Case 2 -

Low-Grade Central Osteosarcoma Anthony Montag University of Chicago Chicago, IL

Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:



under each thumbnail image below. You must have Aperio ImageScope installed on your PC.

If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy:

Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.

If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.

History: A 52-year-old woman presented with a right lower arm mass that had been slowly growing for 4 years. She gave a history of having a lesion in the same area 25 years ago, for which she had surgery. No previous records were available and the patient was unaware of the diagnosis at the time of the previous surgery. On exam the lower arm was markedly distorted by a mass that on radiograph proved to be a poorly marginated fusiform expansion of the distal ulna. Central mineralization and ground glass appearance was present, accompanied by periosteal reaction and mineralization. A biopsy was performed. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 - Clinical appearance of right lower arm prior to surgery Case 2 - Figure 2 - Radiograph of right arm prior to surgery. Note expanded metaphysis/diaphysis and periosteal reaction in the distal ulna. Case 2 - Figure 3 - Low power of biopsy from lesion. Note well formed spicules of bone and intervening fibrous matrix. Case 2 - Figure 4 - Intermediate power of biopsy. Note focal osteoblastic and osteoclastic activity and relative paucicellularity of the stroma. Case 2 - Figure 5 - High power of biopsy. Note the mixed lamellar and woven bone comprising the trabeculae Biopsy Findings: Histologically the lesion is fibrous with well-formed spicules comprised of both lamellar and woven bone, somewhat longer than typically seen in fibrous dysplasia. Osteoblast rimming is focally present, as is osteoclastic activity. The stroma is fibrous, paucicellular, and displays minimal atypia and only very rare mitotic figures. Where residual cortex is present the fibrous tissue appears to infiltrate into the interstices of native bone and Haversian systems. Histologic Differential Diagnosis: Fibrous dysplasia Radiograph is more aggressive than fibrous dysplasia Infiltrative growth pattern not typical of fibrous dysplasia Trabeculae of mixed lamellar and woven bone are not typical of fibrous dysplasia. Osteofibrous dysplasia (Ossifying fibroma) Wrong bone, usually tibia or fibula Usually cortically based Prominent osteoblast rimming Parosteal osteosarcoma Not juxtacortical Desmoplastic fibroma of bone Bone production, but areas of the tumor may have this appearance Low grade Central Osteosarcoma Clinical Presentation: Low-grade central osteosarcoma accounts for approximately 1 to 2% of all osteosarcomas. [1, 2, 3]A ge of occurrence ranges from the first to the ninth decade, with a peak in the second and third decades. In contrast to most bone tumors, the frequency is approximately equal in males and females, or may show a slight female predominance. Most cases are in long bones (81%), with the distal femur and proximal tibia the most common locations. Tumors also occur in flat bones, including the rib, scapula, and bones of the face. All osteosarcoma is relatively less common in the distal upper extremity, but rare cases of low-grade central osteosarcoma in the ulna have been described. Low-grade central osteosarcoma typically presents as a slowly growing mass, frequently of years duration. Previous biopsy with diagnosis of fibrous dysplasia or other benign lesion is not uncommon. Radiology: As with all bone tumors, diagnosis is heavily dependent on radiologic features, but particularly when evaluating a biopsy such as this case. Ideally the consultation of a musculoskeletal radiologist or experienced orthopaedic oncologist should be sought. Low-grade central osteosarcoma is usually medullary in origin (>85%) and metaphyseal, with purely diaphyseal lesions less common. Although slow growth and mineralization leads to an expanded cortex and ground glass appearance similar to fibrous dysplasia, the majority of cases (80%) have features suggestive of an aggressive tumor, including poor margination, cortical destruction, and soft tissue extension. With modern CT and MRI imaging techniques, cortical destruction can be documented in all cases. [4, 5] In the majority of cases, the pre-operative impression will include malignancy based on the radiologic studies. Histology: Histologically, the lesion most frequently resembles fibrous dysplasia, although parosteal osteosarcoma-like and desmoplastic fibroma-like appearances can also be seen depending on the amount of osteoid production. Infiltration of the fibrous stroma into the interstices of native cortical or medullary bone and periosteal extension are diagnostic features that unfortunately are usually absent in biopsy specimens. The majority of cases have greater than 2 mitoses per 10 hpf, but nearly 20% will have fewer. Cytologic atypia is subtle in most cases. In contrast to fibrous dysplasia, where the boney trabeculae are comprised of woven bone, those of low-grade central osteosarcoma tend to be a mixture of woven and lamellar bone. Rarely, thickened irregular plates of lamellar bone can histologically mimic Paget's disease. [6] A less common chondromyxoid fibroma-like variant of osteosarcoma displays lobulated growth with myxoid areas and stellate cells. Increased mitotic figures, cellular zones with pleomorphism and direct production of osteoid by the tumor cells are atypical features indicating malignancy. [7, 8] Treatment and Prognosis: Treatment of low-grade central osteosarcoma is complete surgical excision; intralesional surgery is associated with essentially 100% recurrence, while radical excisions have essentially no local recurrence. [9] In nearly half of cases an initial biopsy will be interpreted as benign, with osteosarcoma diagnosed on subsequent material. [1] Recurrent lesions display dedifferentiation to a high-grade osteosarcoma in15% of cases, and rarely areas of high-grade osteosarcoma are found at primary presentation. [10] There is a high risk of metastatic disease with dedifferentiation. Biology: Low-grade central osteosarcoma has a relatively stable karyotype, in contrast to high grade osteosarcoma, with relatively few changes detected on comparative genomic hybridization studies, typically +12q12-q14, +12p, and +6p21. [11, 12] The 12q13-15 region contains SAS (sarcoma amplified sequence) [13], MDM2, and cyclin dependent kinase 2 (cdk2). SAS amplification has been previously reported in the majority of parosteal osteosarcoma, [14] and is also amplified in 15% of low grade central osteosarcomas. [15] Increased expression of MDM2 and CDK4 has also been reported in both parosteal and low-grade central osteosarcoma. By contrast, P53 mutations, common in high-grade osteosarcoma, are rare in low-grade central osteosarcoma. [16] References: Kurt A, Unni K, McLeod R, Pritchard D. Low-grade intraosseous osteosarcoma. Cancer 1990;65:1418-28. Inwards C, Knuutila S. Low grade central osteosarcoma World Health Organization classification of tumours. Pathology and genetics, tumors of soft tissue and bone. Lyon: IRAC, 2002:pp275-76. Bertoni F, Bacchini P, Fabbri N, Mercuri M, Picci P, Ruggieri P, et al. Low grade intraosseous-type osteosarcoma, histologically resembling parosteal osteosarcoma, fibrous dysplasia, and desmoplastic fibroma. Cancer 1993;71(2):238-345. Andresen K, Sundaram M, Unni K, Sim F. Imaging features of low-grade central osteosarcoma of the long bones and pelvis. Skeletal Radiology. 2004;33:373-79. Ellis J, Siegel C, Martel W, Weatherbee L, Dorfman H. Radiologic features of well-differentiated osteosarcoma. American Journal of Roentgenology 1988;151:739-42. Franchi A, VBacchini P, Della Rocca C, Bertoni F. Central low grade osteosarcoma with pagetoid bone formation: a potential diagnostic pitfall. Modern Pathology 2004;17:288-91. Chow L, Lin JT, Yip K, Kumta S, Ahuja A, King W, et al. Chondromyxoid fibroma-like osteosarcoma: a distinct variant of low-grade osteosarcoma. Histopathology. 1996;29(5):429-36. Mirra J, Gold R, Picci P. Bone Tumors: Clinical, radiologic and pathologic correlations Philadelphia: Lea & Febiger, 1989:pp 359-81. Choong PF, Pritchard DJ, Rock MG, Sim FH, McLeod RA, Unni KK. Low grade central osteogenic sarcoma. A long-term followup of 20 patients. Clin Orthop Relat Res 1996;322:198-206. Kenen S, Ginat DT, Steiner GC. Dedifferentiated high grade osteosarcoma originating from low-grade central osteosarcoma of the fibula. Skeletal Radiology. 2006. Tarkkanen M, Bohling T, Gamberi G, Ragazzini P, Benassi MS, Kivioja A, et al. Comparative genomic hybridization of low-grade central osteosarcoma. Mod Pathol 1998;11(5):421-6. Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors:osteosarcoma and related tumors. Cancer Genetics & Cytogenetics. 2003;145:1-30. Jankowski SA, Mitchell DS, Smith SH, Trent JM, Meltzer PS. SAS, a gene amplified in sarcomas, encodes a new member of the transmembrane 4 superfamily of proteins. Oncogene. 1994;9(4):1205-11. Noble-Topham SE, Burrow SR, Eppert K, Kandel RA, Meltzer PS, Bell RS, et al. SAS is amplified predominantly in surface osteosarcoma. Journal of Orthopaedic Research 1996;14:700-05. Ragazzini P, Gamberi G, Benassi MS, Orlando C, Sestini R, Ferrari C, et al. Anaslysis of SAS gene and CDK4 and MDM2 proteins in low grade osteosarcoma. Cancer detect prev 1999;23(2):129-36. Park HR, Jung WW, Bertoni F, Bacchini P, Park JH, Kim YW, et al. Molecular analysis of p53, MDM2 and H-ras genes in low-grade central osteosarcoma. Pathol Res Pract 2004;200(6):439-45.