Case report: periosteal osteosarcoma of the clavicle

Introduction

Periosteal osteosarcoma is a variant of chondroblastic osteosarcoma, classified under the juxtacortical group of osteosarcomas [1]. It most commonly occurs on the surface of long bones, particularly the femur and tibia. The overall prognosis is better than that of conventional osteosarcoma. We report the second case in the English language literature of periosteal osteosarcoma of the clavicle.

Case report

A 16-year-old Caucasian female presented with a painful mass anteriorly over her right clavicle, which had been increasing in size over the previous 6 months-initially noted after a fall from a horse. She had a history of acute myeloid leukemia (AML) at age 10 months, treated successfully with standard intensive chemotherapy and an autologous bone marrow transplant. There was no family history of malignancy.

Clinical examination revealed a 3~4 cm firm mass over the right clavicle. X-ray showed a poorly defined, surfacebased lesion arising from the mid shaft of the right clavicle. There was cortical thickening that appeared quite solid inferiorly, but at the superior surface there was a Codman's triangle, poorly defined dense mineralization at the surface of the bone, and overlying soft tissue thickening (Fig. 1a). CT scan showed cortical thickening, and a spiculated periosteal reaction perpendicular to the long axis ( Fig. 1b). There was cortical scalloping involving the thickened cortex as well as the underlying native cortex (Fig. 1c). MRI showed cortical thickening, and a circumferential soft tissue mass, which was low signal intensity on all pulse sequences adjacent to the bone surface, corresponding to matrix mineralization. The non-mineralized peripheral part of the mass was isointense to muscle on T1-weighted imaging ( Fig. 1d), hyperintense on T2-weighted sequences (Fig. 1e), and enhanced with contrast ( Fig. 1f). There were a few very small foci of intramedullary marrow signal alteration-hypointense on T1, hyperintense on STIR, and patchy contrast enhancement, indicating either reactive marrow edema or intramedullary tumor extension. The overlying cortex was eroded and irregular, and did not show normal homogeneous low signal intensity, although there was no apparent direct continuity with the surface mass ( Fig. 1f, g). Positron emission tomography (PET) scan revealed low-grade uptake, with no evidence of metastasis. Biopsy of the right clavicle showed tumor tissue with a predominantly chondroid matrix with varying degrees of cytological atypia ( Fig. 2a). There were intermingled foci of hypercellularity composed of highly atypical cells of relatively small size with hyperchromatic nuclei, minimal eosinophilic cytoplasm, and focally, central eosinophilic nucleoli. A tendency to spindling was noted in some areas. Focal malignant osteoid was evident (Fig. 2b). Although the small size of the component cells prompted consideration of Ewing's sarcoma, small cell osteosarcoma and mesenchymal chondrosarcoma, periodic acid schiff (PAS) stain and immunoperoxidase stains for MIC2 (CD99), FLI1, and D240 were negative. The constellation of features were considered most consistent with periosteal osteosarcoma.

The patient underwent 10 weeks of neoadjuvant chemotherapy consisting of Cisplatin, Doxorubicin and high-dose Methotrexate. There was no appreciable change in size of the lesion after pre-operative chemotherapy. A right total claviculectomy was performed. The specimen was bivalved along its long axis showing a 40×25×25-mm whitish gritty tumor surrounding the cortex circumferentially, with focal evidence of cortical erosion and a minor medullary component ( Fig. 3a). Microscopically, the bulk of the tumor was confined to the surface of the clavicle and was composed of necrotic immature osteoid admixed with necrotic chondroid (Fig. 3b). The peripheral limit of the tumor was demarcated by fibrous periosteum of variable thickness. Medullary extension with bone permeation was present focally with an overall measurement of up to 2.5 mm ( Fig. 3c). A diagnosis of periosteal osteosarcoma with minimal medullary invasion and with greater than 95% necrosis was made. A further 13 weeks of post-operative chemotherapy using the same Fig. 1 a. X-ray showing a poorly defined, sclerotic, broad surfacebased lesion arising from the mid-shaft of the clavicle with quite well formed new bone inferiorly, but more aggressive appearing periosteal reaction and cortical thickening superiorly. There is a Codman's triangle at the superior medial edge of the lesion. Axial CT images demonstrating a circumferential surface lesion with spiculated, aggressiveappearing periosteal reaction perpendicular to the long axis of the clavicle (b), and cortical scalloping and erosion which in retrospect corresponded to the small area of intramedullary tumor extension shown at microscopy (c). d. Coronal T1-weighted image showing a circumferential soft tissue mass around the mid shaft of the right clavicle, of similar signal intensity to muscle. The normally hyperintense fatty marrow signal intensity is reduced compared to the left clavicle, implying either reactive marrow edema or invasion. e. Coronal STIR image showing that the soft tissue component around the surface of the bone is of low signal intensity due to the dense matrix mineralization. The more peripheral component is hyperintense, reflecting the chondroblastic content of this tumor. Sagittal (f) and axial (g) post-contrast fat-suppressed T1-weighted images showing enhancement of the peripheral, less densely mineralized component of the soft tissue mass. There is erosion of the cortex anteriorly and loss of the normal uniform cortical hypointensity. There is a thin streak of intramedullary enhancement, but it does not appear to be in direct continuity with the surface mass. Therefore, on imaging, this appearance was not clearly due to intramedullary tumor extension, although a 2.5-mm focus was later confirmed microscopically agents was completed. The patient remains disease free after 30 months post-completion of all therapy and has returned to horseriding.

Discussion

Periosteal osteosarcoma is defined as an intermediate-grade osteosarcoma arising on the bone surface, accounting for 25% of all juxtacortical osteosarcomas, the others comprised largely of parosteal osteosarcoma and occasionally high-grade surface osteosarcoma [2]. Periosteal osteosarcoma was first described by Ewing in 1939 [3]. In 1959, Lichtenstein suggested that it represented a periosteal counterpart of intramedullary osteosarcoma [4]. In 1976, Unni et al. described a series of 23 cases of periosteal osteosarcoma, establishing it as a distinct clinicopathological entity [5].

Periosteal osteosarcoma usually arises on the diaphysis, or the meta-diaphyseal junction of long bones, most commonly the tibia, femur, humerus, and to a lesser extent, the mandible [6]. The peak incidence is in the second to third decade of life, with a slight male predominance [7]. It typically presents as a swelling, with pain and tenderness developing later [7]. Radiologically, periosteal osteosarcoma appears as a radio-opaque soft tissue mass with a broad base attached to the cortex [8]. Periosteal osteosarcoma usually encases part (approximately 50%) of the bone, but less commonly, as in this case, it can be circumferential, lending a more fusiform appearance [7]. Cortical thickening, scalloping, and perpendicular mineralized spiculations are not uncommon, as is the formation of Codman's triangle with subperiosteal new bone formation [7,8]. On MR imaging the soft tissue mass is of similar signal intensity to muscle on T1-weighted sequences, and heterogeneously hyperintense on T2-weighted sequences, due to the largely chondroblastic content of this tumor [8]. Focal areas of adjacent marrow signal alteration are not uncommon but are mostly due to reactive edema. Rarely there may be intramedullary tumor invasion, seen as direct continuity from the soft tissue mass through a focus of cortical breach or infiltration [8]. Chemotherapy often induces ossification and increased maturity within the soft tissue mass [8]. Microscopically, the tumor is composed of lobules of cartilage with varying degrees of atypia, admixed with an intermediategrade osteosarcomatous component predominating at the periphery of the lobules. The latter is usually composed of atypical spindle cells arranged in fascicles, interspersed with lace-like osteoid [7]. In our case, an intramedullary chondroblastic osteosarcoma with periosteal extension was considered, however, given the minimal medullary component this was thought unlikely.

The only other case of periosteal osteosarcoma documented in the clavicle was described by Oda et al. [9]. In this case, the X-ray showed saucerization of the cortex with periosteal reaction and Codman's triangle, and a soft tissue mass with a calcified matrix, while an MRI demonstrated a The clavicle is an unusual site for periosteal osteosarcoma, explained, in part, by the unique nature of clavicular ossification. Embryologically, the clavicle begins to ossify before any other bone in the body [10]. It undergoes intramembranous ossification without prior endochondral stage through two primary centers, medial and lateral, which appear during the fifth to sixth weeks of fetal life, and one secondary center-the sternal, which starts at 18-20 years of life. These ossification centers unite at approximately 25 years.

The present case is also unusual in that at biopsy there was a suggestion of a small cell component, which initially prompted consideration of small cell osteosarcoma, high-grade surface osteosarcoma, mesenchymal chondrosarcoma or Ewing's sarcoma.

Small cell osteosarcoma is usually centered in the medulla with aggressive destruction of the cortex, not evident in our case. Chondroblastic differentiation, prevalent in our case, is not expected histologically. High-grade surface osteosarcoma may have appearances similar to periosteal osteosarcoma on imaging, however, it usually features a higher degree of atypia with osteoblastic, fibroblastic, and chondroblastic differentiation. Ewing's sarcoma, most often occurring in the metaphyseal-diaphyseal region of long bones (similar to periosteal osteosarcoma), usually has a significant medullary component and a characteristic "onion-skin"-like periosteal reaction on radiology with a large soft tissue component. Osteoid and chondroblastic differentiation, as noted in our case, is not expected. Positivity for cytoplasmic glycogen on PAS stain and immunoperoxidase stains for MIC2 (CD99) and FLI1 are expected. Confirmation with EWS-FLI1 translocation on molecular genetics is also typical. In mesenchymal chondrosarcoma, the small cell component usually has a hemangiopericytomatous appearance, and malignant osteoid is not identified.

The prominent chondroblastic component may suggest periosteal chondrosarcoma, a surface chondrosarcoma that usually involves the metaphyses of long bones. Radiologically, this features so-called 'popcorn' opacities adjacent to the shaft. Histologically, it is composed of lobules of cartilage with mild to moderate atypia; osteoid production is not expected and spindle cell areas not seen [11].

Wide local excision is the recommended treatment for periosteal osteosarcoma [12]. Although adjuvant chemotherapy is routinely used in some centers (including ours), its role and impact on survival is unclear. In our case, there was an excellent response to chemotherapy with greater than 95% tumor necrosis. The prognosis of periosteal osteosarcoma is intermediate between that of parosteal osteosarcoma and highgrade surface osteosarcoma, and is superior to that of conventional osteosarcomas. Recent long-term outcome data show that recurrence with progression to metastatic disease tends to occur within the first 3 years after presentation, suggesting that long-term disease-free survival is possible [12]. The metastatic rate has been reported to be approximately 15% [5].

The association of osteosarcoma with AML has previously been reported [ 13] and while this may represent a chance phenomenon, it does raise the possibility of Li-Fraumeni syndrome, an autosomal dominant syndrome involving a germline mutation in the tumor suppressor gene, p53 (TP53), predisposing the affected individual to a wide range of tumors of the breast, brain, acute leukemias, soft tissue sarcomas, osteosarcomas, and adrenal cortical carcinomas. In this case, there was no suspicious family history, and formal genetic for a p53 mutation was negative.

In summary, this is the second reported case in the English-language literature of periosteal osteosarcoma of the clavicle. It illustrates the diagnostic dilemmas in classifying surface osteosarcomas in small biopsy specimens, highlights the importance of clinical and radiological correlation, and in this case, supports the role of neoadjuvant chemotherapy enabling adequate wide local excision.