OBJECTIVE: Dedifferentiated low-grade osteosarcomas, which are considered high grade malignancies, can arise from the dedifferentiation of parosteal and low-grade osteosarcomas. Usually, localized dedifferentiated low-grade osteosarcomas are treated by wide resection, and the efficacy of adjuvant chemotherapy is controversial. We conducted a systematic review of studies that investigated the rates of mortality and significant events, such as recurrence and metastases, in localized dedifferentiated low-grade osteosarcoma patients who received wide resection only and in those who received wide resection and (neo-)adjuvant chemotherapy.
METHODS: We identified 712 studies through systematic searches of Embase, PubMed, and the Cochrane Central Register of Controlled Trials databases. Of those studies, seven were included in this review and none were randomized controlled trials. In the seven studies, 114 localized dedifferentiated low-grade osteosarcoma patients were examined.
RESULTS: Mortality rates of the resection plus chemotherapy (R + C) and the resection only (Ronly) groups were 20.3% and 11.4%, respectively [overall pooled odds ratio, 1.59 (P = 0.662); heterogeneity I2, 0%]. The local recurrence or distant metastasis rate in the R + C group was 36.7% and that in the Ronly group was 28.6% [overall pooled odds ratio, 1.37 (P = 0.484); heterogeneity I2 was 0%].
CONCLUSIONS: Results show a limited efficacy of adjuvant chemotherapy for localized dedifferentiated low-grade osteosarcoma. However, because this was a systematic review of retrospective studies that examined a small number of patients, future randomized controlled trials are needed.

A 23-year-old female patient presented with radicular back pain, perineal numbness, and urinary retention. The patient was diagnosed with cauda equina syndrome and magnetic resonance imaging (MRI) of the spine revealed an enhancing osseous lumbar lesion causing severe central stenosis. A core needle biopsy of the lumbar spine showed microscopic features compatible with a small round blue cell tumor. CD99 and FLI1 were positive in the tumor cells. Next-generation sequencing demonstrated a EWSR1::FLI1 fusion. Given these findings, the spine lesion was diagnosed as Ewing sarcoma. The patient underwent surgical decompression of L2. On further workup, an MRI revealed an ill-defined enhancing mass of the right distal femur. This area was biopsied, demonstrating a fibro-osseous lesion with osteoblast proliferation containing nuclear atypia, low mitotic activity, and SATB2 positivity, diagnosed as low-grade central osteosarcoma (LGCOS). The patient underwent resection, which showed a classic LGCOS by histomorphology. Although fluorescence in-situ hybridization study for MDM2 gene amplification was negative, the overall findings are most consistent with LGCOS. These neoplasms are considered to be synchronous due to the presentation of each entity within 6 months. Considering the aggregate yearly incidence of Ewing sarcoma (approximately 1 case per 750 000 per year) and LGCOS (approximately 1 case per 10 million per year), the aggregate yearly probability of developing both of these genetically unrelated tumors in a single individual is 1 per 7.5 trillion per year, and it is likely such an event has never happened in the past.

Low-grade central osteosarcoma (LGCOS), which arises from the intramedullary cavity of the metaphysis of long bones, occasionally exhibits extraosseous spread. Approximately 10-30% of patients with LGCOS exhibit dedifferentiation, but it is rare to experience a primary tumor with a dedifferentiated component. A 38-year-old female patient presented with right knee pain for two months. Imaging studies revealed a bone mass with extraosseous involvement. Wide resection was performed, and pathologic examination led to the diagnosis of LGCOS with a dedifferentiated extraosseous lesion. A single defect in the bone cortex constituted the boundary between the low- and high-grade components. The extraosseous high-grade component included more tumor cells with p53 overexpression and more murine double minute 2 (MDM2) copies compared with the low-grade component. These genetic mutations and copy number alterations can be associated with malignant transformation of LGCOS.

The treatment of low-grade osteosarcomas is surgical resection with wide margins. In instances of dedifferentiation, a therapeutic paradigm similar to that of conventional high-grade osteosarcoma has not been adequately evaluated in these neoplasms. The main objective of this review was to define whether the addition of chemotherapy to surgical treatment has an impact on the survival of patients with dedifferentiated low-grade osteosarcomas. Secondary objectives were to observe the degree of histological response to neoadjuvant chemotherapy and to describe the percentage of de novo dedifferentiation. A systematic search of articles including dedifferentiated low-grade osteosarcomas, published between 1980 and 2022 was carried out in the PubMed, Cochrane and Scielo databases. A qualitative synthesis of the results was performed. Twenty-three articles comprising 117 patients were included. The survival of patients treated with surgery alone and surgery with chemotherapy was not statistically significant between the two groups. A good histological response was seen in 20% of specimens treated with neoadjuvant chemotherapy. De novo dedifferentiation was seen in approximately a fifth of low-grade osteosarcomas. The evidence available suggests that the addition of chemotherapy does not have an impact on the survival of patients with low-grade dedifferentiated osteosarcomas.

This review examines findings of musculoskeletal neoplasms whose equivocal imaging and/or histopathologic features make it difficult to determine if they will show aggressive behavior. We include both intermediate tumors as defined by the World Health Organization (WHO), and a single low-grade malignancy, low-grade central osteosarcoma, which mimics a benign lesion on imaging and histology. Intermediate tumors are a broad category and are subdivided into tumors that have risk of local recurrence only, and ones that have a risk of distant limb and pulmonary metastases. Difficult intermediate musculoskeletal lesions include atypical cartilaginous tumor/grade 1 chondrosarcoma, atypical lipomatous tumor/grade 1 liposarcoma, and solitary fibrous tumor. We review diagnostic criteria, differential diagnosis, and recommendations for surveillance.

Low-grade central osteosarcoma (LG-COS) is an uncommon variant of osteosarcoma (OS) that sometimes progresses to high-grade OS post-recurrence. We herein present a case of dedifferentiated LG-COS with extensive cystic change arising in the right iliac bone of a 26-year-old man. The LG-COS was initially diagnosed and managed as a simple bone cyst. The lesion recurred thrice, and high-grade OS was diagnosed during the third recurrence. The first lesion appeared as a typical benign cystic mass on radiography. However, a huge malignant osteoblastic mass subsequently developed in the right pelvis at the third recurrence. Extended hemipelvectomy with ipsilateral hemisacral resection was performed. Histologic analysis showed tumor necrosis and irregular neoplastic tumor osteoid, while immunohistochemistry revealed that the tumor was diffusely positive for MDM2 and CDK4. The histologic diagnosis was high-grade OS dedifferentiated from a preceding cystic lesion. Our final diagnosis of the primary lesion was LG-COS with extensive cystic change.

BACKGROUND: Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is an exceedingly rare subtype of low-grade central osteosarcoma (LGCO), accounting for up to 10% of cases and making it difficult to diagnose. CMF-OS is frequently misdiagnosed on a radiological examination and biopsy, even after the initial operation. Its treatment is a controversial issue due to its low-grade classification and actual high-grade behavior.
METHODS: We retrospectively reviewed the medical charts of more than 2000 osteosarcoma patients between 2008 and 2019; 11 patients with CMF-OS were identified, of which six patients were treated by our institution with complete clinical characteristics, including treatment and prognosis, radiological and pathological features were reviewed. Three males and three females with a median age of 46 (range 22-56) years were pathologically proven to have CMF-OS. The radiological presentation of CMF-OS is variable, thus radiological misdiagnoses are common. However, one must not ignore a malignant radiologic appearance. The most distinctive pathological feature conferring the diagnosis of CMF-OS is the presence of osteoid production directly by the tumor cells under a chondromyxoid fibroma (CMF)-like background. Differential diagnoses based on comprehensive data from CMF, LGCO, chondrosarcoma (CHS), conventional osteosarcoma (COS), etc., are needed. All patients were treated with an operation and chemotherapy, and one patient received additional radiotherapy. Nevertheless, recurrence and metastasis are common in CMF-OS patients. Relatively invasive biological behavior of CMF-OS is against the low-grade classification of this disease.
CONCLUSIONS: It is important to recognize CMF-OS and distinguish it from CMF, CHS, COS and other LGCOs. CMF-OS has a relatively poor prognosis despite its low-grade classification.

OBJECTIVE: The purpose of this study was to clarify the clinical behaviour, prognosis, and optimum treatment of dedifferentiated low-grade osteosarcoma (DLOS) diagnosed based on molecular pathology.
METHODS: We retrospectively reviewed 13 DLOS patients (six men, seven women; median age 32 years (interquartile range (IQR) 27 to 38)) diagnosed using the following criteria: the histological coexistence of low-grade and high-grade osteosarcoma components in the lesion, and positive immunohistochemistry of mouse double minute 2 homolog (MDM2) and cyclin-dependent kinase 4 (CDK4) associated with MDM2 amplification. These patients were then compared with 51 age-matched consecutive conventional osteosarcoma (COS) patients (33 men, 18 women; median age 25 years (IQR 20 to 38)) regarding their clinicopathological features.
RESULTS: The five-year overall survival (OAS) rates in the DLOS and COS patients were 85.7% and 77.1% (p = 0.728), respectively, and the five-year progression-free survival (PFS) rates were 57.7% and 44.9% (p = 0.368), respectively. A total of 12 DLOS patients received chemotherapy largely according to regimens for COS. Among the nine cases with a histological evaluation after chemotherapy, eight showed a poor response, and seven of these had a necrosis rate of < 50%. One DLOS patient developed local recurrence and five developed distant metastases.
CONCLUSIONS: Based on our study of 13 DLOS cases that were strictly defined by histological and molecular means, DLOS showed a poorer response to a standard chemotherapy regimen than COS, while the clinical outcomes were not markedly different. Cite this article: Bone Joint J 2019;101-B:745-752.

Low-grade central osteosarcoma (LGCO) is a rare subtype of osteosarcoma, constituting < 2% of all osteosarcomas. If not treated appropriately, the tumor can recur with higher-grade disease. We report two cases of low-grade central osteosarcoma with unusual morphologic features and belonging to different age groups. Both presented with pain and swelling in the lower end of femur. Radiologically, both the lesions revealed a large mass with irregular borders and soft tissue invasion. One patient underwent above-knee amputation and wide local excision of tumor was done in the other patient. Histologically, both the tumors showed spindle cell proliferation displaying mild atypia. In synopsis with radiology, diagnosis of low-grade central osteosarcoma was made in both cases. These cases highlight the varied morphological spectrum of low-grade central osteosarcoma and underscore the diagnostic difficulties faced. Recognition of the variants of low-grade central osteosarcoma is based on aggressive radiological appearance and on adequate tumor sampling for histologic examination.

Low-grade central osteosarcoma is a rare subtype of tumor with low-grade malignancy. Currently, wide resection with negative resection margin is the standard treatment for this disease. The role of neoadjuvant chemotherapy in low-grade central osteosarcoma was controversial and was mostly considered for tumors containing high-grade focal areas. Local tumor recurrences often exhibited a tumor with higher histologic grade or differentiation with the potential for metastases. In low-grade central osteosarcoma, timely wide resection after definite diagnosis can result in 5-year survival for almost 90%. However, the relatively nonspecific radiological and pathological findings make diagnosis very difficult. MDM2 and CDK4 are specific and provide sensitive markers for the diagnosis of low-grade central osteosarcoma, helping to differentiate low-grade central osteosarcoma from some benign lesions, including fibrous dysplasia, bone giant cell tumor, and chondrosarcoma. Here, we report the case of a 19-year-old woman with low-grade central osteosarcoma located at the proximal humerus. The affected site was rare, but the sensitive biomarkers CDK4 and MDM2 were positive. The patient recovered well after wide tumor resection following a proximal humerus endoprosthesis replacement. Our case highlighted the management strategies in low-grade central osteosarcoma. Being familiar with radiographic features, understanding the biological characteristics, and mastering diagnostic biomarkers can help oncologists avoid embarrassing situations in treatment when this rare tumor is highly suspected, even when located at an uncommon site. The discussion in this report focuses on radiographic and pathological features, advances of biomarkers that help in differential diagnosis, and current treatment options in low-grade central osteosarcoma.