Perspective

This is an overview of the diagnostic challenges in central low-grade osteosarcoma with discussion of recent molecular data, which are of help in resolution of the diagnosis.

The designation “low-grade osteosarcoma” usually encompasses surface low-grade or parosteal osteosarcoma and central or intramedullary low-grade osteosarcoma. Rare cases of low-grade osteosarcoma of soft tissues are documented [1].

Low grade central osteosarcoma, first described in 1977 [2], is an uncommon but well-recognised variant of osteosarcoma responsible for approximately 1% of all osteosarcomas. Male and female subjects are equally affected and it afflicts a slightly older age group than conventional osteosarcoma, most individuals being in the second and third decades with an age range from 9 to 83. Any bone may be affected, but there is a strong predilection for the long bones, particularly the femur and tibia, around the knee [3]. Recently characterisation of involvement of gnathic bones has been documented [4].

Most patients complain of pain, fewer complaining of pain and swelling. About 10% have a mass and occasional cases are asymptomatic. The duration of symptoms varies from 2 weeks to 5 years, most occurring over several months. Tumour size varies from 2 to 25 cm, with an average size of 9 to 10 cm. Less than 10% measure fewer than 5 cm [3].

Low-grade central osteosarcoma is characterised by a significantly better prognosis than conventional osteosarcoma, exhibiting slow growth, low metastatic rate, and prolonged survival after adequate treatment. The recommended treatment is that of wide local excision or amputation, after which recurrence is unusual. Curettage or marginal excision inevitably results in recurrence. Transformation into a high-grade form occurs more commonly in these circumstances and several individuals who have had multiple biopsies performed over time prior to diagnosis have shown transformation to a high-grade tumour with consequent higher mortality [2, 3, 5].

Occasional cases with dedifferentiation at diagnosis are documented [6].

Diagnostic features

The radiological and pathological features may be subtle mimicking a benign process.

Diagnosis on imaging may be challenging; however, some worrying features are usually found and one large study has documented that the lesions are often interpreted as “benign appearing overall with focally aggressive features” [7]. Lesions are most commonly lytic with varying thick and coarse trabeculation or thin incomplete trabecula. Some are densely sclerotic and some mixed lytic and sclerotic on plain radiographs. On cross-sectional imaging cortical breach and soft-tissue extension is usual. Overt aggressive features including cortical destruction, soft tissue extension and periosteal reaction may be lacking [7].

Pathologically, the diagnosis of low-grade intraosseous osteosarcoma may be very challenging because of its innocuous appearance. The microscopic features are characteristically bland, comprising spindle cells arranged in interlacing fascicles in a heavily collagenous background with variable bone or osteoid production. There is most often mild nuclear atypia and rare mitoses. More than 80% have only 1 to 2 mitoses per 10 high power fields and none has more than 4 per 10 high power fields [3]. Atypical mitoses are not seen. The cells commonly have a fibroblastic appearance with an interlacing pattern and abundant collagen.

Osteoid production varies from minimal to abundant. It may comprise subtle lace-like osteoid, narrow trabeculae of immature osteoid, or thick trabecula of predominantly woven bone. Many cases are characterised by the production of thick parallel bone trabecula in a bland spindled stroma similar to that seen in parosteal osteosarcoma. Not infrequently, the lesional tissue comprises thin bony trabeculae or osteoid seams with a curvilinear character similar to that seen in fibrous dysplasia.

If osteoid production is scanty and the picture dominated by spindle cell proliferation the appearance may mimic desmoplastic fibroma or low-grade fibrosarcoma. Some may have a slightly fibrochondroid aspect with small areas of cartilage matrix production [3, 8]. Rare cases are characterised by very low cellularity, with the production of extremely dense sclerotic trabecular bone with an irregular mosaic pattern of cement lines closely mimicking that of Paget’s disease. The peculiar pattern of pagetoid bone formation probably results from very slow growth with heavy bone matrix production and remodelling [9].

In all instances, clues to diagnosis include the presence of permeation of the bone marrow with entrapment of the host trabecula, usually most easily identified at the growing edge of the tumour, and/or permeation of the Haversian system. In excision specimens, 80% of cases will have permeation to the periosteum and 40% will show some degree of soft-tissue involvement identifiable grossly. Some are well demarcated [3, 8].

These features may be absent in biopsy material and the differentiation of fibrous dysplasia from fibrous dysplasia-like low-grade central osteosarcoma in biopsy specimens may be particularly difficult given the microscopic similarity.

It is important to remember that, in contrast to low-grade central osteosarcoma, fibrous dysplasia is common, is seen in every age group and has been identified in all of the bones of the human skeleton, sparing only the temporal bone [10]. This is in stark contrast to low-grade intraosseous osteosarcoma, which is very rare, with less than 150 cases documented (personal review, 2011). Although fibrous dysplasia may fill the medullary cavity and compress the cortex with marked thinning and even loss of the cortex in small and slender bones, particularly the ribs and the fibula, progressive invasion does not occur. Histologically, permeation of the cortex and Haversian system is not expected, and entrapment of the host bone trabeculae at the perimeter of the lesion is not seen [3, 7, 8].

In all cases, and in biopsy specimens in particular, radiological evaluation is critical in achieving an accurate diagnosis. While low-grade fibrous dysplasia-like osteosarcoma may have imaging features in part mimicking fibrous dysplasia, more ominous features are usually identifiable in which cortical disruption and soft-tissue extension is expected in most instances [7]. Similarly, in a setting where thick coalescent plates of tumour are present, prompting consideration of Paget’s disease, appropriate radiological correlation should allow differentiation [9].

In general, in worrying cases where the differential diagnosis includes fibrous dysplasia-like osteosarcoma and fibrous dysplasia or Paget’s disease, careful clinical and radiological assessment will allow accurate differentiation. Desmoplastic fibroma, which forms part of the differential diagnosis in cases lacking osteoid on biopsy, is usually radiolucent and often exhibits pseudotrabeculation on imaging [11]. As the recommended treatment for these is wide local excision, treatment is usually adequate and ultimately bone production within the tumour will allow accurate classification without undue consequences for the patient.

Recent advances

Low-grade osteosarcomas (including parosteal osteosarcoma) have a simple genetic profile with supernumerary ring chromosomes due to telomeric deletions. There is amplification of chromosome 12q13–15, including the Cyclin-dependant kinase 4 (CDK4) and murine double minute type 2 (MDM2) gene region. Similar cytogenetic abnormalities occur in other low-grade malignant mesenchymal lesions including well-differentiated liposarcoma where their expression is currently used for diagnosis. Overexpression and gene amplification of MDM2and CDK4 located on chromosome 12q13–16 are considered to form a pathway of tumorigenesis or tumour progression in various human sarcomas. Two major growth pathways may be inhibited. MDM2 may downregulate the P53-mediated growth control and CDK4 may affect the retinoblastoma tumour suppressor protein (pRb)-mediated events. These genes, although located in two discontinuous regions, are closely linked and frequently co-amplified, leading to deregulation of the cell [12]. Several studies now strongly support a role for the analysis of CDK4 and MDM2 proteins in the differentiation of low-grade osteosarcoma from its mimics [12, 13].

Amplification of MDM2 and/or CDK4 immune reactivity has been identified in up to 90% of low-grade osteosarcoma specimens, including both parosteal and low-grade central osteosarcomas. Immunohistochemical expression for these proteins has also been confirmed and appears to be specific, providing a sensitive marker for the differentiation of these tumours from benign mimickers, including benign fibrous and other fibro-osseous lesions, all of which are negative. Testing has included immunohistochemical examination, comparative genomic hybridisation array and amplification by fluorescence in situ hybridisation (FISH) or quantitative real-time polymerase chain reaction (RT-PCR). As such, testing for amplification of both MDM2 and CDK4 in difficult cases is recommended [12, 13]. The combination of MDM2 and CDK4 expression has 100% sensitivity and 97.5% specificity for the diagnosis of low-grade osteosarcoma in one study [13].

In addition, GNAS1 mutations, characteristic of fibrous dysplasia, can be identified in paraffin-embedded tissue by the mutation specific restriction enzyme digest (MSRED) method, a finding not usually expected in low-grade osteosarcoma [14].

In summary, the accurate differentiation of low-grade intraosseous osteosarcoma can be achieved in most cases by careful pathological and radiological correlation. In difficult cases, resolution can be achieved by the application of techniques to identify amplification of MDM2 and/or CDK4, reflecting the amplification of chromosome 12q13–15, which includes the Cyclin-dependant kinase 4 (CDK4) and murine double minute type 2 (MDM2) gene regions. These are seen in most, if not all, cases of low-grade osteosarcoma and not in their mimics.