EOS refers to osteosarcoma that occurs in organs and soft tissues outside bones. It is a rare soft tissue mesenchymal malignant tumour that was first reported by Wilson in 1941 [
8] and is histologically similar to primary osteosarcoma of bone. The aetiology of EOS is still unclear. At present, many scholars accept the theory of chemical biology and believe that muscle fibroblasts are stimulated by external or internal factors, metaplastic osteoblasts or chondroblasts and evolve into osteosarcoma. Some studies have suggested that a history of trauma and irradiation may be related to the occurrence of EOS [
1,
9,
10]. In the early stage, according to Lee et al. [
9], the following 3 criteria must be met for a carcinoma to be identified as EOS: (1) it must occur in soft tissue without attachment to bone or periosteum, (2) have a uniform sarcomatous pattern(excluding mixed malignant stromal tumours), and (3) it must produce an osteoid and/or cartilage matrix. However, according to the latest WHO classification of tumours of bone and soft tissue, although EOS tumours do not originate from bone, they may involve bone structures with disease progression [
11].
Clinical manifestations
Unlike osteosarcoma, which originates in bone, EOS is more common in adults, especially in people over 50 years of age, and slightly more common in males [
9,
12]. EOS occurs in the extremities, with the thigh being the most common site [
3,
13], followed by the buttocks, upper limbs, trunk, abdominal cavity and retroperitoneum. EOS has also been reported in the lungs, liver, uterus, bladder and other parts [
14‐
17]. The clinical features of EOS lack specificity. Generally, the onset is insidious, with no obvious symptoms in the early stage. The duration of the disease varies from several weeks to several decades. The most common clinical manifestation is a gradually increasing mass but can also present short-term rapid increase. The mass feels hard to the touch, and hardness is determined by the amount of bone tissue contained in the tumour. The mass is usually large, and lesions located in the abdominal cavity may cause symptoms such as abdominal pain and intestinal obstruction; a mass located in the limbs can limit the movement of adjacent joints.
Imaging manifestations and histology
Although the imaging manifestations of EOS lack specificity, calcification and ossification are important manifestations. Calcification or ossification has been reported to occur in approximately 50% of cases of EOS [
7]. X-ray of soft tissue masses is limited and is not good for soft tissue masses without calcification or bone tumour. Plain CT scans usually show soft tissue masses with uneven density, cystic degeneration and necrotic areas, accompanied by different degrees of calcification or ossification, the size and shape of which vary from nodular to mass. In this study, 2 patients had mature bone tumour masses. The distribution of calcification or the bone tumour is often heterogeneous, located in the centre and/or periphery of a mass; both situations were observed in the patients in this study, but most calcifications were located in the periphery, which is consistent with a previous report [
2]. Histologically, EOS is mainly composed of spindle cells, bone or osteoid tissue, and cartilaginous tissue. The osteoid tissue of the tumour is directly formed by spindle cells and is mainly concentrated in the centre of the tumour, which is different from myositis ossificans [
12]. Microscopically, the osteoid and osseous tissues are sometimes distributed in fine branching lace-like patterns and sometimes in broad sheets [
4,
12].
On MRI, most of the masses had relatively clear boundaries, and some of them had complete or incomplete capsules.The capsule was composed of tumour cells, fibrous tissue, and various inflammatory components produced by the interaction between the tumour and surrounding normal tissues. On T1WI, the parenchyma of the mass was close to the muscle signal, and T2WI showed isointensity or slight hyperintensity; fibrous septa were evident in some masses, and both T1WI and T2WI showed low signals. Cystic degeneration is very common in EOS and can be clearly observed on MRI. In 2 patients in this study, haemorrhagic signals were observed in areas of cystic degeneration, manifesting as a fluid‒fluid sign. Haemosiderin, with a low signal on T2WI, was deposited in the lower layer of the cystic area. Excisional biopsy showed a grey‒red mass with multiple cysts on the cut surface in one case. This phenomenon has been reported for telangiectatic osteosarcoma [
18‐
20]. Contrast-enhanced CT or MRI scans showed marked enhancement or mild enhancement in the parenchyma. MRI can also clearly show tumour invasion into surrounding structures.
Differential diagnosis
EOS needs to be differentiated from a variety of soft tissue osteoblastic lesions, including myositis ossificans, dermatomyositis with ossification, and a variety of soft tissue tumours, such as extraskeletal chondrosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, fibrosarcoma, and liposarcoma.
Myositis ossificans is a nonneoplastic ectopic bone and cartilage entity formed locally near muscle tissue and bone. In the early stage of the disease, it is difficult to distinguish myositis ossificans from EOS. With the progression and maturation of the disease, the characteristic zoning phenomenon, well-organized mature layered bone in the periphery, intermediate osteoid area and central immature nonossifying cell (fibroblast) lesions are observed in histology and imaging [
21]. On imaging, myositis ossificans showed progressive mineralization from the periphery to the centre with higher peripheral density than the centre, while the EOS showed reverse zoning (central deposition of bone-like material and peripheral proliferation of atypical spindle cells). Most patients with myositis ossificans have a history of trauma and are prone to paraplegia [
21,
22]. Dermatomyositis with mineralization is more likely to occur in patients with juvenile myositis. Calcium deposits are found in the skin, subcutaneous tissue or deeper fascia and muscle. The morphology is diverse, usually diffuse, linear, flaky, and can gradually develop into a massive solid mass [
23]. Notably, both myositis ossificans and dermatomyositis can be secondary to EOS.
The majority of soft tissue chondroma occurs in the finger region, followed by the foot, but occurrence in other parts is rare. The tumour cells of extraskeletal chondrosarcoma are surrounded by a cartilage matrix, and the peripheral cartilage matrix is mineralized [
24,
25]. Hyaline cartilage nodules with a high water content and peripheral cartilage mineralization are characteristic findings. Imaging shows a typical “ring-arc” cartilage matrix mineralization, and the nonmineralized area has a high water content, low density on CT, and high signal intensity on MRI T2-weighted imaging [
26]. However, these signs are less common in high-grade chondrosarcomas, showing more tumour cells, less cartilage matrix and less mineralized areas.
Osteoid or bone formation can be found in malignant tumours such as undifferentiated sarcoma, synovial sarcoma, and liposarcoma, and osteogenesis is mostly localized and can be reactive and neoplastic. Undifferentiated sarcoma has clinical and pathological similarities with EOS. It is difficult to distinguish EOS with less osteogenesis, which requires more adequate tissue sampling. Undifferentiated sarcoma does not have the disorderly, fine branching lace-like structure of EOS [
12]. Clinically, undifferentiated/unclassified sarcoma and EOS are common in adult limbs, which are prone to cystic degeneration and bleeding, but undifferentiated/unclassified sarcomas have more fibrous components or fibrous septa, a low signal on T2WI, and progressive or continuous enhancement in parenchyma [
27].
Synovial sarcoma can occur at any age. It is more common among young and middle-aged people and usually occurs near the large joints of the extremities [
28,
29]. Synovial sarcoma manifests as “triple signal intensity” on T2WI, i.e., low signal, isointensity, and high signal area relative to fat, corresponding to fibrous tissue, haemorrhage, and cystic components [
30]. Calcification is also a common sign [
29]. Abdominal EOS mainly needs to be differentiated from gastrointestinal exophytic stromal tumours and omentum and mesenteric stromal tumours. This requires careful observation of the relationship between the mass and the adjacent bowel. A mass that is closely related to the bowel and can change its position should be considered a stromal tumour first.
Treatment and survival
The prognosis of EOS is generally poor, and recurrence and metastasis are common, among which the lungs are the most common site for recurrence, followed by lymph nodes, liver, bone, soft tissue, etc. [
7]. The 5-year overall survival rate in the current study ranged from 25–77% [
31,
32]. In our study,Four patients died (follow-up time ranging from 2 to 49 months), and the survival rate was approximately 63%. Previous studies have shown that a tumour diameter less than 5 cm is associated with a better prognosis [
1,
3]. Cases with masses less than 5 cm in diameter showed better prognosis in our study. At present, wide excision is the main treatment method, followed by postoperative adjuvant radiotherapy and chemotherapy. However, for elderly patients and abdominal mass surgery, caution should be taken. In this group, one patient with uterine osteosarcoma was admitted to the hospital due to dyspnoea one month after surgery and eventually died of respiratory failure. Recent studies have shown that the survival rate of patients with negative surgical margins is better [
1,
3,
13]. Of these 8 patients who underwent surgery,2 patients had positive surgical margins. 1 patient had lung metastasis 6 months after operation and died 19 months after operation. Another patient declined postoperative radiation therapy and had a recurrence 2 months after surgery. The treatment effects of radiotherapy and chemotherapy for EOS are controversial. Several studies suggest that neither radiotherapy nor chemotherapy can improve the survival rate of patients with EOS but that adjuvant radiotherapy reduces the recurrence rate of patients with radically resectable EOS; however, chemotherapy cannot reduce the risk of systemic recurrence [
3,
33,
34].
Several studies have shown that alkaline phosphatase and lactate dehydrogenase levels are correlated with the prognosis and metastasis of osteosarcoma [
35‐
37]. High levels of alkaline phosphatase and lactate dehydrogenase were significantly associated with reduced overall survival (OS). In our study, of the 4 patients with elevated alkaline phosphatase levels, 2 died (2 months and 11 months of follow-up), and 1 survived with disease (5 months of follow-up). Of the 4 patients with normal alkaline phosphatase levels, 1 died after 19 months of follow-up, and the others survived without disease(12 months, 32 months and 34 months of follow-up).
Because this study was a retrospective study and due to different policies in different regions and different family conditions of patients, the management of examination, surgery, chemotherapy and follow-up were not consistent. Unfortunately, there were 3 patients with missing surgical margin information, which is very important for the treatment of patients. In addition, there are few cases in this group, and some cases are followed up for a short time, so more time is needed to observe.Regular follow-up and scientific management of patients with EOS are very important for a better understanding of EOS.