Osteosarcoma of the Jaws: A Literature Review.

Osteosarcoma of the jaws (OSJ) is a relatively rare disease, accounting for between 2% and 10% of all cases of osteosarcoma. It is morphologically and radiologically identical to the trunk and extremity variant, but distinct in several crucial aspects. The lesion is characterized by sarcomatous cells which produce a variable amount of osteoid bone. It arises centrally within the bone and can be subdivided into osteoblastic, chondroblastic and fibroblastic subtype, depending on the predominant cell type. Radiographically, these tumors display a spectrum of bone changes from well-demarcated borders to lytic bone destruction with indefinite margins and variable cortical bone erosion or, in some cases, images of sclerotic bone. Therapeutic options for OSJ include surgery, chemotherapy and radiotherapy, which are employed according to age of the patient, histological classification and localization of the tumor. Today, there is no general consensus in the treatment guidelines for the OSJ though surgery represents the key to the treatment. The main prognostic factor deeply influencing the patient's prognosis remains the complete tumor resection with negative surgical margins. The aim of the present review is to describe state of the art regarding diagnostic and surgical treatment aspects of the primary osteosarcoma of the jaws.

p16 protein expression and correlation with clinical and pathological features in osteosarcoma of the jaws: Experience of 37 cases.

BACKGROUND: In literature, no markers have been reported as predictive and prognostic factors in osteosarcoma of the jaw. METHODS: A retrospective analysis of p16 expression was performed in 37 patients with high-grade osteosarcoma of the jaw to investigate its potential prognostic and predictive value. RESULTS: p16 positivity was found in 56.7% of cases. The absence of p16 expression was associated with an adverse disease-free survival (P = .003). At the multivariate Cox regression, positive margins were the only independent factor. In the subgroup of 17 patients who underwent neoadjuvant chemotherapy, a significant association was noted between p16 expression and pathological response to chemotherapy (P = .015) and the negativity of p16 increased the risk of negative outcome (P = .01). CONCLUSION: Our data indicate that the wide surgical margin is the most important prognostic factor. The expression of p16 confers greater sensitivity to chemotherapy and its loss of expression is associated with a worse prognosis.

Ameloblastic Fibrosarcoma of the mandible evolving from a prior Ameloblastic Fibroma after two years: an unusual finding.

Transformation of an ameloblastic fibroma to an ameloblastic fibrosarcoma has been reported rarely in the literature. The present case report describes such evolution in a patient under long-term follow-up. The patient was first treated in 2008, and he developed the malignant counterpart of the disease 2 years later. The patient is currently under careful long-term follow-up and is free of disease. This article describes the clinical and radiographic features, histological characteristics, immunohistochemical findings, and surgical treatment of the tumor.

Active TGF-ß signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart.

Angiosarcomas constitute a heterogeneous group of highly malignant vascular tumors. Angiosarcoma of bone is rare and poorly characterized. For angiosarcoma of soft tissue, some pathways seem to be involved in tumor development. Our aim was to evaluate the role of these pathways in angiosarcoma of bone. We collected 37 primary angiosarcomas of bone and used 20 angiosarcomas of soft tissue for comparison. Immunohistochemistry was performed on constructed tissue microarrays to evaluate expression of CDKN2A, TP53, PTEN, BCL2, CDK4, MDM2, cyclin D1, ß-catenin, transforming growth factor-ß (TGF-ß), CD105, phospho-Smad1, phospho-Smad2, hypoxia-inducible factor-1α, plasminogen activator inhibitor type 1 (PAI-1), VEGF, CD117 and glucose transporter--1. PIK3CA was screened for hotspot mutations in 19 angiosarcomas. In nearly 55% of the angiosarcoma of bone, the retinoblastoma (Rb) pathway was affected. Loss of CDKN2A expression was associated with a significantly worse prognosis. No overexpression of TP53 or MDM2 was found, suggesting that the TP53 pathway is not important in angiosarcoma of bone. Angiosarcoma of bone showed highly active TGF-ß signaling with immunoreactivity for phospho-Smad2 and PAI-1. Although the phosphatidylinositol 3-kinase (PI3K)/Akt pathway seems to be active in both tumor groups, different mechanisms were involved: 41% of angiosarcoma of bone showed a decrease in expression of PTEN, whereas in angiosarcoma of soft tissue overexpression of KIT was found (90%). PIK3CA hotspot mutations were absent. In conclusion, the Rb pathway is involved in tumorigenesis of angiosarcoma of bone. The PI3K/Akt pathway is activated in both angiosarcoma of bone and soft tissue, however, with a different cause; PTEN expression is decreased in angiosarcoma of bone, whereas angiosarcomas of soft tissue show overexpression of KIT. Our findings support that angiosarcomas are a heterogeneous group of vascular malignancies. Both angiosarcoma of bone and soft tissue may benefit from therapeutic strategies targeting the PI3K/Akt pathway. However, interference with TGF-ß signaling may be specifically relevant in angiosarcoma of bone.

A case of pneumatosis cystoides intestinalis mimicking familial adenomatous polyposis.

In rare cases the diagnosis of Familial Adenomatous Polyposis (FAP) may not be simple or straightforward. We describe the case of a 54-year man in whom endoscopic and histological features of FAP led to proctocolectomy with ileoanal anastomosis. At anatomical examination, air-filled cystic formations in the submucosa and subserosa of the entire large bowel led to the diagnosis of "Pneumatosis Cystoides Intestinalis", a rare clinical condition featured by the infiltration (or the production) of gas within the intestinal wall. In this case the disease was associated with a long-lasting ingestion of acarbose; as suggested by previous reports, it is possible that gas produced by the fermentation of this unabsorbable carbohydrate penetrates the bowel wall giving origin to cystic formation and to the endoscopic appearance of several polypoid lesions in the large bowel. This report indicates that in rare occasions Pneumatosis Intestinalis can lead to a wrong diagnosis of FAP.

Syndecan-4 and fibronectin in osteosarcoma.

AIMS: Syndecan-4 (SDC4) and fibronectin (FN), which belong to the cell adhesion molecules, have been reported to correlate with tumour growth and invasion in various carcinomas. We aimed to investigate the prognostic value of these molecules in osteosarcoma. METHODS: Using immunohistochemistry, we compared the expression of these molecules in high grade osteosarcoma to low grade central osteosarcoma, osteoid osteoma and normal bone. Further, the expression of SDC4 and FN were analysed with prognostic factors of high grade osteosarcoma. RESULTS: In high grade osteosarcoma, SDC4 was expressed in 50 of the 65 samples; of these, 32 of 65 showed strong expression profiles. FN was expressed in 46 of 65 samples, and 29 of 65 had evidence of strong expression of this molecule. SDC4 and FN expression were increased in high grade osteosarcoma as compared to other tissues. Strong SDC4 expression was associated with the occurrence of distant metastasis and a large tumour size, and strong FN expression was associated with the occurrence of distant metastasis. Strong expression of SDC4 or FN was associated with significantly shorter overall survival, respectively. CONCLUSIONS: [corrected] Increased expression of SDC4 and FN may be underlying molecular alteration of osteosarcoma which accounts for more aggressive clinical behaviour.

Multicentric osteosarcoma: clinicopathologic and radiographic study of 56 cases.

Multicentric osteosarcoma (M-OGS) is characterized by multicentricity of osseous osteosarcomas, either synchronous or metachronous, without visceral involvement. The study's purpose was to clinicopathologically and radiographically analyze 56 cases of M-OGS (22 synchronous and 34 metachronous). The distal femur was the most common site. Histologically, all tumors were high grade. Of 22 patients with synchronous M-OGS, 16 had 3 or more simultaneous tumors; the axial skeleton was involved in 14 (64%) of 22 cases. In metachronous M-OGS, the second malignancy occurred after a median of 22 months. Treatment was surgery, chemotherapy, radiotherapy, or a combination of these. Patients with metachronous osteosarcoma had a median survival longer than did patients with synchronous tumors. Overall, 8 long-term survivors were treated by aggressive surgery with wide margins (plus chemotherapy and/or radiotherapy). M-OGS combines multiple skeletal locations of high-grade conventional osteosarcomas and has a poor prognosis. Aggressive surgery may result in improved long-term survival, particularly in patients with metachronous disease.

Distinct histological features characterize primary angiosarcoma of bone.

AIMS: To define the histological criteria of primary angiosarcoma of bone. METHODS AND RESULTS: Forty-two angiosarcomas of bone in 23 males and 15 females were studied. Histological criteria were related to patients' outcome. Eleven patients had multifocal lesions. Lesions were located in the long and short tubular bones followed by the pelvis, spine and trunk. Tumour cells were positive for CD31 in 38 of 40, von Willebrand Factor in 21 of 35, CD34 in 15 of 38, smooth muscle actin in 22 of 36, D2-40 in 11 of 35 and keratin AE1AE3 in 27 of 39. Thirty-nine tumours showed an epithelioid phenotype. One- and 5-year survival rates were 55% and 33%, respectively. Survival analysis showed that a macronucleolus, three or more mitoses per 10 high-power field (HPF) and fewer than five eosinophilic granulocytes per 10 HPF within a tumour was associated with an even worse survival compared to the overall group. CONCLUSIONS: Because keratin positivity is seen in the majority of cases, pathologists should avoid misinterpretation as metastatic carcinoma. A macronucleolus, three or more mitoses per 10 HPF and fewer than five eosinophilic granulocytes per 10 HPF can be used to further define angiosarcoma of bone.

Expression of heat shock proteins in osteosarcomas.

AIMS: Heat shock proteins (HSPs) protect cells against stress-associated injuries and are overexpressed in several malignant tumours. We investigated the potential roles of HSP27, HSP60, and HSP70 in conventional and low grade central osteosarcoma. METHODS: Expressions of HSP27, HSP60, and HSP70 were analysed using immunohistochemistry on tissue sections from 52 cases of conventional osteosarcoma and 21 cases of low grade central osteosarcoma. We evaluated the expression of each protein and examined its relationship with clinicopathological parameters. RESULTS: We found significantly different expressions of HSP27 and HSP70 between conventional and low grade central osteosarcoma [34.6% versus 4.8% (p = 0.008), 88.5% versus 14.3% (p < 0.001)]. However, HSP60 was highly expressed in both kinds of osteosarcoma (92.3% versus 85.7%). In conventional osteosarcoma, a higher expression of HSP27 was significantly related to distant metastasis (p = 0.034) and histological subtype [osteoblastic versus non-osteoblastic (p = 0.041)]. The expressions of HSP60 and HSP70 were not significantly related to any tested clinicopathological parameter. CONCLUSIONS: HSP27 and HSP70 may be used as differential markers to distinguish conventional and low grade central osteosarcoma. HSP27 may be used as a possible prognostic marker in conventional osteosarcoma cases.

Histological heterogeneity of Ewing's sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support.

Ewing's sarcoma (ES)/peripheral neuroectodermal tumor (PNET) are malignant neoplasms affecting children and young adults. We performed a study to typify the histological diversity and evaluate antibodies that may offer diagnostic/prognostic support. In total, 415 cases of genetically confirmed paraffin-embedded ES/PNET were analyzed on whole sections and in tissue microarrays. This study confirms the structural heterogeneity of ES/PNET, distinguishing three major subtypes: conventional ES (280 cases); PNET (53 cases); and atypical ES/PNET (80), including large cells, vascular-like patterns, spindle pattern, and adamantinoma-like configuration. All cases presented positivity for at least three of the four tested antibodies (CD99, FLI1, HNK1, and CAV1). CAV1 appeared as a diagnostic immunomarker of ES/PNET being positive in CD99-negative cases. Hence, the immunohistochemical analysis confirmed the diagnostic value of all four antibodies, which together cover more than 99% of the tumors, independently of the histological variety. The univariate analysis for survival revealed atypical ES as the only histological parameter apparently associated with less favorable clinical outcome, particularly in the subgroup of patients treated with surgery. In conclusion, the diagnosis of atypical ES is a challenge for the pathologist and needs support from molecular techniques to perform an optimal differential diagnosis with other small round cell tumors.

Dedifferentiated peripheral chondrosarcomas: regulation of EXT-downstream molecules and differentiation-related genes.

Dedifferentiated peripheral chondrosarcoma is a rare subtype of chondrosarcoma arising superimposed on the cartilage cap of a preexisting osteochondroma. It consists of two clearly defined components, a low-grade malignant, well-differentiated cartilage component and a high-grade non-cartilaginous sarcoma. Signaling pathways having a role in normal cartilage development were analyzed in these tumors, and compared with available data of other cartilaginous tumors. Sixteen well-characterized dedifferentiated peripheral chondrosarcomas were immunohistochemically analyzed for parathyroid hormone-like hormone (PTHLH)-BCL-2, fibroblastic growth factor (FGF), and transforming growth factor-beta signaling molecules, as well as matrix molecules and p53, comparing the chondrogenic component of dedifferentiated peripheral chondrosarcomas with the anaplastic component and with previously published data obtained from conventional grade I and II secondary peripheral chondrosarcomas. Results were correlated with clinical outcome. In the anaplastic component, various lines of differentiation could be found (collagen I (6/16), CD31 (1/16), smooth muscle actin (12/16), muscle-specific actin (12/16) and desmin (2/9)). Compared with the anaplastic component, the chondrogenic component of dedifferentiated peripheral chondrosarcomas shows more often expression of cyclin D1 (P=0.05), p53 (P=0.008), plasminogen activator inhibitor 1 (PAI-1) (P=0.005), and CD44 (P=0.030). Compared with secondary peripheral chondrosarcomas, more samples were positive in the chondrogenic component of dedifferentiated peripheral chondrosarcomas for FGF signaling (FGF receptor 3 P=0.000; bFGF P=0.003) and CD44 (P=0.000). Lower expression of BCL-2 (P=0.025) and absence of CD44v3 (P=0.000), a splice variant of CD44, was observed in the chondrogenic component of dedifferentiated peripheral chondrosarcomas compared with secondary peripheral chondrosarcomas. With regard to clinical data, PAI-1 expression in the chondrogenic component of dedifferentiated peripheral chondrosarcomas correlated with better survival (P=0.019). In conclusion, in the chondrogenic component of dedifferentiated peripheral chondrosarcomas, FGF signaling pathway is active, whereas PTHLH signaling seems to be low/downregulated. Interestingly, although the chondrogenic component of dedifferentiated peripheral chondrosarcoma is CD44+/CD44v3-, secondary peripheral chondrosarcomas is CD44-/CD44v3+, which suggest different splicing (preference). The prognostic value of PAI-1 in dedifferentiated peripheral chondrosarcomas might also be of interest for the more common dedifferentiated central chondrosarcomas.

Primary hydatid cyst of the root of the thigh: a case report and review of the literature.

Hydatid disease of bone is a rare event, and it is characterized by a high diagnostic and therapeutic complexity. We report a case of primary hydatidosis of the proximal thigh involving both the soft tissues and the proximal femur in a 59-year-old man. It has been possible to establish the diagnosis only 8 years after the appearance of the first symptoms (painful swelling over the root of the left thigh), when the patient came to our institution after several investigations.

Expression of embryonic lethal abnormal vision (ELAV)-like protein HuR and cyclooxygenase-2 (COX-2) in Ewing sarcoma.

AIMS AND BACKGROUND: HuR is a member of the family of ELAV (embryonic lethal abnormal vision)-like proteins that stabilize several cellular mRNAs by binding to AU-rich elements in the 3' untranslated region of the mRNA. Cyclooxygenase-2 (COX-2) is a well known enzyme that promotes tumor growth and metastasis. Recent studies have shown that HuR can stabilize the mRNA of COX-2, and cytoplasmic expression of HuR is associated with increased COX-2 expression in some cancers. The aim of this study was to investigate the correlation between COX-2 and HuR in Ewing sarcoma. METHODS: The expression patterns for HuR and COX-2 were assessed via immunochemical analysis of 70 Ewing sarcoma samples. RESULTS: Nuclear HuR expression was observed in 12 of 70 (17.1%) cases, but cytoplasmic expression was not observed. COX-2 expression was seen in 25 of 70 (35.7%) samples. Nuclear HuR and COX-2 were simultaneously expressed in 8 of 70 (11.4%) samples. The expression of nuclear HuR was significantly associated with COX-2 expression (P = 0.014). Neither HuR nor COX-2 expression showed a correlation with age or sex. CONCLUSIONS: COX-2 expression in Ewing sarcoma may not be directly related to mRNA stabilization by HuR. However, a correlation between COX-2 expression and nuclear HuR expression through indirect mRNA stabilization can be suggested.

High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute.

BACKGROUND: High-grade surface osteosarcoma is a rare variant of surface osteosarcoma and is associated with a poor prognosis. METHODS: This retrospective study includes all cases of high-grade surface osteosarcoma filed at the Rizzoli Institute. A complete clinical, histologic, and radiologic review was performed of 25 cases. RESULTS: There were 19 males and 6 females with an average age of 21 years. All tumors were localized at the lower limb and the most frequently involved segments were the femoral and the tibial diaphysis. All lesions demonstrated the histologic aspect of a high-grade osteosarcoma, 20 were osteoblastic, and 5 were chondroblastic. The circumferential involvement was on average 53% and in approximately half of the cases medullary canal involvement was detected. Nineteen patients underwent a combination of surgery and chemotherapy for treatment of their initial lesion, whereas 5 patients were managed with surgery alone. The average follow-up was 9 years and the overall 5-year survival rate was 82%. CONCLUSIONS: High-grade surface osteosarcoma is an extremely rare subtype of osteosarcoma. The current series demonstrates good overall survival for patients with this tumor. Metastatic disease and limb-sacrificing surgery were associated with a worse prognosis. Wide surgical excision and chemotherapy might improve the outcome.

Clear cell chondrosarcoma of bone: long time follow-up of 18 cases.

INTRODUCTION: Clear cell chondrosarcoma is a variant of conventional chondrosarcoma behaving as low grade malignant bone tumor. We reviewed our cases of clear cell chondrosarcoma with the aim to assess the best diagnostic and curative approach to this rare tumor. MATERIALS AND METHODS: We report 18 cases of clear cell chondrosarcoma treated at the authors' institution. Pertinent clinical information, pre and postoperative serum alkaline phosphatase (SAP) level were obtained from the patients charts. Available imaging studies including plain roentgenograms, computed tomography (CT) images (in 6 patients) and magnetic resonance imaging (MRI) images (in 2 patients). RESULTS: Eight cases were firstly treated in other institutions, seven with one or more curettage, while one, presented with pathologic fracture, was treated with repeated osteosynthesis. Of the seven patients treated with curettage, five were referred with local recurrence, the mean time between surgical treatment and local recurrence was 52.2 months (from 12 to 132). The other two patients were curetted out 4 and 1 month before, respectively, and were then referred to us to decide about further treatment after incidental diagnosis. Of these cases, three (37.5%) recurred again after our treatment and two of them presented with late bone metastases. Eight patients were originally treated with wide (six) or marginal (two) surgical margins by us. Among them only one proximal humerus (wide margins) had local recurrence 26 months from the first operation. Two patients underwent curettage in our institution, and one of them had a local recurrence. Pre-operative SAP level were obtained in 17 patients. Among them, 11 patients had high pre-operative SAP level (64.7%) and 6 cases were normal. Post-operative SAP levels were obtained in nine patients. After removal of the tumors; SAP levels decreased to normality in seven of the nine patients with high pre-operative SAP. In the other two patients, although the SAP levels were normal, post-operative SAP levels were decreased. CONCLUSION: Serum alkaline phosphatase can be used as a good tumor marker in diagnosis and follow-up. Due to the occurrence of local recurrences and distant metastasis after curettage, we suggest surgical treatment with "en bloc" resection from the first presentation.

Prognostic significance of immunohistochemical expression of ezrin in non-metastatic high-grade osteosarcoma.

BACKGROUND: Ezrin is a membrane-cytoskeleton linker protein involved in regulating growth and metastatic behaviour of cancer cells. The study evaluated ezrin expression and its prognostic value in patients with non-metastatic osteosarcoma. PROCEDURES: Ezrin expression and pattern of staining (cytoplasmic or membraneous and cytoplasmic) were assessed using immunohistochemistry on slides from tumour biopsy. We studied 95 patients (median 16 years, range: 4-39 years) with primary non-metastatic osteosarcoma of the extremity treated by neoadjuvant chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. RESULTS: Seventy-six patients (80%) showed ezrin immunoreactivity: in cytoplasm (37, 47%) and in cytoplasm and membrane (42, 53%) of tumour cells. Immunohistochemical staining score was: 1+ (16, 24%), 2+ (10, 13%), 3+ (17, 21.5%) and 4+ (36, 45.5%). Ezrin and score expression were not related to gender, site, alkaline phosphatase (AP), LDH serum levels, chemotherapy-induced tumour necrosis or patient outcome. A significant association was seen between expression pattern and prognosis. The 3-year probability of disease-free survival was 80% for patients with only cytoplasmic immunostaining and 54% for patients with cytoplasmic and membranous immunostaining (P < 0.02). CONCLUSION: Ezrin immunoreactivity can be detected in the majority of patients with non-metastatic osteosarcoma of the extremity. The pattern of ezrin staining can identify patients with different risks of relapse. In patients who only have ezrin cytoplasmic expression, a probability of EFS >80% at 5 years can be expected. These results suggest further investigations to define the relation between expression pattern, ezrin functional status and outcome in patients with non-metastatic osteosarcoma.

Mesenchymal chondrosarcoma. An analysis of patients treated at a single institution.

BACKGROUND: We analyzed clinical and treatment-related factors influencing the outcome of patients with mesenchymal chondrosarcoma (MC). Twenty-six patients (median age, 31 years) were identified using the Tumor Center and Chemotherapy Department database of the study institute. METHODS: Patients received surgery (24 patients) and/or radiotherapy (5 patients), and chemotherapy (12 patients). RESULTS: After a median follow-up of 48 months (7-237 months) 10 patients were alive. The 10-year overall survival (OS) was 27% in those who achieved complete surgical remission and 0% in those who did not (P = 0.0007). A worse 10-year probability of OS was observed in patients who were metastatic at presentation (metastatic 0%, localized 31%, P = 0.02), in patients with soft tissue MC (soft tissue MC 0%, bone MC 29%, P = 0.06) and in hemangiopericytoma-like MC (hemangiopericytoma-like MC 0%, Ewing's-like MC 33.5%, P = 0.9). In those patients who achieved complete surgical remission, the 10-year DFS was 76% for those who received chemotherapy and 17% for those who did not (P = 0.008). CONCLUSIONS: Our experience confirmed the importance of complete surgical remission in MC treatment and suggests that the addition of chemotherapy should offer a benefit in terms of DFS. Due to the rarity of MC, multicentrer studies are needed to identify the most active chemotherapy regimen.

Predictive factors of histologic response to primary chemotherapy in patients with Ewing sarcoma.

A correlation between chemotherapy-induced necrosis and prognosis has been reported in Ewing sarcoma. To identify factors influencing histologic response data from 122 patients with Ewing sarcoma surgically treated were reviewed. Primary chemotherapy was based on vincristine, doxorubicin, cyclophosphamide, ifosfamide, actinomycin-D, and etoposide. Patients with complete necrosis or only scattered foci of viable tumor cells were good responders (GRs), the remaining patients poor responders (PRs). Age, sex, site and size of the tumor, fever at diagnosis, and lactate dehydrogenase level were clinical variables investigated. Mean age was 13.3+/-6 in GR and 18.1+/-9 in PR (P<0.0005); GR rate was 71% in patients18 years (P=0.003). Female were more likely to achieve a GR (F 64% vs. M 42%, P<0.02). After multivariate analysis sex and age retained statistical significance. Age and sex influence the histologic response in patients with Ewing sarcoma.