP2 and UCP1) could usefully be added to the list of criteria for the diagnosis of primary liposarcoma of bone. Outcome following surgery alone of primary lipo- sarcoma of bone is relatively poor, and there is little data on the use of adjuvant or neoadjuvant chemother- apy or radiotherapy. A review of the literature shows Fig. 5 Post-resection AP plain radiograph demonstrates a Stanmore that 16 patients (55%) died after a mean of 13 (range, prosthesis with integral distal femur and modular proximal tibial component ½–36)  months, whereas 11 (38%) were alive at a mean follow-up of 28 (range 5–60) months (Table 1). Only five cases were treated with chemotherapy. In one case neo- adjuvant MAP chemotherapy resulted in 54% tumour excluding osteosarcoma and un-differentiated pleomor - necrosis; after surgery the treatment was switched to phic sarcoma, both of which are FABP4/aP2 negative [6]. ifosfamide and etoposide with no recurrence reported Expression of UCP1 was consistent with the finding of after 13  months follow-up [18]. Torigoe et  al. reported numerous brown fat–like cells within the tumour. UCP1 no effect of high dose ifosfamide; a change to cispl - was also expressed by lipoblasts in the tumour. Our case atin and doxorubicin resulted in liver toxicity and dete- did not show tumour cell expression of S100 or evidence rioration [32]. Macmull et  al. [28] found no effect with of MDM2/CDK4 amplification. Absence of S100 has doxorubicin, and when chemotherapy was changed to been noted in more than 50% of soft tissue pleomorphic ifosfamide and etoposide no relapse after 16 months fol- liposarcomas in which MDM2 and CDK4 amplification is low up. In a further two cases treated with chemotherapy, also typically absent [35]. there was no reported efficacy, both patients dying within Most previously reported intraosseous liposarco- 1.5  years of follow-up [19, 20]. There is now discussion mas have been noted to exhibit morphological fea- within the sarcoma community that rare high-grade pri- tures in keeping with the pleomorphic liposarcoma mary malignant bone tumours should have their chemo- subtype. However, other high-grade primary malignant therapy tailored according to their individual histological tumours containing liposarcomatous elements have been subtype [38, 39]. In our case neoadjuvant MAP treatment described in bone. These include a liposarcoma contain - resulted in an unexpectedly good tumour response after ing osteosarcomatous foci [25], a mesenchymoma of two cycles, with background FDG signal of the meta- bone showing liposarcomatous features [36] and a pri- static sites of disease and more than 95% necrosis in the mary dedifferentiated liposarcoma of the femur that pre - primary tumor noted after surgery. Pleomorphic liposar- sented as a malignant fibrous histiocytoma [29]. Downey coma of bone is rare tumour and there is no clinical trial et  al. [25] specified that several criteria must be met for data available to guide the optimal chemotherapeutic the acceptance of a diagnosis of a primary intraosseous Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 7 of 9 Table 1 Reported cases of primary liposarcoma of bone Authors (reference) Age/sex Site Subtype Treatment Metastasis Outcome (comment) Fender [12] 23/F Fibula? Unknown Decompression Intracranial Alive, 22 months follow-up (primary uncertain) Barnard [13] 30/F Humerus Unknown Amputation Lung Died after 2 months Rehbock et al. [14] 56/F Femur Unknown Stabilisation and radiation Bone, lymph nodes Died after 14 months (case not convincing) 60/M Iliac bone Unknown – – Died after 2 weeks (case not convincing) Duffy et al. [15] 49/M Femur Unknown Amputation, radiation – Alive, 60 months follow-up Dawson et al. [3] 28/F Femur Unknown Amputation Lung Died after 11 months Retz [16] 40/M Tibia Unknown Amputation – Alive 24 months follow-up Johnson et al. [17] 25/M Humerus Unknown Amputation Lung Died after 26 months 46/M Humerus Unknown – Lung Died after 18 months Catto et al. [2] 16/F Tibia Unknown Amputation Lung Alive, 9 months follow-up Goldman et al. [18] 33/M Ulna Unknown Amputation – Alive, 5 months follow-up Ross et al. [19] 15/M Fibula Unknown Resection, radiation Lung Died after 5 months Schwartz et al. [20] 49/M Tibia Unknown Amputation – Alive, 7 months follow-up Larsson et al. [21] 52/F Femur Unknown Radiation Lung Died after 5 months Schneider et al. [22] 69/M Fibula Unknown Amputation – Unknown, 24 months follow-up Pardo-Mindan et al. [23] 39/M Humerus Unknown Unknown Unknown Unknown Cremer et al. [24] 58/F Femur Unknown Amputation Lung Progression after 2,5 years with pulmonary metas- 37/F Ilium Unknown Radiation, methotrexate, cordotomy Cerebral tasis Died after 3 years of cerebral metastasis Downey et al. [25] 15/F Ischium Ilium Unknown Hemi-pelvectomy Lung Died after 2 months of pneumothorax, Pleomorphic liposarcoma with osteosarcomatous foci Addison et al. [4] 19/M Humerus Unknown Amputation, radiation, chemotherapy Lung Died after 10 months Kenan et al. [26] 57/M Scapula Myxoid Curettage – Alive, 36 months follow up Seo et al. [27] 69/M Temporal bone Well-differentiated Resection – Alive, 24 months follow-up Macmull et al. [28] 26/M Femur Well-differentiated 2 cycles of neoadjuvant MAP, resection, adjuvant – Alive, 16 months follow-up 4 cycles ifosfamide & etoposide. Zhang et al. [29] 26/M Femur De-differentiated Wide resection – Alive, 12 months follow-up Torok et al. [30] 34/M Femur Pleomorphic Wide resection, radiation, chemotherapy Lung Died after 16 months, cause unknown Hamlat et al. [31] 45/F Thoracic spine Pleomorphic Laminectomy T7-T8 and radiotherapy After 13 months 19 months follow-up, gradual deterioration of lung and rib disease Torigoe et al. [32] 38/F Humerus Pleomorphic Wide resection with endoprosthesis replace- Liver Died after 8 months of disease and liver failure ment. Initial high-dose ifosfamide without effect, followed by cisplatin and doxorubicin Lmejjati [33] 45/M Lumbar spine Pleomorphic Emergency decompression at L4/L5 and radio- None Died after 3 months of deterioration from disease therapy (45 Gy) Rasalkar [34] 13/M Femur Pleomorphic Neoadjuvant MAP 2 cycles (methotrexate, Lung No recurrence of local disease and complete adriamycin/cisplatin), Surgery, Adjuvant 1 response at 13 months follow-up cycle MAP and further chemotherapy with combinations of ifosfamide/etoposide and adriamycin/cisplatin Tiemeier et al. Clin Sarcoma Res (2018) 8:2 Page 8 of 9 6. Bennet JH, Shousha S, Puddle B, Athanasou NA. Immunohistochemical approach. Treatment findings in our case provide some identification of tumours of adipocytic differentiation using an antibody support for the use for neoadjuvant MAP chemotherapy to aP2 protein. J Clin Pathol. 1995;48:950–4. to treat this rare tumour. 7. Vlychou M, Teh J, Whitwell D, Athanasou NA. 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Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Dec 1, 2018

Keywords: cancer research; oncology; surgical oncology

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