Parosteal Osteosarcoma Research Articles

MDM2 and CDK4 expression in periosteal osteosarcoma.

Periosteal osteosarcoma is defined by the World Health Organization as an intermediate-grade, malignant, cartilaginous, and bone-forming neoplasm arising on the surface of bone. Unlike other subtypes of osteosarcoma, no data have been published about mouse double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) expression. For this reason, we evaluated the molecular and immunohistochemical features of MDM2 and CDK4 in 27 cases relative to 20 patients with a diagnosis of periosteal osteosarcoma, surgically treated at the Rizzoli Institute between 1981 and 2014. When possible, these results were compared with the MDM2 amplification status as determined by fluorescence in situ hybridization (FISH). All but 1 case (26/27, 96.3%) were negative for MDM2 protein using immunohistochemistry both in primary and in recurrent periosteal osteosarcoma, whereas gene amplification of MDM2 was not detected in any tumor analyzed (10 cases). The positive immunohistochemical case shows a weak/moderate focal nuclear expression of MDM2 antibody in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid production in a primary periosteal osteosarcoma. CDK4 immunohistochemical expression was negative in all 27 cases. This retrospective analysis has demonstrated that MDM2 and CDK4 are very rarely expressed in primary and recurrent periosteal osteosarcomas and therefore do not appear to be molecules central to the control of cancer development, growth, and progression in periosteal osteosarcoma. Therefore, when compared with low-grade central and parosteal osteosarcomas, MDM2 and CDK4 markers cannot be used diagnostically to differentiate this subtype of osteosarcoma.

Osteosarcomas in the upper distal extremities: Are their oncological outcomes similar to other sites?

AimsTo investigate whether the oncological outcomes of patients with osteosarcomas in the upper distal extremity are similar to other sites and assess if limb-salvage surgery is safe in this location. MethodsThe centre database was used to identify all patients with osteosarcomas in the lower humerus and distally between 1985 and 2012. Patient, tumor, treatment and outcome data was collected. ResultsTwenty-six patients were included in this study. There were 9 males and 17 females with a mean age of 33 years (9–90). Seventeen osteosarcomas were located in the forearm bones (65%), six in the distal humerus (23%), and three (12%) in the hand. The three most common sub-diagnoses were parosteal 7/21 (33%), fibroblastic 4/21 (19%) and osteoblastic osteosarcomas 3/21 (14%). 2 patients (8%) had Paget's disease and 19 patients (73%) had high-grade tumors. Local excision was carried out in 12 patients (48%), 4 patients underwent endoprosthetic replacement (16%) and 9 underwent amputation (36%). The overall risk of local recurrence was 4% in our series. The five-year overall survival rate was 67%, with low tumor grade and parosteal type of osteosarcoma being positive predictors of survival. ConclusionThis series has shown that patients with high-grade osteosarcomas of the upper distal extremities have a higher amputation risk than other limb sites but have favorable outcomes with limb-salvage surgery, comparable to other anatomical sites. Parosteal osteosarcomas in particular have a good prognosis.

Surface osteosarcomas: Diagnosis, treatment and outcome.

Surface osteosarcomas are a rare form of osteosarcomas accounting for around 3-6% of all osteosarcomas. Three major groups of surface osteosarcomas are parosteal, periosteal and the high grade surface osteosarcomas. Of these, the parosteal osteosarcoma is the most common. Parosteal and periosteal osteosarcomas are distinct clinical entities and it is important to identify the clinicoradiological differences between the two types. Surface osteosarcomas occur at a later age as compared to conventional osteosarcomas. The classical site is the lower end of the femur followed by the upper end of the tibia and upper end of humerus, in that order. The periosteal variant affects the tibia more commonly than the parosteal variety. Neo-adjuvant chemotherapy is the standard of care for high grade surface osteosarcomas. Parosteal osteosarcomas, being low grade lesions, can be treated by upfront wide excision without adjuvant systemic therapy. Controversy prevails over the need for chemotherapy in periosteal osteosarcomas, which are intermediate grade lesions.

Parosteal osteosarcoma.

Parosteal osteosarcoma is a rare malignant bone tumor arising from the bone cortical surface. It most commonly occurs in young women over the metaphyseal region, especially the long bones near the knee joint. Patients usually report a slow-growing mass for years. The tumor is characterized by its bland microscopic morphology, prone to be misdiagnosed as other benign tumors. In the absence of dedifferentiation, the prognosis is generally better than that of conventional osteosarcoma. Recent studies demonstrated distinctive cytogenetic abnormality resulting in amplification of the CDK4 and MDM2 genes, which may serve as markers for molecular diagnosis. In this article, we review the clinical, radiologic, and pathologic features of parosteal osteosarcoma and identify some diagnostic pitfalls, discuss the prognostic variables, and update recent molecular advances and their application in the diagnosis.

Osteosarcomas of jaw: Experience of a single centre

Although osteosarcoma is the most common primary malignant tumour of bone, osteosarcomas of jaw are rare. In osteosarcomas of jaw, evaluating the clinicopathological factors affecting the prognosis is not easy because of different approaches to diagnosis, treatment, and follow-up. This study reviewed 14 cases of JOS that were diagnosed between 1990–2010, in terms of age, gender, site, clinical history, histopathologic type and histopathologic grade, treatment, and prognosis. Median age was 35 years, while male:female ratio was 1.8:1. Eight tumours were located in the mandible. Osteoblastic differentiation was the predominant feature in seven cases followed by chondroid osteosarcoma (four cases), fibroblastic osteosarcoma, low-grade (parosteal) osteosarcoma associated with fibrous dysplasia, and postradiation osteosarcoma (one cases each). During follow-up, recurrence was seen in four patients at least once and they all died. In conclusion, early diagnosis and complete resection seems to be effective in prognosis. Therefore, clinicians and pathologists should be aware of its characteristics and main differential diagnosis to avoid late recognition.

Activating GNAS Mutations in Parosteal Osteosarcoma

Parosteal osteosarcoma is a surface-based osteosarcoma that often exhibits deceptively bland cytologic features, hindering diagnosis in small biopsies or when correlative radiologic imaging is not readily available. A number of benign and malignant fibro-osseous lesions, including fibrous dysplasia (FD) and low-grade central osteosarcoma, fall within the morphologic differential diagnosis of parosteal osteosarcoma. Somatic mutations in GNAS, encoding the α-subunit of the heterotrimeric G protein complex (Gsα), occur in FD and McCune-Albright syndrome but have not been reported in parosteal osteosarcoma. We evaluated GNAS mutational status in parosteal osteosarcoma and several of its histologic mimics to determine its utility in differentiating these entities. Eleven of 14 (79%) FD cases had GNAS mutations within codon 201 (5 R201C and 6 R201H mutations). GNAS mutations were not detected in any cases of adamantinoma or osteofibrous dysplasia. Direct sequencing of 9 parosteal osteosarcomas, including 3 of low grade and 6 with dedifferentiation, revealed activating GNAS mutations in 5 cases (55%), distributed as 4 R201C-mutated tumors and 1 tumor with an R201H mutation. GNAS codon 227 mutations were not detected in any of the cases. There was no association between GNAS mutational status and patient demographics, histologic dedifferentiation, or clinical outcome. To our knowledge, we report the first series of parosteal osteosarcomas harboring activating GNAS mutations. Our data suggest that GNAS mutational status may have limited utility as an ancillary technique in differentiating benign and malignant fibro-osseous lesions of the bone.

MDM2 and CDK4 expression in periosteal osteosarcoma

Periosteal osteosarcoma is defined by World Health Organization as an intermediate-grade, malignant cartilage and bone forming neoplasm arising on the surface of bone. At difference to the other subtypes of osteosarcoma, in literature no data has been published about MDM2 and CDK4 expression. For this, we evaluate the immunohistochemistry expression of MDM2 and CDK4 to detect overexpression caused by gene amplification in 18 cases of periosteal osteosarcoma, surgically treated in Rizzoli Institute between 1981 and 2013. All but one case (17/18, 94.4%) were negative for MDM2 and CDK4 using immunohistochemistry. The positive case shows a strong nuclear expression of both antibodies in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid-producing. In conclusion, at difference to low grade central osteosarcoma and parosteal osteosarcomas, MDM2 and CDK4 are very rarely expressed in periosteal osteosarcoma and therefore do not appear to be a molecule central to the control of cancer development, growth and progression in periosteal osteosarcoma. These two markers can be used diagnostically to differentiate these subtypes of osteosarcoma and underline a different genetic pathway for the pathogenesis of this rare subtype of osteosarcoma. Periosteal osteosarcoma is defined by World Health Organization as an intermediate-grade, malignant cartilage and bone forming neoplasm arising on the surface of bone. At difference to the other subtypes of osteosarcoma, in literature no data has been published about MDM2 and CDK4 expression. For this, we evaluate the immunohistochemistry expression of MDM2 and CDK4 to detect overexpression caused by gene amplification in 18 cases of periosteal osteosarcoma, surgically treated in Rizzoli Institute between 1981 and 2013. All but one case (17/18, 94.4%) were negative for MDM2 and CDK4 using immunohistochemistry. The positive case shows a strong nuclear expression of both antibodies in the prevalent cartilaginous component and in the spindle cells of peripheral fibroblastic areas associated with osteoid-producing. In conclusion, at difference to low grade central osteosarcoma and parosteal osteosarcomas, MDM2 and CDK4 are very rarely expressed in periosteal osteosarcoma and therefore do not appear to be a molecule central to the control of cancer development, growth and progression in periosteal osteosarcoma. These two markers can be used diagnostically to differentiate these subtypes of osteosarcoma and underline a different genetic pathway for the pathogenesis of this rare subtype of osteosarcoma.

Parosteal osteosarcoma: Report of a rare juxtacortical variant of osteosarcoma affecting the maxilla

Parosteal osteosarcomas are rare, low-grade juxtacortical variant of osteosarcoma, especially in the jaws, representing 1.6% of all bony malignant tumours and upto 5% of all osteosarcomas. Only 12 cases of intraoral parosteal osteosarcomas have been reported in the English literature. In the jaws males are more commonly affected with peak occurrence at 39 years and nearly equal site predilection for maxilla and mandible. Radiographically, parosteal osteosarcomas are radiodense, lobulated masses with a broad stalk to the cortex of the bone with no periosteal reaction and medullary invasion. Microscopically, shows well-differentiated tumor with minimum atypia and rare mitotic figures separating trabeculae of woven bone. Unlike classical and periosteal osteosarcoma, it is considered to have a good prognosis. A case report of this rare entity in 22-year-old female patient with bony hard, painless swelling of 9 months duration in maxillary premolar-molar region is presented. The need for differential diagnostic approach is emphasized from other seemingly benign clinical entities.

Rare Repeated Recurrence of Parosteal Osteosarcoma Adjacent to a Prosthesis after 15 Years: A Case Report

Late relapsing parosteal osteosarcoma has been reported very rarely; however, to the best of our knowledge, long-term repeated recurrence of this tumor has not been reported yet. Herein, we present a case of late relapsing low grade parosteal osteosarcoma after 15 years in popliteal cavity after advising tumor excision, removal of the organ involved, and the placement of prosthesis.

An uncommon calvarial osteosarcoma: Case report & literature review

Introduction: Parosteal osteosarcomas are low-grade variants of osteosarcoma and rarely occur in the head and neck region. As noted in literature, their typical localisation is the distal femur. Even though clinical and radiographic features are informative, definitive diagnosis requires histopathology, supported by genetic studies.

Hemicortical resection and reconstruction using pasteurised autograft for parosteal osteosarcoma of the distal femur

The aim of this study was to assess a specific protocol for the treatment of patients with a parosteal osteosarcoma of the distal femur with limb salvage involving hemicortical resection and reconstruction using recycled pasteurised autograft and internal fixation. Between January 2000 and January 2010, 13 patients with a mean age of 26.5 years (17 to 39) underwent this procedure. All the tumours were staged according to Enneking's criteria: there were eight stage IA tumours and five stage IB tumours. The mean follow-up was 101.6 months (58 to 142), and mean post-operative Musculoskeletal Tumour Society functional score was 88.6% (80% to 100%) at the final follow-up. All the patients had achieved bony union; the mean time to union was 11.2 months (6 to 18). Local recurrence occurred in one patient 27 months post-operatively. No patient had a pulmonary metastasis. A hemicortical procedure for the treatment of a parosteal osteosarcoma is safe and effective. Precise pre-operative planning using MRI is essential in order to define the margins of resection. Although it is a technically demanding procedure, gratifying results make it worthwhile for selected patients.

Diagnosis and treatment of low-grade osteosarcoma: experience with nine cases

Low-grade osteosarcoma, including low-grade central osteosarcoma and parosteal osteosarcoma, is an extremely rare variant, and the diagnosis is occasionally difficult. In this article we present cases of low-grade osteosarcomas that should be reviewed by a clinical oncologist. Nine cases of histologically diagnosed Broder grade 1 osteosarcoma were retrospectively reviewed. The pathological diagnoses included parosteal osteosarcoma, low-grade central osteosarcoma, and low-grade chondroblastic osteosarcoma in four, four, and one cases, respectively. Duration from initial surgical intervention including biopsy to final diagnosis as low-grade osteosarcoma was a mean of 9.4 months. The initial benign diagnoses on biopsy specimens included fibrous dysplasia in three cases, chondroblastoma in one case, and a giant cell tumor in one case. The average number of histological examinations was 1.8. Low-grade osteosarcomas are well suited for biological reconstruction: seven cases were reconstructed by frozen autografts, distraction osteogenesis, or vascularized bone grafts. Low-grade osteosarcomas can be misdiagnosed as benign lesions, especially fibrous dysplasia. If the diagnosis of a low-grade osteosarcoma is not established on the basis of radiologic findings, care should be exercised, even when a biopsy suggests a benign lesion. Low-grade osteosarcomas should be treated with wide excision, even after an intralesional excision. Biological reconstruction might be a better option for low-grade osteosarcomas.

Salvage therapy by hemicortical excision and reconstruction for low-grade malignant bone tumour

To treat low-grade limb malignant tumors with hemicortical excision and reconstruction of the defect with recycled pasteurized autograft. From January 2005 to January 2011, 10 patients [age (27.0±6.5) years] suffering from low-grade limb malignant tumors were treated with hemicortical excision and reconstruction of the defect with recycled pasteurized autograft: 7 were histopathologically diagnosed as parosteal osteosarcoma, and 3 as peripheral chondrosarcoma. According to the Enneking staging system, 8 were in Stage IA and 2 were in IB. All the patients were followed-up for (50±23) months. All the patients had bony union at the last follow-up. The length of tumor bone resection was (9.5±2.7) cm, operation time was (150±45) min, intraoperative blood loss was (1000±350) mL, and drainage volume was (450±200) mL. The only fracture in the host bone during the operation was treated by internal fixation. Local recurrence occurred in 1 patient was treated by a wide operative margin and reconstruction with a prosthesis. There was no distal metastasis. A ccording to the Enneking system, 9 patients had excellent results and 1 had good results. Hemicortical excision for low-grade limb malignant tumors is safe and effective.

A popliteal giant synovial osteochondroma mimicking a parosteal osteosarcoma

Both giant synovial osteochondroma and parosteal osteosarcoma are rare musculo-skeletal tumors, often localized in the vicinity of the knee. Misdiagnosis of a malignant bone tumor can entail fatal consequences. Etiology of giant synovial osteochondroma is widely unsolved but is believed to originate from synovial chondromatosis, a mostly benign metaplasia of the synovial membrane. Parosteal osteosarcoma is a low-grade surface osteosarcoma with a propensity of local recurrence and the potential of distant metastasis and therefore requiring a different therapeutical approach. We report the case of a popliteal giant osteochondroma mimicking a parosteal osteosarcoma. Relevant facts of this rare entity regarding pathogenesis, treatment, and differential diagnoses will be discussed.

Clinical Outcome of Parosteal Osteosarcoma

Purpose The purpose of this study was to evaluate the oncologic outcomes of parosteal osteosarcoma (POS) and to ascertain the fates of patients after local recurrence (LR). Materials and Methods The authors retrospectively reviewed 22 POS patients with an average follow-up of 114 months (range: 36–235 months). Seven of the 22 patients were referred after LR. There were 17 Stage IB and 5 Stage IIB (G2, 2; dedifferentiation, 3). Tumors were located in the femur (11) and in other locations (11). Initial surgical margins were wide in 10, marginal in 5, and intralesional in 7. Correlations between clinico-pathologic variables and LR and clinical courses after LR were evaluated. Results The 10-year overall survival rate was 85.7%. Three (14%) patients developed distant metastasis and all of them succumbed to the disease. Nine (41%) patients developed LR. Tumor location, resection type, and surgical margin were found to be correlated with LR. At final follow-up, 7 of the 9 patients that experienced local failure achieved no evidence of disease. Conclusion A substantial risk of misdiagnosis exists, especially for POS in other than a femoral location. Recurrent tumor re-excision is possible in most cases; however, patients with an aggressive recurrence pattern deserve special attention.

A case of parosteal osteosarcoma with a rare complication of myositis ossificans

We report the case of a parosteal osteosarcoma of the distal ulna, treated with wide resection without reconstruction. The patient developed lung metastasis and a mass in the interosseus membrane of the forearm proximally to the osteotomy. The lung mass was found to be a metastasis from parosteal osteosarcoma and the biopsy of the forearm mass revealed a myositis ossificans. The suspicion of a recurrence of parosteal osteosarcoma, already metastatic, led to a second wide resection with no reconstruction. A slice of the radial cortex was taken during this second procedure. From a histological point of view, good margins were achieved and diagnosis of myositis ossificans was confirmed. Two months later, a radius fracture occurred and a synthesis, with plate and screws, as added with poly(methyl methacrylate) (PMMA) to reconstruct the bone loss, was performed. Indication of the reconstructive technique and the complication after distal ulna resection in oncologic surgery are discussed in this paper.

Distinct profiles of oxidative stress–related and matrix proteins in adult bone and soft tissue osteosarcoma and desmoid tumors: A proteomics study

Osteosarcomas rarely occur in older adults. Proteomics has not been reported to date in osteosarcoma occurring in the older adult population. This proteomic investigation was conducted to identify differentially expressed proteins in osteosarcoma occurring in various backgrounds from older adults. Desmoid tumors, known to recur locally but not metastasize, were also analyzed. Protein digests isolated from formalin-fixed, paraffin-embedded tumor tissue specimen representing 14 primary osteosarcomas of soft tissue and bone and 18 desmoid tumors were analyzed by high-resolution liquid chromatography-tandem mass spectrometry for protein identification and relative quantification by spectral counting. Elevated abundance levels of several proteins including heat shock protein 90 (HSP90), elastin microfibril interface-located protein 1, and clusterin were identified in osteosarcoma with slight differences in proteomic profiles. Desmoids had an abundance of collagen II and periostin only. The findings were confirmed by immunohistochemical staining for HSP90 and clusterin in the experimental samples and additionally in 16 posttherapy conventional osteosarcomas in tissue microarrays constructed from heterogeneous sarcomas and benign lesions. All osteosarcomas were positive for HSP90 and clusterin to a variable extent. One case of well-differentiated parosteal osteosarcoma was negative. Thirty of 75 other high-grade sarcomas including cases of chondrosarcoma were positive for HSP90. Low-grade and benign lesions and scars and 18 desmoid tumors had little or no expression of these proteins. HSP90 and clusterin represent candidate markers of aggressiveness in osteosarcoma occurring in older adults and may be indicative of drug resistance.

DACH1 Expresison in Osteosarcoma and Its Relationship with Proliferation and Angiogenesis.

The aim of this study was to investigate the expression of DACH1 in osteosarcoma as well as its relationship with cell proliferation and angiogenesis in the tumor. DACH1 expression was detected by immunohistochemical staining in the serial sections of the osteosarcoma. The microvessel density (MVD) was counted by CD34 immunohistochemical staining, and immunohistochemical staining of PCNA staining showed the cell proliferation. The impacts of DACH1 expression on tumor proliferation and angiogenesis were evaluated by statistics. The DACH1 had different expression patterns in different osteosarcoma. Conventional osteosarcoma showed stronger DACH1 staining (conventional vs. parosteal: P = 0.037; conventional vs. periosteal: P = 0.028) and more PCNA-positive tumor cells than parosteal and periosteal osteosarcoma (conventional vs. parosteal: P = 0.041; conventional vs. periosteal: P = 0.045), the difference was significant. In addition, conventional osteosarcoma showed more cytoplasmic staining of DACH1 than parosteal and periosteal (conventional vs. parosteal: P = 0.023; conventional vs. periosteal: P = 0.030). Parosteal and periosteal osteosarcoma showed no significant difference in DACH1 expression and cell proliferation index. On the other hand, DACH1 different expression patterns showed significantly different impacts on angiogenesis. In spite of the different subtypes of osteosarcoma, the MVD showed a significant difference in cytoplasmic and nuclear expression patterns of DACH1 (nuclear expression vs. cytoplasmic expression: 5.72 ± 1.19 vs. 9.65 ± 1.24, P = 0.042). Moreover, in the conventional osteosarcoma, the MVD also showed a significant difference in DACH1 cytoplasmic and nuclear staining (nuclear expression vs. cytoplasmic expression: 5.58 ± 0.71 vs. 13.65 ± 1.30, P = 0.019). However, the DACH1 expression intensity showed no significant different impacts on MVD of all kinds of osteosarcoma. DACH1 had different expression patterns and intensity. Cytoplasmic and nuclear expression of DACH1 might play different roles in cell proliferation and angiogenesis of osteosarcoma. Cytoplasmic DACH1 might promote cell proliferation and be associated with angiogenesis.

Parosteal osteosarcomas: Unusual findings

ObjectiveTo study and evaluate the unusual findings in the natural history of parosteal osteosarcomas. Parosteal osteosarcomas are well-differentiated tumours of low grade malignancy, but may dedifferentiate into a more aggressive lesion. Material and methodsWe reviewed 7 parosteal osteosarcomas treated in La Paz Hospital between 2005 and 2009 (3 were dedifferentiated parosteal osteosarcomas (ddPO)). The authors analysed the clinical and radiological features, histology, treatment and outcomes in this patient group. ResultsThere were 5 men and 2 women, with a mean age of 32.14 years, range 24–47 years. Three of seven tumours (42.8%) were dedifferentiated osteosarcomas. All three patients received chemotherapy. One patient presented with pulmonary metastases. No patient died. ConclusionsIt is important to understand that the biological phenomenon of dedifferentiation can occur in parosteal osteosarcomas. The prognosis, treatment and survival changes radically.

12q amplification defines a subtype of extraskeletal osteosarcoma with good prognosis that is the soft tissue homologue of parosteal osteosarcoma

Extraskeletal osteosarcomas are rare tumors with neoplastic cells synthesizing bone, usually associated with poor prognosis. We present the case of a 40-year-old man with an extraskeletal osteosarcoma that was treated by surgery and adjuvant radiotherapy. Thirteen years after the diagnosis, he remains disease-free, without any recurrences or metastases. Histopathological analysis favored the diagnosis of chondroblastic extraskeletal osteosarcoma grade II. G-banding, comparative genomic hybridization (CGH), and real-time PCR for the MDM2 and CDK4 genes were performed to describe the genetic profile of this tumor and revealed aberrations that are common findings of parosteal osteosarcomas. Ring chromosomes, giant marker chromosomes, and a telomeric association were found with G-banding. CGH revealed that 12q was amplified in the ring and giant markers identified by G-banding. Real-time PCR for MDM2 and CDK4 confirmed the amplification of these genes located in 12q. Our findings suggest that a variant of extraskeletal osteosarcoma, which is genotypically similar to parosteal osteosarcoma, exists and is associated with good prognosis.