On plain radiograph, TOS presents as a destructive, osteolytic tumor with little or no matrix mineralization or periosteal bone formation (Figure 1). On MRI, a marrow-replacing process with an associated soft-tissue mass may be accompanied by fluid-fluid levels. Gross evaluation displays a bag of blood appearance, with a cystic, cavitary lesion with little solid tumor tissue, lack of dense bone, and blood clots. Histologically, the tumor has single or multiple cystic cavities containing blood or necrotic tissue with septa that house the anaplastic tumor cells. Given the tumor’s radiographic appearance, it can be easily misinterpreted as a benign entity such as aneurysmal bone cyst or giant cell tumor of bone. Histologically, blood-filled spaces lined by malignant spindle cells producing osteoid confirm the diagnosis. Ideally, the interface of the cystic area and surrounding bone is sampled such that a diagnosis can be more reliably made.^1,2 Once the diagnosis is clear, treatment is the same as for conventional high-grade osteosarcoma: chemotherapy and wide surgical excision. Originally, TOS was thought to be a more aggressive variant portending a worse outcome, but studies have shown equivalent to better survival outcomes in these patients. TOS seems to have improved responses to chemotherapy, which may account for this observation.^4,5,6

Roentgenographic studies generally will have findings supporting an aggressive malignant process with cortical destruction, periosteal reaction, and soft-tissue extension or mass. Varying degrees of lytic, blastic, and/or sclerotic changes as well as mineralization can be present. Advanced imaging with CT, MRI, and bone scintigraphy will support these findings, showing more detail of these aggressive changes.^3,7,8

Histologically, the lesion is composed of small round cells or short, spindled cells. Sheets of small round blue cells conjure a differential diagnosis including Ewing sarcoma, mesenchymal chondrosarcoma, lymphoma, neuroblastoma, and rhabdomyosarcoma. The presence of osteoid is key to the diagnosis; however, in these lesions, it is often scant and lacelike, which can be missed or misinterpreted as collagen or fibrin as seen in Ewing sarcoma.^8,9 As in all sarcomas, the marriage of clinical, radiographic, and pathologic findings is critical to arrive at the correct diagnosis. In discerning between SCOS and Ewing sarcoma, which can mimic each other radiographically and histologically, advanced testing is important, particularly when mineralized tumor matrix in the soft-tissue mass is absent and osteoid is not confirmed histologically. Although both SCOS or Ewing sarcoma can be positive for CD99 antigen, selective positivity for SATB2 protein in SCOS and for the EWS-FLI1 gene rearrangement by fluorescent in situ hybridization in Ewing sarcoma can distinguish the two sarcomas.^{8,10,11,12,13}

After the correct diagnosis is established, treatment at this time remains the same as for conventional osteosarcoma. Prognosis for SCOS classically has been regarded as poor; however, its rarity has not allowed rigorous study. In one of the largest series, which includes only 16 patients, the 5-year overall survival rate was 28.6%. However, this spanned several decades, predating and postdating the chemotherapy age. Median survival time in those patients treated after 1975, with chemotherapy and surgery, versus those treated before 1975 with surgery alone was significantly greater at 13.4 years versus 1.1 years. Overall survival at 5 years for those treated after 1975 was 68.6%.^3,7 Whether alternative chemotherapy protocols for this variant would be more effective is unknown. Similarly, given that SCOS is a round cell tumor variant, its sensitivity to radiation also remains unproven. Although osteosarcomas in general are considered radioresistant, there are individual reported cases and in vitro studies that may support some utility in this rare subtype.¹⁴

The less common low-grade variants comprise less than 5% of all osteogenic sarcomas and can be further subclassified based on their location. These may occur in the intramedullary or central location or juxtacortically. Juxtacortical osteosarcoma arises with its epicenter at or around the cortex or periosteum. The low-grade surface osteosarcoma is classically referred to as parosteal. Low-grade central osteosarcoma (LGCOS) and POS diverge from each other radiographically; however, the two entities are histologically indistinguishable, and both have similar genetic profiles with gains in chromosome 12.¹⁵ Parosteal low-grade osteosarcoma (LGOS) tends to occur most commonly about the knee and then proximal humerus, whereas the central form is more evenly distributed throughout the skeleton including in flat bones. Both tend to present in a slightly older age group than conventional osteosarcoma, averaging in the third decade, and patients typically have pain for months to even years before diagnosis. The mainstay of treatment is wide resection alone, without chemotherapy unless a dedifferentiated focus is identified. Both have similar rates of local recurrence, rate of metastasis, dedifferentiation, and disease-specific survival.¹⁶

LGCOS represents only 1% to 2% of osteosarcomas, as discussed in a 2023 study.¹⁷ Radiographic features can be variable, but often present as large medullary tumors at the ends of long bones. Features may be quite bland, contributing to the diagnostic difficulty. There may be trabeculation and varied degrees of sclerosis, but the more aggressive features of periosteal reaction and associated soft-tissue mass are less common. Initial diagnoses may be mistaken for fibrous or other potentially benign lesions. Skilled clinicians will look closely for a small region with poor margination, cortical breach, soft-tissue extension, calcification, or periosteal reaction. Macroscopically, the lesion is firm and gritty but lacks the fleshy constitution of high-grade sarcomas. Microscopically, spindled cells in interlacing bundles or herringbone patterns are seen with nuclei that are minimally hyperchromatic and irregular with scarce mitotic figures and subtle cytologic atypia. It can be difficult to distinguish LGCOS from other benign conditions such as fibrous dysplasia. Although both entities demonstrate mature osteoid formation, LGCOS exhibits a permeative nature to the sheets of tumor cells. Moreover, one study discusses how guanine nucleotide-binding protein and alpha subunit mutations are highly specific for fibrous dysplasia and are thought to rarely occur if ever in LGOSs.¹⁸ Imaging findings can also overlap with bone island and sclerotic metastasis.¹⁷

Treatment of LGOS is with surgery alone. The 5- and 10-year survival rates are 90% and 85%, respectively. As with any bone sarcoma, the goal is a wide surgical margin. Intralesional treatment is associated with a high risk of local recurrence and, in some cases, presentation of higher grade lesions and/or dedifferentiation. Dedifferentiated lesions are typically managed according to a high-grade osteosarcoma paradigm; however, there remain questions regarding the value of chemotherapy in these circumstances.^19,20 Studies have identified amplification of FRS2, CDK4, and MDM2 in LGOS and its dedifferentiated counterparts, which may therefore be used as a diagnostic adjunct.^21,22,23,24 Metastases most often arise in the setting of recurrence to a higher grade lesion; however, there are rare reports of low-grade disease spread, which can occur quite late, resulting in death.²⁵

POS is most commonly a low-grade surface osteosarcoma that originates from the periosteum, a thin membrane that covers bone and exhibits osteogenic activity.²⁶ POS comprises approximately 4% to 6% of all osteosarcomas and classically presents as a stuck-on metaphyseal lesion most commonly on the posterior distal femur, followed by the proximal humerus and tibia.²⁷ Radiographically, a lobulated, exophytic mass with central dense ossification sits adjacent to the bone with a cleavage plane, also known as the string sign, separating the normal bone and tumor, with the absence of an aggressive periosteal reaction²⁶ (Figure 2). CT better defines the extent of the tumor and relationship to the normal underlying cortex and bone. MRI is optimal for evaluating heterogeneity of the lesion, the ideal biopsy site, relationship to critical soft-tissue structures, and the presence of medullary involvement. The radiographic differential diagnosis includes myositis ossificans, fracture callus, Nora lesion, periosteal osteosarcoma, or chondrosarcoma. POS can be mistaken for osteochondromas, particularly in situations where there is slow but real progression of the tumor through the cortex and invasion of the marrow mimicking the preserved medullary and cortical continuity seen in sessile osteochondromas.²⁸ More than one-half of POS lesions have a cartilaginous component and 25% of those may be present at the surface of the tumor, further overlapping with osteochondroma. Microscopically, the cartilage cap of an osteochondroma is composed of hyaline cartilage resembling the physis. In POS, a cartilage cap, if present, shows mild atypia and does not have the columnar arrangement of a physis.²⁹ In a confusing scenario of cortical and medullary continuity mimicking a sessile osteochondroma, different appearances of the medullary cavities of the lesion and the host bone should raise suspicion.²⁸ Similar to low-grade intramedullary osteosarcoma, immunohistochemical markers MDM2 and CDK4 have high sensitivity and specificity for low-grade POS.^16,29 Although POS predominantly presents as a low-grade lesion, some will have a higher grade or dedifferentiated component. According to one study, in 27.5% of patients, tumor grade was reclassified based on the biopsy results after analysis of the excised specimen, almost always leading to a higher-grade lesion.²⁷

Staging is generally similar to that for conventional osteosarcoma; however, a retrospective review of 71 patients (59.2% low-grade POS and 40.8% dedifferentiated POS) showed that only one patient (dedifferentiated POS) had an identified metastases in the lung on initial staging. All of the metastases that subsequently developed were dedifferentiated POS, according to a 2021 study.³⁰ Treatment of low-grade POS is with surgery only and reconstruction as appropriate. For the stereotypical distal posterior femur location, satisfactory oncologic and functional outcomes with low recurrence rates are noted after hemicortical resection and allograft reconstruction, as discussed in a 2022 study.³¹ Local recurrence has been reported between zero and 18% and is associated with incomplete resection and may occur many years after surgery, necessitating long-term surveillance for these patients. In addition, local recurrence has been associated with worsened survival, likely related to the potential for high-grade dedifferentiation in these recurrent lesions. Metastasis is a very rare event, especially with low-grade POS, seen more frequently in higher-grade lesions. Disease-specific survival is excellent
with 5- and 10-year rates of 91.8% and 87.8%, respectively. If a high-grade dedifferentiated POS is encountered, outcomes are generally worse than those for the low-grade variant; however, it does appear to be associated with later local recurrence and a longer disease-free survival than for conventional high-grade sarcoma. The benefit of chemotherapy in this specific entity has not been demonstrated.²⁷