Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors.

BACKGROUND: Synovial sarcoma (SS) is a malignant soft tissue sarcoma with a poor prognosis because of late local recurrence and distant metastases. To our knowledge, no studies have minimum follow-up of 10 years that evaluate long-term outcomes for survivors. PATIENTS AND METHODS: Data on 62 patients who had been treated for SS from 1968 to 1999 were studied retrospectively in a multicenter study. Mean follow-up of living patients was 17.2 years and of dead patients 7.7 years. RESULTS: Mean age at diagnosis was 35.4 years (range 6-82 years). Overall survival was 38.7%. The 5-year survival was 74.2%; 10-year survival was 61.2%; and 15-year survival was 46.5%. Fifteen patients (24%) died of disease after 10 years of follow-up. Local recurrence occurred after a mean of 3.6 years (range 0.5-14.9 years) and metastases at a mean of 5.7 years (range 0.5-16.3 years). Only four patients were treated technically correctly with a planned biopsy followed by a wide resection or amputation. Factors associated with significantly worse prognosis included larger tumor size, metastases at the time of diagnosis, high-grade histology, trunk-related disease, and lack of wide resection as primary surgical treatment. CONCLUSIONS: In SS, metastases develop late with high mortality. Patients with SS should be followed for >10 years.

The additional value of CT images interpretation in the differential diagnosis of benign vs. malignant primary bone lesions with 18F-FDG-PET/CT.

OBJECTIVE: To evaluate the value of a dedicated interpretation of the CT images in the differential diagnosis of benign vs. malignant primary bone lesions with 18 fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT). MATERIALS AND METHODS: In 50 consecutive patients (21 women, 29 men, mean age 36.9, age range 11-72) with suspected primary bone neoplasm conventional radiographs and 18F-FDG-PET/CT were performed. Differentiation of benign and malignant lesions was separately performed on conventional radiographs, PET alone (PET), and PET/CT with specific evaluation of the CT part. Histology served as the standard of reference in 46 cases, clinical, and imaging follow-up in four cases. RESULTS: According to the standard of reference, conventional 17 lesions were benign and 33 malignant. Sensitivity, specificity, and accuracy in assessment of malignancy was 85%, 65% and 78% for conventional radiographs, 85%, 35% and 68% for PET alone and 91%, 77% and 86% for combined PET/CT. Median SUV(max) was 3.5 for benign lesions (range 1.6-8.0) and 5.7 (range 0.8-41.7) for malignant lesions. In eight patients with bone lesions with high FDG-uptake (SUV(max) >or= 2.5) dedicated CT interpretation led to the correct diagnosis of a benign lesion (three fibrous dysplasias, two osteomyelitis, one aneurysmatic bone cyst, one fibrous cortical defect, 1 phosphaturic mesenchymal tumor). In four patients with lesions with low FDG-uptake (SUV(max) < 2.5) dedicated CT interpretation led to the correct diagnosis of a malignant lesion (three chondrosarcomas and one leiomyosarcoma). Combined PET/CT was significantly more accurate in the differentiation of benign and malignant lesions than PET alone (p = .039). There was no significant difference between PET/CT and conventional radiographs (p = .625). CONCLUSION: Dedicated interpretation of the CT part significantly improved the performance of FDG-PET/CT in differentiation of benign and malignant primary bone lesions compared to PET alone. PET/CT more commonly differentiated benign from malignant primary bone lesions compared with conventional radiographs, but this difference was not significant.

Relevance of translocation type in myxoid liposarcoma and identification of a novel EWSR1-DDIT3 fusion.

The clinical course of myxoid/round cell liposarcoma (MRCL) is characterized by frequent local recurrences and metastases at unusual sites. MRCLs carry specific translocations, t(12;16) or rarely t(12;22), linking the FUS or the EWSR1 gene with the DDIT3 gene, respectively. Nine FUS/DDIT3 and three EWSR1/DDIT3 variants of fusion transcripts have been described thus far. In search of prognostic markers for MRCL, we analyzed the translocation types of 31 patients and related them to the event free and overall survival. Using break-apart FISH and RT-PCR combined with DNA sequencing, we detected FUS/DDIT3 fusions in 30 sarcomas, while an EWSR1/DDIT3 translocation was identified in one tumor. FUS/DDIT3 type II (exons 5-2) was most commonly detected (20 cases), followed by type I (7-2) (7 cases) and type III (8-2) (3 cases). A single tumor carrying a t(12;22) translocation expressed a hitherto unknown EWSR1-DDIT3 fusion transcript (13-3) linking the complete RNA-binding domain of EWSR1 with a short piece of the 5'-UTR and the entire open reading frame of the DDIT3 gene. Interestingly, five of six patients with type I (7-2) FUS/DDIT3 fusions displayed local recurrences and/or metastatic spread within the first 3 years, generally requiring chemotherapeutical treatment (median disease-free survival 17 months). In contrast, 9 of 13 patients with type II FUS/DDIT3 translocations remained at 3 years disease-free (median disease-free survival 75 months). Since the total number of patients is still limited, further studies are required to verify a putative association of type I FUS/DDIT3-fusion transcripts with a prognosis of MRCL.

Late solitary bone metastasis of a primary pulmonary synovial sarcoma with SYT-SSX1 translocation type: case report with a long follow-up.

Primary synovial sarcoma outside its classical presentation in para-articular soft tissue of young patients is rare but regularly reported. One of the rarest primary locations is the lung. We describe a 73-year-old female patient who presented with a solitary malignant bone tumor 8 years after the resection of a lung neoplasm. The bone tumor was classified as an osteosarcoma and the lung tumor as an atypical carcinoid tumor at their first respective diagnostic work-ups. The resection of the affected humerus with allograft and endoprosthesis implantation followed. Reevaluation of the tumor samples at the time of the local recurrence of the bone tumor 6 years following the initial symptoms of the bone tumor lead to the reclassification of both specimens as synovial sarcomas. Both neoplasms contained the SYT-SSX1 type of the diagnostic translocation t(X;18) as detected by the reverse-transcription polymerase chain reaction analysis. The patient died 14 years after the resection of the primary synovial sarcoma of the lung and 6 years following the occurrence of the bone metastasis. This prolonged clinical course is uncommon for the SYT-SSX1 translocation, which, in other locations, is usually associated with an unfavorable prognosis.

Expression of EDA+ and EDB+ fibronectin splice variants in bone.

The extracellular matrix component fibronectin (fn) has fundamental functions in cell attachment, differentiation, proliferation, and migration. Isoforms of cellular fibronectin, named EDA+ fibronectin or embryonal EDB+ fibronectin, are generated by alternative splicing of its mRNA precursors. Little is known about the expression of EDA+ and EDB+ fibronectin splice variants in human bone. The aim of this study was to investigate the expression pattern of fibronectin splice variants in bone cell lines and in different human bone tissue samples (mature bone, early stages of fracture healing, hypotrophic nonunion, osteosarcoma). Analysis was done by immunostaining with recombinant and monoclonal antibodies, qualitative RT-PCR and LightCycler-based real-time quantitative RT-PCR assay. In osteoblast and osteosarcoma cell lines, abundant expression of EDA+ and EDB+ fibronectin was found in immunocytochemistry. High transcription levels of both splice variants mRNA were seen in quantitative RT-PCR in osteosarcoma cell lines. In mature bone, EDA+ and EDB+ were not detectable in immunohistochemistry. Transcription of mRNA in both splice variants was absent in these samples. Early stages of fracture healing and osteosarcoma cell samples exhibited extensive staining for EDA+ and EDB+ fibronectin, and high mRNA levels were found. Both osteosarcoma and bone fracture healing tissue expressed high mRNA levels of the fibronectin splice variants independent of benign or malignant behavior. Low level of EDA+ fibronectin mRNA transcription and focal immunohistochemical staining of EDA+ fibronectin was found in hypotrophic nonunions, whereas EDB+ fibronectin was not detected by immunohistochemistry and qualitative or quantitative PCR. EDA+ fibronectin was found in granulation tissue-forming processes in bone independent from bone-forming activity. EDB+ fibronectin was seen only in high-turnover new osteoid-forming processes like early stages of fracture healing and osteosarcoma and was absent in low-turnover processes like mature bone and hypotrophic nonunion. Both EDA+ and EDB+ fibronectin mark active processes in bone without differentiation between malignant or benign activity. In conclusion, EDA+ and EDB+ fibronectin splice variants are strong markers for active fibrogenetic and osteoid-forming processes in human bones.

Tumor size and prognosis in aggressively treated osteosarcoma.

PURPOSE: The aim of this retrospective analysis was to investigate the prognostic significance and optimal measures of tumor size in osteosarcoma treated with intensive neoadjuvant chemotherapy. PATIENTS AND METHODS: Initial anterior-posterior (AP) and lateral x-ray films of 128 patients treated within the trials Cooperative Osteosarcoma Study (COSS)-80, -82, and -86, were evaluated for the following three tumor diameters: length, width, and depth. Metastasis-free survival (MFS) analyses were performed in univariate and multivariate models with one, two, and three dimensions of the tumor as absolute or relative measures (tumor length, referred to bone length, plane and volume to body-surface area). RESULTS: Univariate analyses of MFS showed a high prognostic significance of all absolute measures. Relative measures, at best, showed a comparable predictive value. Cox regression analysis indicated the high prognostic significance of absolute tumor volume (ATV; P < .0001) and histologic response (P < .0001). None of 19 patients with an ATV < or = 70 cm3 and only four of 53 with an ATV < or = 150 cm3 relapsed, while in patients with an ATV more than 150 cm3, the relapse rate remained 40% to 60%, irrespective of further increase in volume. CONCLUSION: Initial tumor size is an important and easily obtainable prognostic factor in osteosarcoma and may serve as a basis for risk-adapted therapy. It is best represented by the absolute three-dimensional measure ATV. There is a cut-off point regarding the incidence of metastases at a tumor volume of approximately 150 cm3 as calculated from two-plane x-ray films.

High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma.

The German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewing's sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m2 per day, days 1-5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m2 per day, days 1-5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m2 per day on days 1-3) or Adriamycin (30 mg/m2 per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) regime used in the previous CESS 81 trial.

Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial.

The German Society of Pediatric Oncology in 1981 initiated the Cooperative Ewing's Sarcoma Study (CESS 81) using a four-drug combination of chemotherapy prior to definitive local control with surgery and/or radiation. From January 1, 1981 until February 28, 1985, 93 patients were registered at the trial office from 54 participating institutions in West Germany, Austria, Switzerland, and the Netherlands. On February 1, 1987, 54 of 93 patients were disease-free. Using the Kaplan-Meier life table analysis, the estimated disease-free survival (DFS) rate was 60% at 36 months and 55% at 69 months. The median period of observation was 29 months, ranging from 22 months to 69 months. Twenty-one of 93 patients (23%) had local failure, 18 of 93 patients (19%) developed systemic metastases. The local failure rate was particularly high in patients treated with radiation and was reduced when radiation planning was centralized within the study based upon the extent of disease at diagnosis. Cox regression analysis of prognostic factors showed that tumor volume was a significant factor influencing prognosis. The estimated 3-year DFS rate was 80% for patients with small tumors (volume less than 100 ml) compared to 31% for patients with large tumors (volume greater than or equal to 100 ml). In patients who had surgery for local control, the histologic response to chemotherapy was analyzed on the surgical specimen and had a strong influence on survival: 79% DFS at 3 years for patients with less than 10% viable tumor (good responders) compared to 31% DFS for patients with more than 10% viable tumor (poor responders). Tumor load and responsiveness to chemotherapy are the two major factors influencing prognosis in patients with primary Ewing's sarcoma of bone.

Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide.

A boy, aged 7 months, of consanguineous parents presented with an acute onset of vomiting, fever, nonketotic hypoglycemia and acidosis and died from cardiac arrest after ventricular fibrillation. He had hepatomegaly and echocardiographically a non-obstructive cardiomyopathy. Autopsy was not allowed. After birth the child had suffered from a severe respiratory distress syndrome, transient metabolic acidosis and had a sweaty feet odour. Later on, development was retarded with a severe muscular hypotonia. Post mortem, numerous unusual organic acids were found in high concentrations in urine, e.g. dicarbonic acids, 2-hydroxyisobutyric, isovaleric, 3-hydroxyisovaleric acid, N-acyl glycines, isovalerylglutamic acid and sarcosine. This pattern indicated deficiencies of several acyl-Co A dehydrogenases in the metabolism of leucine, isoleucine, valine, lysine, short-chain fatty acids and sarcosine. This could be confirmed using cultured skin fibroblasts which were shown to degrade the corresponding labeled substrates insufficiently to 14CO2. It is assumed that the functional multiple acyl-Co A dehydrogenation deficiency is caused by a deficiency of a common link in the electron transfer system of these dehydrogenases which is inherited autosomal recessively in this family. Among the 12 patients reported, 7 died within the first 5 days of age.