Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup

Large randomised trials are mandatory when one wants to examine the effects of different aspects (such as the treatment modality) of a pathological condition on the overall outcome. This is especially true when studying a disease in which there is a multifactorial influence on progression and outcome such as osteosarcoma. Data on 570 patients with biopsy-proven primary central osteosarcoma of an extremity included in two consecutive studies of the European Osteosarcoma Intergroup (EOI) were analysed in order to evaluate if the histological subtype of the biopsy specimen correlated with the subtype of osteosarcoma represented in the resected specimen, if there was a relationship between the histological subtype and overall survival and if there was a relationship between the histological subtype and histological response to chemotherapy. High-grade osteosarcoma, as defined by established criteria, was subtyped as either conventional, chondroblastic, teleangiectatic, small cell, fibroblastic, osteoclast rich, anaplastic and sclerotic/osteoblastic well differentiated. A panel of experienced pathologists with a special interest in bone pathology was appointed to review the histological diagnosis and to assess the tumour response to chemotherapy on the resected specimen of each patient entered into the trials. Subtyping on the biopsy specimen proved to be highly representative for the subtype of the whole tumour. In 102 patients for which subtyping was performed on the biopsy and the resected specimens, there were only two discrepancies. Of the 568 patients for whom subtype was available, 404 (71%) were of the conventional type, 54 (10%) were chondroblastic, 53 (9%) had fibroblastic tumours and the remainder consisted of rare subtypes. A good response to preoperative chemotherapy was defined as 90% or more necrosis. The proportion of patients responding well to chemotherapy differed significantly between subtypes (Chi-square test statistics=11.44, P=0.01 on 3 degrees of freedom (d.f.)). In comparison with the conventional subtype, there was a higher proportion of good responders in the fibroblastic group and a lower proportion of good responders in the chondroblastic group. Good responders had a significantly better survival than patients who responded poorly to the pre-operative chemotherapy (logrank statistic=25.20, P<0.01 on 1 df). Survival did not differ significantly according to subtype (logrank statistic=2.72, P=0.44 on 3 df), although there was a suggestion that patients with chondroblastic tumours experienced a better long-term survival. This large set of prospectively-collected data provides important information on the relationship between pathological subtype, histological response and survival. Histological response has a known prognostic effect on survival, and we have shown that the rates of response differ by subtype. There is some evidence from this study that the specific histological subtypes, i.e. the chondroblastic subtype, experience better survival. However, despite this large multi-institutional study, we have insufficient numbers of non-conventional tumours to examine this unambiguously for these subsets.     

Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.     

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.     

Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: Analogies and differences between the two tumors

Background: Malignant fibrous histiocytoma (MFH) is a rare bone tumor usually treated like osteosarcoma. Studies on analogies and differences between the two tumors have seldom been reported.Patients and methods: Between March 1982 and December 1994, 51 patients with high-grade MFH of bone and 390 with high-grade osteosarcoma were treated with the same regimen of neoadjuvant chemotherapy. All of the tumors in both groups were located in the limbs. Preoperative chemotherapy was performed according to three different, successively activated, regimens consisting of MTX/CDP intraarterially, MTX/CDP/ADM, and MTX/CDP/ADM//IFO.Results: The rate of limb salvage was the same in both the MFH (92%) and osteosarcoma (85%) patients. MFH showed a statistically significantly lower rate of good histologic response, 90% or more tumor necrosis (27% vs. 67%, P = 0.00001) for all three regimens. Despite this low chemosensitivity, the disease-free survivals of the two neoplasms were similar (67% vs. 65%).Conclusions: In terms of histologic response to primary chemotherapy, MFH has a lower chemosensitivity than osteosarcoma. Nevertheless, the two tumors have similar prognoses when treated with chemotherapy regimens based on MTX, CDP, ADM and IFO.     

Prognostic significance of serum alkaline phosphatase in osteosarcoma of the extremity treated with neoadjuvant chemotherapy: recent experience at Rizzoli Institute.

In 560 patients with high-grade osteosarcoma of the extremity treated with 5 different protocols of neoadjuvant chemotherapy at a single institution between 1983 and 1995, the pre-treatment serum alkaline phosphatase (SAP) was examined to evaluate whether the enzyme levels had a clinical value in predicting the course of the disease. SAP was normal in 302 (54%) patients and high in 258 (46%). High levels of SAP was observed significantly and independently more frequently in male patients over 14-years-old, and in tumours larger than 150 ml and of osteoblastic subtypes. The 5-year event-free survival (EFS) and overall survival (OS) for all patients were respectively 60 and 68%. With multivariate analysis only two factors were independently correlated with the 5-year EFS: SAP levels (p=0.002) and the grade of chemotherapy-induced necrosis (p=0.0001). The authors conclude that in planning randomized clinical trials of neoadjuvant treatment for osteosarcoma, patients should be stratified according to SAP levels, and that when tailoring the aggressiveness of postoperative chemotherapy to the risk of relapse, in addition to the histologic response to preoperative treatment, the SAP levels should also be considered.     

Therapeutic response of various histological osteosarcoma subtypes to high-dose methotrexate treatment

The successful or unsuccessful chemotherapy of osteosarcoma has given rise to the division of these tumors into responders and non responders from the clinical point of view. In order to work out drug sensitive tumor components we studied 9 osteosarcomas by a histological subdivision of the osteosarcoma tissue into 6 subtypes. Seven of the 9 osteosarcoma patients had developed lung metastases under adjuvant high dosage methotrexate (HDMTX) therapy. The aim was to identify the components of the primary tumors which had endured HDMTX-therapy as lung metastases. As HDMTX-sensitive histologic differentiation form of osteosarcoma tissue we regarded the no matrix producing-subtype (III), because it did not occur in the lung metastases. The classical subtype (IV) seems to be only partially sensitive because the corresponding lung metastases showed a higher osteoblastic differentiation with increased osteoid production. No therapeutic effect could be observed in the chondromatous (I) and in the sarcomatous (II) subtypes as well as in the two subtypes with intensive osteoid production being termed trabecularly sclerosing (V) and massively osteoid producing subtypes (VI).     

Telomerase activity in juxtacortical and conventional high-grade osteosarcomas: correlation with grade,proliferative activity and clinical response to chemotherapy

Seven samples from seven patients with juxtacortical osteosarcomas, and 27 samples from 19 patients with conventional high-grade osteosarcomas were investigated for a possible correlation between telomerase activity and clinicopathological features such as age, sex, and response to chemotherapy. Of seven juxtacortical osteosarcomas, telomerase activity was weakly positive in three parosteal osteosarcomas, and highly positive in one parosteal osteosarcoma. In contrast, of 27 conventional high-grade osteosarcomas, telomerase activity was weakly positive in eight tumors and highly positive in three. Of all samples, 44.1% of the osteosarcomas showed telomerase activity (57.1% of juxtacortical and 40.7% of conventional osteosarcomas). The majority of poor responders to chemotherapy showed no telomerase activity (nine of 11), whereas five of seven good responders showed strong or weak telomerase activity. There was a significant correlation between telomerase activity and the response to chemotherapy (P<0.05). Telomerase activity was not correlated with MIB-1 proliferation index, age at the time of surgery, or sex. These findings suggest that telomerase activation occurs early in the oncogenesis of osteoblastic tumors without having an effect on the progression of these tumors. In malignant osteoblastic tumors, the biological significance of telomerase activation is different from that described for most epithelial cancers.     

骨肉瘤肺转移手术后的生存预测因素分析

目的：评估骨肉瘤患者肺部转移（ PM）完全切除（ CR）后的预后因素。方法回顾性分析62例转移性骨肉瘤患者接受治疗和随访的资料。单因素和多因素分析转移性骨肉瘤的人口统计学和疾病相关的特性对总体生存（ OS）的影响。结果总共有25例PM患者行完全切除,并纳入分析。5年OS和无病生存率分别为30％和21％。单变量分析较差的OS相关的因素包括软骨细胞亚型,后化疗原发肿瘤坏死＜90％,新辅助或辅助化疗期间检测到转移,病理识别肿瘤细胞达到任何切除结节的内脏胸膜表面。在多变量分析中,软骨细胞亚型是唯一的独立的不良预后因素（ HR＝4．6,95％CI：1．0～21．3,P＝0．044）。结论肿瘤生物学相关的因素,原发肿瘤坏死不彻底,化疗期间癌细胞转移,软骨细胞亚型和内脏胸膜受累都是手术预后差的相关因素。     

Expression of Snail2 in long bone osteosarcomas correlates with tumour malignancy

Snail2 is a marker of malignancy in epithelial tumours; however, in sarcomas, it is not known if this protein is present. Here we examine the expression of Snail2 in one type of sarcoma, osteosarcoma, and explore its relationship to tumour grade, subtype and anatomical location in cases of long bone and cranial bone osteosarcoma. Long bone osteosarcomas typically have a much greater metastatic capability and a poorer prognosis. We find that Snail2 is expressed in the three main subtypes of long bone osteosarcoma—osteoblastic, chondroblastic and fibroblastic. Regression analysis showed that Snail 2 expression was statistically correlated with tumour grade (p = 0.014) in all of these subtypes. Snail2 was only expressed in high-grade cranial bone osteosarcomas, suggesting a link between Snail2 expression and metastasis. This is the first time Snail2 has been associated with any sarcoma, and this study shows that Snail2 may be a useful prognostic marker for this disease.     

Relationship between changes in the histologic subtype of small cell carcinoma of the lung and the response to chemotherapy

It has been documented that changes in the histopathologic subtype of small cell carcinoma of the lung (SCCL) may occur after chemotherapy. The significance of such changes with respect to response to treatment has not yet been studied. In a retrospective review of 25 patients, we correlated their response from chemotherapy with morphologic changes seen in subsequent histologic material. Eleven patients responded to therapy and 14 failed to respond. A difference in original histologic subtype was found in 10 (71%) of the nonresponders and in only two (18%) of the responders. The difference was statistically significant (p less than 0.05). We conclude that patients with "pure" SCCL in the initial biopsy specimen who fail to respond to chemotherapy are likely to have mixed or combined histologic subtypes in subsequent tissue specimens, although we cannot preclude their pre-existence. An attempt to search for different histologic subtypes is warranted in patients who do not respond to chemotherapy regimens considered to be efficacious in SCCL.     

Prognostic relevance of increased angiogenesis in osteosarcoma.

PURPOSE: The purpose of this work was to evaluate the prognostic relevance of microvessel density (MVD) for response to chemotherapy and long-term outcome in osteosarcoma. EXPERIMENTAL DESIGN: Pretherapeutic tumor biopsies of 60 patients with high-grade central osteosarcoma, who were treated according to multimodal neoadjuvant protocols of the German-Austrian-Swiss Cooperative Osteosarcoma Study Group, were evaluated for intratumoral MVD. MVD was correlated with demographic and tumor-related variables, response, and survival. RESULTS: The median intratumoral MVD was 52 microvessels per 0.26-mm2 field area (interquartile range, 31-77 microvessels per 0.26-mm2 field area). At a median follow-up period of 3.5 years, patients with a high (>median) MVD had significantly higher 5- and 10-year overall survival rates (84%) than patients with low (< or =median) MVD (49%; P = 0.0029). Furthermore, increased relapse-free survival for patients with high MVD (P = 0.0064) was observed. In a subgroup analysis of 44 patients with primary high-grade central osteosarcoma of the extremities without primary metastases and good surgical remission, high MVD was associated with 5- and 10-year overall survival rates of 91% compared with 58% for low MVD (P = 0.034). Cox regression analysis revealed that MVD was an independent prognostic factor for survival. A good response to chemotherapy (histologic grading scale of Salzer-Kuntschik) correlated significantly with a high MVD (P = 0.006). CONCLUSIONS: Increased angiogenesis is a prognostic indicator for higher survival and response rates to chemotherapy in patients with osteosarcoma. Thus, measurement of MVD might be useful in decisions selecting patients for future neoadjuvant treatment.     

Dedifferentiated parosteal osteosarcoma: the experience of the Rizzoli Institute

BACKGROUND: Dedifferentiated parosteal osteosarcoma (DPOS) is a variant of osteosarcoma in which a high-grade sarcoma coexists with a conventional parosteal osteosarcoma (c-POS), either at presentation (synchronous type) or at the time of recurrence (metachronous type). Only approximately 60 patients have been reported in the literature. The objective of this study was to analyze the clinicopathologic and radiographic features of a relatively large number of patients with DPOS in an attempt to define further the histologic and biologic behavior of this rare entity. METHODS: In a series of 120 patients with parosteal osteosarcoma who were seen at the Rizzoli Institute from 1958 to 2000, the authors identified 29 patients who were diagnosed with DPOS. The authors reviewed the clinical and radiologic features, histologic sections, treatments, and outcomes in this group of patients with DPOS. RESULTS: Twelve patients were male, and 17 patients were female. The patients ranged in age from 15 years to 65 yrs (average, 36 years; median, 32 years). One tumor involved the scapula, one involved the ilium, and another involved the skull. All 26 of the other tumors were located in the long bones (14 in the femur, 5 in the humerus, 3 in the tibia, 3 in the fibula, and 1 in the ulna). In 18 patients, radiographic areas of lucency were seen within an otherwise sclerotic lesion. Histologically, the dedifferentiated component was high-grade osteoblastic osteosarcoma in 14 patients, fibroblastic osteosarcoma in 10 patients, giant cell-rich osteosarcoma in 3 patients, and chondroblastic osteosarcoma in 2 patients. All tumors were Stage IIB, and invasion of the medullary canal was detected in 19 patients (65%). Twenty-eight patients underwent surgery, and 18 of those patients received chemotherapy (5 patients received neoadjuvant chemotherapy, and 13 patients received adjuvant). Nine patients were dead and 20 patients were alive (average follow-up, 107 months; range, from 3 months to 36 years) at the last follow-up. Of the nine patients who died, one patient received no treatment, five patients underwent surgery (with three patients achieving adequate margins) in combination with chemotherapy, and three patients underwent surgery only (with adequate margins achieved). Of the 20 patients who remained alive, 13 patients underwent surgery (with 10 patients achieving adequate margins) in combination with chemotherapy, whereas 7 patients underwent surgery only (all with adequate margins). Seven of the nine patients who died had widespread metastases. One patient died of causes unrelated to the tumor, and another patient died shortly after undergoing resection of a lesion in the skull. CONCLUSIONS: Dedifferentiation occurred in approximately 24% of patients with c-POS. The prognosis for patients with DPOS was better than the prognosis for patients with dedifferentiated central and dedifferentiated peripheral chondrosarcoma.     

Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution

BACKGROUND: The evaluation variables influencing systemic and local recurrence and final outcome are extremely important in defining risk-adapted treatments for patients with nonmetastatic osteosarcoma of the extremity. METHODS: A homogeneous group of 789 patients treated at a single institution between March 1983 and March 1999 with different protocols of neoadjuvant chemotherapy, with a minimum followup of 5 years, were retrospectively evaluated in relation to gender, age, serum levels of alkaline phosphatase, tumor site and size of the pathologic fracture, type of surgery, protocol of chemotherapy, surgical margins, and histologic response to preoperative treatment. RESULTS: The 5-year event-free survival (EFS) and overall survival rates were 60.1% and 67.5%, respectively. Upon univariate analysis, EFS was significantly related to the age of patients, serum value of alkaline phosphatase, tumor volume, histologic subtype, type of surgery, surgical margins, histologic response to preoperative treatment, and chemotherapy protocol. Local recurrences (4.8%) were significantly correlated with surgical margins. The 5-year post-recurrence EFS survival was 17% and was significantly lower for patients who had a local recurrence and metastases than for those with metastases only. Patients who had a recurrence only in the lung had a post-recurrence survival rate significantly better than others, correlated with the number of metastatic nodules and the length of the disease-free interval. CONCLUSIONS: Upon multivariate analysis, age < or = 14 years, high serum levels of alkaline phosphatase, tumor volume > 200 mL, a two-drug regimen chemotherapy, inadequate surgical margins, and poor histologic response to treatment maintained independent prognostic values on the outcome of nonmetastatic osteosarcoma of the extremities. These factors must be considered when deciding risk-adapted treatments for osteosarcoma patients.     

Pre- and post-chemotherapy alkaline phosphatase levels as prognostic indicators in adults with localised osteosarcoma

The prognostic value of alkaline phosphatase (AP) measured before and after chemotherapy, but before surgery was established in a retrospective survey of patients. The patients were 18 years or older, with non-metastatic high-grade osteosarcoma. Pre-chemotherapy AP was available in 89 cases, post-chemotherapy AP in 86 patients, and both in 71 cases. AP was classified as Normal (<100% upper limit), High (100% AP < 200%) or Very High (AP 200%). Osteosarcoma subtype was predominantly conventional. No correlation was found between subtype and chemotherapy response, local recurrence or survival. Pre-chemotherapy AP was raised more in the osteoblastic subtype. Post-chemotherapy AP and normalisation were the same among different subtypes. AP was not correlated with local recurrence. Normal or High pre-chemotherapy AP correlated with better survival at 10 years (64% and 70%) than Very High pre-chemotherapy AP (37%, P = 0.005). Post-chemotherapy AP correlated with survival (68%, 39% and 25% in the Normal, High and Very High group, P = 0.0007) and response to chemotherapy (P = 0.049). A pre-chemotherapy AP above twice Normal correlated with worse survival. If AP decreased after chemotherapy, but was still raised, survival was better, but still worse than if AP normalised. A raised post-chemotherapy AP predicts poor chemotherapy response.     

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.     

Relationship between P-glycoprotein positivity, doxorubicin binding ability and histologic response to chemotherapy in osteosarcomas.

We previously reported that the doxorubicin binding ability detected by the doxorubicin (adriamycin) binding assay was closely correlated with the chemosensitivity of human osteosarcomas. In this study, we undertook to clarify the relationship between P-glycoprotein positivity (%PPG) and doxorubicin binding ability (%DB) in human osteosarcomas in order to determine which is a more sensitive index of histologic response to chemotherapy. Ten primary osteosarcomas were analyzed by the doxorubicin binding assay and by immunofluorescence to detect cellular P-glycoprotein positivity. Three good responders to chemotherapy containing doxorubicin showed a %DB greater than 90% (average: 96.43%), whereas the seven poor responders had values less than 80% (average: 35.31%). The difference between the two groups was statistically significant (P = 0.0167). However, the average %PPG of the three good responders was 6.73%, whereas the %PPG of the seven poor responders was 14.27%. There was no significant difference in %PPG between the two groups (P = 0.3051). No negative correlation between the %DB and the %PPG of all osteosarcomas (r = 0.536, P = 0.1104) was found, although there was a trend that those tumors with a high %PPG showed a low %DB. These results suggest that osteosarcomas showing a low %DB and %PPG with poor response to chemotherapy, may have multidrug resistance mechanisms other than P-glycoprotein. Therefore, we conclude that doxorubicin binding ability, which reflects all of the doxorubicin-resistant mechanisms, was more sensitive than P-glycoprotein positivity in predicting the chemosensitivity of human osteosarcoma.     

Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases

The clinical records and histopathologic features in 26 cases of extraskeletal osteosarcoma (ESOS) diagnosed at M.D. Anderson Cancer Center (Houston) between 1950 and 1987 were reviewed. Presentation was usually that of an enlarging soft tissue mass. The thigh (11 cases), upper extremity/shoulder girdle (three cases), and retroperitoneum (three cases) were the most common anatomic sites. Tumor size ranged from 2.5 to 30 cm. The predominant histologic pattern was osteoblastic in four cases, chondroblastic in two, fibroblastic or pleomorphic malignant fibrous histiocytoma (MFH)-like in four, giant cell type MFH-like in one, and small cell in one. Various mixtures of these patterns were seen in the remaining 14 tumors. The telangiectatic pattern was not seen as the predominant component in any primary tumor but was observed as a minor component. Thirteen tumors recurred locally and 16 metastasized; five patients had distant metastases at presentation. The lungs, bone, and soft tissue were the most frequent metastatic sites. Sixteen patients died of disease at 2 to 54 months, one patient died of unrelated causes at 61 months, seven patients were alive with no evidence of disease (NED) at 30 to 122 months, and two patients were alive with disease at 28 and 54 months, respectively. Tumor size (less than 5 cm versus greater than or equal to 5 cm) was the main prognostic factor; all patients alive with NED for whom accurate tumor measurements were available (six of seven) had neoplasms measuring less than 5 cm that were amenable to complete surgical excision. Histologic pattern and other clinicopathologic features did not significantly affect outcome.     

Telangiectatic osteosarcoma: the St. Jude Children's Research Hospital's experience

BACKGROUND: Telangiectatic osteosarcoma (TOS) is a rare subtype of osteosarcoma (OS). The authors reviewed their experience with TOS to characterize its histologic, radiologic, and clinical features. METHODS: The authors reviewed records, pathology material, and imaging studies from all patients with TOS who were treated between 1978 and 2005 and compared their outcomes with the outcomes of patients with all other subtypes of high-grade osteosarcoma (OS). RESULTS: Among 323 patients with OS, 22 patients (6.8%) had TOS. Two additional patients who were treated in Chile on a recent OS trial were included. The median age at diagnosis of the 24 patients was 15.7 years. Four patients (17%) had metastatic disease, and 9 of 21 patients (43%) had pathologic fractures. Only 5 patients (who were treated after 1994) underwent limb-salvage surgery. Estimates of 5-year event-free survival (58.3% +/- 11.9%) and overall survival (66.8% +/- 11.6%) were similar to those for patients with other OS subtypes (P > or = .85). The absence of local disease progression and chemotherapy with > or =3 agents that were active against OS were correlated with improved outcome (P < or = .005). The presence of a pathologic fracture was not associated with surgery type or patient outcome. CONCLUSIONS: TOS was associated with a high rate of pathologic fracture. With multimodality therapy, the outcome of patients with TOS was similar to that of patients with other high-grade OS subtypes. The absence of local disease progression and chemotherapy with > or =3 active agents were associated with a favorable outcome.     

Initial tumor size predicts histologic response and survival in localized osteosarcoma patients

BACKGROUND: To evaluate the correlation between histologic response and size parameters, and to analyze the prognostic importance of size parameters on metastasis-free survival in localized osteosarcoma patients. METHODS: We retrospectively reviewed 331 patients with stage II osteosarcoma treated with surgery and chemotherapy. The tumor size parameters were measured and calculated based on MR images. The mean metastasis-free interval was 77.8 months (range, 3-205 months; median, 67 months). RESULTS: Tumor size is best defined by relative tumor plane (RTP). Patients with a large tumor (RTP>27.5 cm2/m2) had a significant correlation with poor histologic response and distal femoral tumor location. The independent prognostic factors for metastasis-free survival were American Joint Committee on Cancer (AJCC) stage, RTP, proximal humerus location, chondroblastic subtype, and poor histologic response. CONCLUSION: The initial tumor size is closely related to histologic response and is an important prognostic factor in osteosarcoma. Tumor size is best represented by AJCC stage and RTP. These parameters may serve as a basis for risk-adapted therapy in combined stratification with histologic response.     

Evaluation of chemotherapy response in pediatric bone sarcomas by [F-18]-fluorodeoxy-D-glucose positron emission tomography

BACKGROUND: Response to neoadjuvant chemotherapy is a significant prognostic factor for osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT). Conventional radiographic imaging does not discriminate between responding and nonresponding osseous tumors. [F-18]-fluorodeoxy-D-glucose (FDG) positron emission tomography (PET) is a noninvasive imaging modality that accurately predicts histopathologic response in patients with various malignancies. To describe the FDG PET imaging characteristics and to determine the correlation between FDG PET imaging and chemotherapy response in children with bone sarcomas, we reviewed our single institution experience. METHODS: Thirty-three pediatric patients with OS or ESFT with osseous primary sites were evaluated by FDG PET. All patients received standard neoadjuvant chemotherapy. FDG PET standard uptake values before (SUV1) and after (SUV2) chemotherapy were analyzed and correlated with chemotherapy response assessed by histopathology in surgically excised tumors. Twenty-six patients had SUV1, SUV2, and surgical excision. RESULTS: Although the mean SUV1 in children with OS or ESFT were similar (8.2. vs. 5.3, P = 0.13), mean SUV2 for OS patients was greater than the values for ESFT patients (3.3 vs. 1.5, P = 0.01). All ESFT patients and 28% of OS patients had a favorable histologic response to chemotherapy (>or= 90% necrosis). Combining ESFT and OS patients, both SUV2 and the ratio of SUV2 to SUV1 (SUV2:SUV1) were correlated with histologic response (P = 0.01 for both comparisons). CONCLUSION: FDG PET evaluation of pediatric bone sarcomas demonstrated significant alteration in response to neoadjuvant chemotherapy. SUV2 and SUV2:SUV1 correlated with histopathologic assessment of response and potentially could be used as a noninvasive surrogate to predict response in patients.