The role of imaging for the surgeon in primary malignant bone tumors of the chest wall.

Primary malignant chest wall tumors are rare. The most frequent primary malignant tumor of the chest wall is chondrosarcoma, less common are primary bone tumors belonging to the Ewing Family Bone Tumors (EFBT), or even rarer are osteosarcomas. They represent a challenging clinical entities for surgeons as the treatment of choice for these neoplasms is surgical resection, excluding EFBT which are normally treated by a multidisciplinary approach. Positive margins after surgical procedure are the principal risk factor of local recurrence, therefore to perform adequate surgery a correct preoperative staging is mandatory. Imaging techniques are used for diagnosis, to determine anatomic site and extension, to perform a guided biopsy, for local and general staging, to evaluate chemotherapy response, to detect the presence of a recurrence. This article will focus on the role of imaging in guiding this often difficult surgery and the different technical possibilities adopted in our department to restore the mechanics of the thoracic cage after wide resections.

Imaging patterns in elastofibroma dorsi.

INTRODUCTION: Elastofibroma dorsi is a rare pseudotumor of the soft tissues. Its clinico-radiologic characteristics lead to a correct diagnosis. MATERIAL AND METHODS: We followed 43 patients with elastofibroma dorsi with a confirmed histological diagnosis or on the basis of typical imaging pattern (ultrasound, CT, MR) confirmed by evolution. RESULTS: Elastofibroma is prevalent in females, its onset occurs around 60 years of age and is most frequently localized in the deep subscapular region (93%), bilateral in 54% of cases. In 7% it was found in an atypical isolated suprascapular region, in 7% it was synchronous to that in the subscapular region. Four ultrasound patterns were detected: Type I (54%) inhomogeneous fasciculated, Type II (22%) inhomogeneous aspecific, Type III (15%) hyperechogeneous, Type IV (9%) hypoechogeneous. Three patterns were detected at CT and MR: Type A (84%) inhomogeneous fasciculated corresponding to Types I and III and partially to Type II ultrasound pattern, Type B (8%) inhomogeneous aspecific corresponding to Type II ultrasound pattern; Type C (8%) homogeneous isodense or isointense to the muscle corresponding to Type IV ultrasound pattern. CONCLUSION: A solid, slow-growing lesion, in the deep periscapular region in females aged between 50 and 60 years, with a typical fasciculated pattern is pathognomonic of elastofibroma dorsi and bilateral location convalidates diagnosis. Ultrasound is sufficient to orientate diagnosis. CT and/or MR are reserved only for non-fasciculated ultrasound patterns, when site is atypical or in candidates for surgery. Biopsy is reserved only in cases where integrated imaging shows a non-fasciculated pattern to differentiate it from other malignant lesions.

Sex- and age-related chemotherapy toxicity in patients with non-metastatic osteosarcoma.

The influence of age and sex on chemotherapy-related toxicity was evaluated in children and adults with non metastatic osteosarcoma. treatment consisted of methotrexate (MTX, 12 g/m(2)), cisplatin (CDP 120 mg/m(2)) and doxorubicin (ADM 75-90 mg/m(2)) and high-dose ifosfamide (HDIFO). toxicity data from 1,051 courses (295 with MTX, 756 based on doxorubicin, cisplatin and high-dose ifosfamide) were analyzed. Children (4-14 yrs) and females showed a higher incidence of grade 4 neutropenia and thrombocytopenia and were more frequently hospitalized for neutropenic fever compared to adolescents and young adults (AYA, 15-19 yrs) and adults (>20-40 yrs). Delayed MTX excretion was higher in adults than AYA and children. Adults (up to 40 years) can be treated with pediatric protocols for osteosarcoma and they experience lower hematologic toxicity compared to pediatric population. further investigations on sex-related susceptibility to chemotherapy in osteosarcoma patients are recommended.

Response to high-dose ifosfamide in patients with advanced/recurrent Ewing sarcoma.

AIM: To determine activity and toxicity of high-dose ifosfamide (HDIFO) in recurrent or advanced Ewing sarcoma family tumors (EFT). METHODS: Thirty-seven EFT patients [median age 17 years (6-45 years)] previously treated with chemotherapy regimens including standard dose ifosfamide were enrolled. HDIFO was administered for metastatic recurrent disease in 33 patients and for progression during neoadjuvant chemotherapy in 4 patients. All patients who received two courses of 15 g/m(2) ifosfamide were evaluable for radiographic response assessed according to RECIST criteria. RESULTS: Transient Grade 4 neutropenia and thrombocytopenia in 97% and 54% HDIFO courses respectively and severe CNS toxicity in one patient were observed. Thirty-five patients were evaluable: 12 (34%) had complete (2) or partial (10) response, 11 (32%) had stable disease, and 12 (34%) had progression. CONCLUSIONS: In patients with relapsed or advanced EFT previously treated with standard dose ifosfamide HDIFO is active and it should be considered a treatment option.

Adjuvant and neo-adjuvant chemotherapy for Ewing's sarcoma family tumors and osteosarcoma of the extremity: further outcome for patients event-free survivors 5 years from the beginning of treatment.

BACKGROUND: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarcoma (OS) treated with adjuvant and neo-adjuvant chemotherapy and event-free survivors 5 years from the beginning of treatment we evaluated outcome in the following years. Post 5-year follow-up for these patients was 9.7 years (5.5-29 years). PATIENTS AND METHODS: Adverse events observed after 5-year follow-up were 73 (7.6%): 38 late relapses, nine leukemia, 14 second solid tumor, seven radioinduced sarcoma, three severe adriamycin-related cardiomyopathy, one suicide and one death by car crash. RESULTS: Of the patients who developed late events, 16 (22.5%) are alive and event free after 8 years from the last treatment (2-22 years). CONCLUSION: We conclude that the high rate of late adverse events after 5 years in patients with OS and ESFT is noteworthy and indicates that these patients should be followed for >5 years.

Ewing's sarcoma family tumours. Differences in clinicopathological characteristics at presentation between localised and metastatic tumours.

Despite local treatment with systemic chemotherapy in Ewing's sarcoma family tumours (ESFT), patients with detectable metastases at presentation have a markedly worse prognosis than those with apparently localised disease. We investigated the clinical, pathological and laboratory differences in 888 patients with ESFT, 702 with localised disease and 186 with overt metastases at presentation, seen at our institution between 1983 and 2006. Multivariate analyses showed that location in the pelvis, a high level of serum lactic dehydrogenase, the presence of fever and a short interval between the onset of symptoms and diagnosis were indicative of metastatic disease. The rate of overt metastases at presentation was 10% without these four risk factors, 22.7% with one, 31.4% with two, and 50% for those with three or four factors. We concluded that in ESFT the site, the serum level of lactic dehydrogenase, fever, and the interval between the onset of symptoms and diagnosis are indicators of tumours having a particularly aggressive metastatic behaviour.

Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients.

Between 1986 and 2002, 42 patients with synchronous multifocal osteosarcoma were treated with two different protocols of neoadjuvant chemotherapy. When feasible, the primary and secondary tumours were excised as a combined procedure. After initial chemotherapy 26 patients were excluded from simultaneous excision of all their secondary bone lesions as their disease was too advanced. In 12 patients only isolated excision of the primary lesion was possible. For 16 patients simultaneous operations were conducted to excise the primary and secondary lesions. This involved two supplementary sites in 15 patients and four additional sites in one patient. Of these, 15 attained remission but 12 relapsed and died (11 within two years). Three patients remained disease-free at five, six and 17 years. The histological response to pre-operative chemotherapy of the primary and secondary lesions was concordant in 13 of the 16 patients who underwent simultaneous operations at more than one site. The prognosis for synchronous multifocal osteosarcoma remains poor despite combined chemotherapy and surgery. The homogeneous histological responses in a large proportion of the primary and secondary lesions implies that synchronous multifocal osteosarcoma tumours are not multicentric in origin, but probably represent bone-to-bone metastases from a single tumour.

Proteases and interleukin-6 gene analysis in 92 giant cell tumors of bone.

BACKGROUND: Giant cell tumor of bone (GCT) is a benign tumor with a significant tendency to recur locally and rarely to produce pulmonary metastases. It is characterized by the presence of multinucleated osteoclast-like giant cells together with mononuclear spindle-shaped cells. Few prognostic markers have been reported to predict the clinical outcome of GCT patients, so is very important to find the factor that can be implicated in its potential aggressiveness. PATIENTS AND METHODS: Different groups of GCT patients were selected for this study, including patients without evidence of disease and patients who recurred locally or with lung metastasis. The total of 92 tumor samples also included the specimens of the local recurrences and the lung metastases. By using immunohistochemistry and real-time quantitative polymerase chain reaction techniques, the genetic and proteic analyses were performed on the urokinase-type plasminogen activator (u-PA), its receptor (u-PAR) and its inhibitor (PAI-1), which have been described to be frequently implicated in the process of degradation of the extracellular matrix during the metastatic process. Interleukin-6 (IL-6), a cytokine released by GCT cells, which stimulates resorption of bone, was also analyzed. RESULTS: IL-6, u-PA, u-PAR and PAI 1 genes were found amplified, respectively, in 7%, 5%, 8% and 12% of total cases (92). In particular, the percentages of amplified genes were higher in the GCT cells that gave rise to metastases (12 cases) and in the samples of lung metastases (nine cases) compared with the disease-free group of patients (60 cases). CONCLUSIONS: These results suggest a possible association of these factors with a higher biological aggressiveness of GCT. Morever, it appears that increased expression of the IL-6, u-PA, u-PAR and PAI1 proteins might not depend on mutation of the corresponding genes.

Metalloproteinase expression and prognosis in soft tissue sarcomas.

BACKGROUND: Degradation of extracellular matrix by tumor-associated proteases can promote cell invasion and metastasis. This study assessed the prognostic role of MMP2, MMP9 metalloproteinases, and of the metalloproteinase inhibitor TIMP2, related to disease-free survival (DFS), in soft tissue sarcoma (STS) patients. MATERIALS AND METHODS: Level and distribution of MMP2, MMP9, and TIMP2 expression were evaluated on 73 biopsies by immunohistochemistry and immunoblotting. Biopsies included 29 liposarcomas, 29 synovial sarcomas, and 15 malignant peripheral nerve sheath tumors (MPNST). Association between DFS and overall survival with different variables was assessed. RESULTS: In terms of DFS, increased MMP2 reactivity and lack of TIMP2 expression were significant for poor prognosis in all samples (P = 0.0005 and P = 0.006 respectively). MMP2 correlated to histologic grade (P = 0.005). Lack of TIMP2 expression was a poor prognostic factor for DFS in synovial sarcoma (P = 0.009), while MMP2 and MMP9 correlated with metastasis (P = 0.008 and P = 0.005, respectively) and grade (P = 0.001 and P = 0.04 respectively) in liposarcoma. CONCLUSIONS: These prognostic markers that influence growth and spread of tumor cells might be useful to define tumor aggressiveness and risk of the metastasic event.

Analysis of 12q13-15 genes in parosteal osteosarcoma.

The region q13-15 of chromosome 12 frequently is altered in human sarcomas, and several genes, such as SAS, CDK4, and MDM2, have been found to be amplified in bone and soft tissue sarcomas. These genes and their products were studied by quantitative polymerase chain reaction and immunohistochemical analysis in 25 parosteal osteosarcoma samples (22 Grades I or II, three dedifferentiated) to evaluate if the possible alterations detected of the genes on chromosome 12 could have a role in the development of this rare bone tumor. Immunohistochemical analysis was performed on formalin fixed, paraffin embedded tumor sections to evaluate CDK4 and MDM2 protein expression. To measure the degree of SAS and CDK4 gene amplification, quantitative polymerase chain reaction was done on deoxyribonucleic acid derived from the same samples. The results showed that CDK4 protein was expressed in 92% of the cases. Strong and uniform CDK4 and MDM2 immunoreactivity was found respectively in three of three and two of three dedifferentiated parosteal osteosarcomas. SAS and CDK4 genes were found to be amplified fourfold in two Grade II tumors and in one dedifferentiated tumor. These findings, which should be investigated further, might suggest a possible role of the chromosome 12 genes in the pathogenesis of parosteal osteosarcoma.

Secondary tumors in bone sarcomas after treatment with chemotherapy.

New oncologic treatments have improved survival in osteosarcoma and Ewing's sarcoma. However, these treatments may cause secondary malignancies after radiotherapy. This study evaluated the incidence of secondary malignancies after neoadjuvant chemotherapy. Between April 1972 and December 1990, 518 osteosarcoma and 299 Ewing's sarcoma patients entered neoadjuvant chemotherapy protocols. Follow-up records of all patients were analyzed and malignant tumors were reported. Nine patients developed another malignancy, including 5 leukemias, 1 astrocytoma, 1 liposarcoma, 1 parotid, and 1 breast carcinoma. Four leukemias were found in patients treated for osteosarcoma with chemotherapy, but not radiotherapy. Only one leukemia developed after Ewing's sarcoma treated with chemotherapy and radiotherapy. The incidence of leukemias is high, while the other tumors can be explained as unrelated cases. Incidence densities for leukemia were calculated for both groups of patients. Treated osteosarcoma patients seem to have a predisposition to develop leukemias, but whether this is chemotherapy induced needs to be investigated.

Alteration of pRb/p16/cdk4 regulation in human osteosarcoma.

Cell-cycle regulation depends on a fine balance between cyclin-cyclin-dependent kinase complexes and a family of kinase inhibitors that bind cyclin-cdk complexes and block their activity. To investigate the role of mechanisms regulating cell-cycle progression in human osteosarcomas (OS), pRb/p16/cdk4 expression was analyzed in 39 high-grade OS; 19 of these developed metastasis during follow-up. Positive reaction for functional pRB was shown by 18/39 (46%) OS, while 21/39 (54%) were negative. A higher probability of metastasis was seen in patients with negative pRb expression (p < 0.05). Furthermore, while functional pRb and D1 expression are inversely associated to metastasis occurrence, the presence of D1/cdk4 complex in our study was related to poor prognosis. We found that 10/18 pRb-positive and 14/21 pRb-negative tumors were p16-positive. No significant correlation was found between pRb and p16 expression. On the other hand, high cdk4 levels in p16-positive tumors as compared with p16-negative tumors resulted in a positive association between p16 and cdk4 expression (Chi squared = 5.98; p = 0.01). No extensive p16INK4A genomic alterations were found in tumors lacking p16-protein expression. To determine which mechanisms are involved in the down-regulation of p16 protein, the methylation status of the p16INK4 gene was evaluated on the 15 p16-negative tumors: 8 samples showed 5' CpG-island methylation; 4/8 had a complete methylation status, while in the remaining 4 the gene was only partially methylated. These data confirm the role of the pRb/p16/cdk4 pathway in OS development.

Increased c-myc oncogene expression in Ewing's sarcoma: correlation with Ki67 proliferation index.

AIMS AND BACKGROUND: Ewing's sarcoma is a highly malignant musculoskeletal tumor composed of small round cells. Although important results have been achieved with surgery associated with chemotherapy, recurrent disease is still a major problem. In order to define new prognostic factors useful for therapeutic decision-making, we conducted a study on 38 Ewing's sarcoma samples in which c-myc oncogene expression and Ki67 proliferation index were correlated with clinical outcome. METHODS AND STUDY DESIGN: Nineteen patients developed metastases during follow-up and 10 of these patients died. C-myc and Ki67 protein expression was evaluated by immunohistochemistry performed on 5 microm formalin-fixed and paraffin-embedded sections, while the c-myc mRNA transcript was localized using in situ hybridization. RESULTS: A statistically positive correlation was found between c-myc protein and Ki67 (P = 0.001) and c-myc mRNA and Ki67 expression (P = 0.047). The 38 patients were divided into two groups using as the cutoff 50% of Ki67-positive cells. The disease-free survival and overall survival estimates were 68% and 90%, respectively, in the group of patients with a percentage of Ki67-positive cells <50%, and 25% and 50%, respectively, in the group with a percentage of Ki67-positive cells > or = 50%. The difference between the survival curves was statistically significant (P <0.05 and P <0.01). Furthermore, relapsed patients had a high and uniform expression of c-myc protein and mRNA compared to disease-free patients. CONCLUSION: These results suggest a possible role of the c-myc oncogene and Ki67 antigen in the malignant progression of Ewing's sarcoma.

C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression.

The c-myc and c-fos proto-oncogenes have several putative functions, including regulation of cell growth. In many neoplasms c-myc overexpression has been linked to poor prognosis. In order to study the role of c-myc and c-fos expression on the tumorigenesis, and the metastatic spread of osteosarcoma, frozen and paraffin-embedded tissue 38 primary osteosarcoma and 10 lung metastases were analyzed. The mRNA analysis was performed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. The protein expression was studied by Western blot analysis and immunohistochemistry. C-myc and c-fos were found overexpressed in a high percentage of the relapsed tumors and of the metastases, and overexpression of both oncogenes in the same tumor was strongly correlated to the development of metastases (p < 0.05), as 6 of the 7 primary tumors overexpressing both the oncogenes gave metastases. In conclusion, both c-myc and c-fos are involved in the growth and spread of osteosarcoma and a synchronous overexpression of both oncogenes is highly significant for a metastatic potential of a primary tumor.

Prognostic significance of cyclin expression in human osteosarcoma.

To evaluate the distribution of cyclin protein expression, in relation to cell proliferation rate and clinical behavior, an immunohistochemical study was performed on 92 tumor samples of patients with high grade osteosarcoma (OS). A large cyclin A- and cyclin E-positive fraction was found respectively in 59% and 47% of the osteosarcomas, while immunostaining for cyclin D1 was weak or absent in most tumor samples. A positive, statistically significant correlation was found between A and E cyclins and Ki67 expression (p<0.001). Disease-free survival (DFS) analysis included 69 of the 92 patients. A significantly higher probability of metastasis was seen in patients lacking cyclin D1 compared to those in which cyclin D1 was positive (p<0.01). Conversely, patients with >40% of cyclin A-positive cells relapsed more frequently than those with <40% of cyclin A-positive cells (p<0.05). The multivariate analysis demonstrated that cyclin A had a lower predective risk in terms of disease-free survival as opposed to the loss of cyclin D1 that is considered a powerful prognostic factor.

Tumours of the patella.

We report 15 cases of primary tumours and pseudotumours of the patella. The radiographic features and the surgical treatment of the different histological types are described in relation to Enneking's surgical staging and data derived from the literature.

Primary chemotherapy and delayed surgery for malignant fibrous histiocytoma of bone in the extremity.

Between March 1983 and September 1988, 22 patients with non-metastatic malignant fibrous histiocytoma MFH of bone of the extremities were treated with two regimens of neo-adjuvant chemotherapy successively activated. Preoperatively, the patients received moderate doses of methotrexate and cisplatinum-Regimen 1- or high dose methotrexate, cisplatinum and adriamycin-Regimen 2. Cisplatinum was delivered intraarteriously, the other drugs intravenously. Limb salvage surgery was performed in 20 patients, and 2 patients were amputated. The surgical margins were adequate (radical or wide) in 18 cases and inadequate (marginal) in 4. The histologic response to chemotherapy was good (90% or more tumor necrosis) in 8 patients. In both regimens postoperative chemotherapy was tailored according to the grade of necrosis determined by preoperative treatment on the primary tumor. At an average follow-up of 40 months (15-70), 15 patients (68%) remained continuously disease-free and 7 relapsed with metastases. No local recurrences were observed. Regimen 2 was slightly more effective than Regimen 1 in terms of good histologic response (5/10 vs 1/12) and continuous disease-free survival (8/10 vs 7/127). The results demonstrate that, as in osteosarcoma, in non-metastatic malignant fibrous histiocytoma of bone in the extremities a high percentage of patients can be cured with neoadjuvant chemotherapy and that in most of them limb sparing surgery is possible and safe.

Effect of perioperative transfusions on survival in osteosarcoma treated by multimodal therapy.

We report on a retrospective study of 155 patients amputated for nonmetastatic osteosarcoma of the long bones. Among the various prognostic variables considered, a significant correlation was found only between survival and transfusions. In this report, the authors consider some hypotheses reported by others for tumors of a different nature and site and conclude that perioperative transfusion may induce depression in the immune response, which is the cause of a shorter survival in the patients reviewed.