Localized Myxofibrosarcoma: A Retrospective Analysis of Primary Therapy and Prognostic Factors in 134 Patients in a Single Institution.

BACKGROUND: Primary therapy of localized myxofibrosarcoma (MFS) remains controversial. Primary resection is complicated by a high rate of local recurrence, and the refractoriness to non-surgical treatment results in a higher risk of metastasis. The aim of the present study was to contribute the findings of a single sarcoma-specialized center and encourage investigating new treatment options. PATIENTS AND METHODS: We analyzed 134 patients treated with localized MFS in our center regarding prognostic factors defining overall survival, local recurrence, and metastasis. We focused on multimodal treatment of localized MFS: surgery, radiation, chemotherapy, hyperthermia, and isolated limb perfusion. RESULTS: The 5-year OS was 74.9%. From a total of 134 patients: 74 (55.2%) stayed disease free, 48 (35.8%) had a local recurrence (LR), and 23 (17.2%) developed a distant metastasis (DM). The 5-year LR-free survival (LRFS) and DM-free survival (DMFS) were 66.1% and 80.8%, respectively. Older age, tumor size (cT) cT ≥ 2, non-extremity localization, and distant metastasis were adverse predictive factors for OS. Performing an incision biopsy, surgery in a sarcoma-center, wide local excision or compartment-oriented excision, negative margins, and radiotherapy were positive predictive factors for LR. Tumor size cT ≥ 3 was a negative predictive factor for DM. Grading was a negative predictive factor for LR (G ≥ 2) and for DM (G3) in the multivariable analysis. CONCLUSION: Adjuvant radiation had a positive impact on LRFS in all localized tumor stages, even in cT1 tumors. Chemotherapy did not have a significant impact on DMFS, regardless of tumor stage. Our findings indicate that myxofibrosarcoma may be a chemotherapy-resistant entity and a much closer monitoring is required, in case of neoadjuvant treatment.

Osteosarcoma as a secondary malignancy following rhabdomyosarcoma: A report of 28 affected patients from the Cooperative Osteosarcoma Study Group (COSS).

BACKGROUND: Osteosarcoma may arise as a secondary malignancy following rhabdomyosarcoma (RMS). We utilized the Cooperative Osteosarcoma Study Group (COSS) database to better understand this association. PATIENTS AND METHODS: The COSS database (1980-05/2023) was searched for patients whose osteosarcoma was preceded by RMS. Eligible patients were analyzed for patient-, tumor-, and treatment-related variables as well as outcomes. RESULTS: The search revealed 28 eligible osteosarcomas (27 high-grade central, one periosteal; male:female = 16:12; median age RMS 2.1 [range: 0.9-10.0] years, osteosarcoma 13.5 [7.2-29.0] years). Genetic tumor-predisposition syndromes were documented in 12 patients. One patient had had a distinct malignancy prior to RMS, two intermittently, seven following osteosarcoma. Local RMS treatment had included radiotherapy in 20/26 cases (two unknown). Secondary osteosarcoma sites were extremity 13, trunk seven, head and neck eight; 15 osteosarcomas were radiation-associated. There was only one case of primary osteosarcoma metastases. Osteosarcoma treatment included chemotherapy (27), surgery (26), or radiotherapy (2). A macroscopically complete remission of all osteosarcoma sites was achieved in 24 cases. Median follow-up was 5.8 (range: 0.5-18.4) years after osteosarcoma and 8.1 (1.0-15.4) years for 14 survivors. Actuarial 5-year overall and event-free survival were 66% (standard error 9%) and 45% (10%), respectively. Five of 14 deaths were caused by further malignancies. CONCLUSION: This series offers a benchmark for patients who develop a secondary osteosarcoma after RMS. Affected patients are generally still in the pediatric age. The results obtained strongly argue for genetic predisposition testing in RMS and against therapeutic leniency in comparable situations.

H3F3A-mutated giant cell tumour of bone without giant cells-clinical presentation, radiology and histology of three cases.

AIMS: Giant cell tumour of bone (GCTB) is histologically defined as a lesion containing reactive giant cells and a neoplastic mononuclear cell population; in up to 92% of cases, GCTB is characterised by a specific mutation of the histone gene H3F3A. The cellular composition ranges from giant-cell-rich to giant-cell-poor. The diagnosis of GCTB can be challenging, and several other lesions need to be excluded, e.g. aneurysmal bone cysts, non-ossifying fibromas, chondroblastomas, brown tumours, and giant-cell-rich osteosarcomas. Our aim was to analyse the clinical history, imaging, molecular pathology and histology of three H3F3A-mutated bone tumours without detectable giant cells. None of the patients received denosumab therapy. METHODS AND RESULTS: Diagnostic material was obtained by curettage or resection and/or biopsy. Common histomorphological features of all three reported lesions were fibrocytic, oval cells in a background of osteoid and an absence of multinuclear giant cells as confirmed with CD68 immunohistochemistry. We used immunohistochemistry and Sanger sequencing to demonstrate positivity for the H3.3 p.G34W mutation. Differential diagnoses were systematically excluded on the basis of histomorphology, immunohistochemistry, and fluorescence in-situ hybridisation. The imaging (radiography, computed tomography, and magnetic resonance imaging) for all three cases is presented and discussed. CONCLUSIONS: We believe that these GCTBs without giant cells expand one end of the heterogeneous range of GCTB. Because of the lack of giant cells, correct diagnosis of GCTB is challenging or even impossible on histological grounds alone. In these cases, detection of the characteristic H3F3A mutation (G34W-specific antibody RM263 or sequencing) is extremely helpful for diagnosing those lesions without giant cells as giant cell tumours of bone.

Osteoporosis Caused by Systemic Mastocytosis: Prevalence in a Cohort of 8392 Patients with Osteoporosis.

Indolent systemic mastocytosis (ISM) is a group of heterogenous diseases characterized by abnormal accumulation of mast cells in at least one organ. ISM can be a cause of osteoporosis. The aim of this study is to determine the prevalence, and the prognosis of ISM in a cohort of patients with osteoporosis. In this monocentric and retrospective study, patients with osteoporosis who did not receive a bone biopsy (cohort 1) and patients that subsequently received a diagnostic bone biopsy for differential diagnosis (cohort 2) are compared with patients who are diagnosed with ISM (cohort 3). A total of 8392 patients are diagnosed with osteoporosis. Out of these patients 1374 underwent a diagnostic bone biopsy resulting in 43 patients with ISM. These figures indicate that ISM is diagnosed in 0.5% of patients with osteoporosis and in 3.1% (men 5.8%) of patients who underwent bone biopsies. Patients with ISM sustained significantly more vertebral fractures in comparison to patients in cohort 2 (4.4 ± 3.6 versus 2.4 ± 2.5 vertebral fractures, p < 0.001) and women were significantly younger compared to cohort 2 (57.3 ± 12 versus 63.6 ± 12 years, p < 0.05). Only 33% showed an involvement of the skin (urticaria pigmentosa). ISM is a rare cause of osteoporosis (0.5%). However, in a subgroup of rather young male patients with osteoporosis the prevalence is more than 5%. Thus, ISM should be considered in premenopausal women and men presenting with vertebral fractures even if urticaria pigmentosa is not present.

Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and α-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor.

Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.

Metastatic Potential of Grade I Chondrosarcoma of Bone: Results of a Multi-institutional Study.

BACKGROUND: Little is known about the metastatic potential of low-grade chondrosarcoma. This study was designed to evaluate the rate of metastasis to identify possible risk factors. METHODS: The files of 225 patients with newly diagnosed, grade I chondrosarcoma of bone treated between 1975 and 2012 were retrospectively analyzed. Median follow-up was 80 months for survivors (range 24-445 months). Nonparametric analyses were performed with the Mann-Whitney U test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: Fourteen patients developed metastases after a median of 49 months. Metastasis-free survival probability (MFS) was 95 % at 5 years and 92 % at 10 years. Post-metastasis survival probability amounted to 27 % after 5 years. Tumor size at diagnosis (P = 0.698) and surgical margin width (P = 0.514) had no influence on MFS. Patients who developed local recurrences had a significantly lower 10-year MFS than patients without recurrences (69 % vs. 99 %, P < 0.001). Patients with grade I recurrences had a significantly poorer MFS than patients without recurrences (P = 0.013) but a significantly higher MFS than patients with grade II recurrences (P = 0.006). Patients with thoracic wall tumors had a significantly lower 10-year MFS of 66 % compared with patients with tumors of the upper (100 %, P < 0.001) and lower extremity (93 %, P = 0.033). CONCLUSIONS: The biological behavior of low-grade chondrosarcoma appears to be more consistent with the WHO definition of rarely metastasizing bone tumors, rather than the one of locally aggressive neoplasms. Thoracic wall tumors and the development of local recurrences were associated with a higher metastasis rate in this study.

Histological response assessment following neoadjuvant isolated limb perfusion in patients with primary, localised, high-grade soft tissue sarcoma.

PURPOSE: Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis. PATIENTS AND METHODS: This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P = 0.227) or event-free (EFS) (P = 0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P < 0.001), EFS (P = 0.002) and post-relapse survival probability (P = 0.030) compared to patients with an intermediate or high mitotic count. CONCLUSIONS: The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP.

Is vitamin D insufficiency or deficiency related to the development of osteochondritis dissecans?

PURPOSE: The aetiology of osteochondritis dissecans is still unclear. The aim of this prospective pilot study was to analyse whether vitamin D insufficiency, or deficiency, might be a contributing etiological factor in the development of an OCD lesion. METHODS: The serum level of vitamin D3 in 23 consecutive patients (12 male and 11 female) suffering from a stage III, or stages III and IV, OCD lesion (mostly stage III) admitted for surgery was measured. RESULTS: The patients' mean age was 31.3 years and most of them already exhibited closed epiphyseal plates. In the majority of patients (18/23), a distinct vitamin D3 deficiency was found, two patients were vitamin D3-insufficient and, in three patients, the vitamin D3 level reached the lowest normal value. CONCLUSION: These first data show that a vitamin D3 deficiency rather than an insufficiency may be involved in the development of OCD lesions. Probably, with a vitamin D3 substitution, the development of an advanced OCD stage could be avoided. Further analyses, including morphological analyses regarding a possible osteomalacia, and examination of the PTH and other determinants of the bone metabolism, should be undertaken to either confirm or refute these data. LEVEL OF EVIDENCE: IV.

Osteosarcoma in patients with Rothmund-Thomson syndrome.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited. PROCEDURE: Seven patients with osteosarcoma, treated in the Cooperative Osteosarcoma Study Group-trials, had a diagnosis of RTS. Their patient-, tumor- and treatment-related variables and outcome were reviewed retrospectively. RESULTS: Median age at diagnosis of osteosarcoma was 13 years (range 7-16), five were female, two male. Tumor involved proximal tibia (n = 4), distal tibia (n = 1), distal fibula (n = 1) and proximal ulna (n = 1). Three patients had metastatic disease at diagnosis. All patients received surgery and chemotherapy. Four of seven patients required dose modifications and three of them terminated treatment prematurely. Complete resection of the primary tumor was achieved in all individuals. Two of three affected patients failed to achieve surgical clearance of their primary metastases and died. The third patient relapsed with multiple metastases and died. Two of four patients with localized disease were alive in first complete remission, a third patient in second complete remission after recurrence and a fourth patient died of acute leukemia, while still in first complete remission of osteosarcoma. CONCLUSIONS: Patients with RTS and osteosarcoma may be cured of their cancer with appropriate multimodal therapy. They should be treated like other osteosarcoma patients but preexisting disorders, needs for special support and development of toxicities have to be considered.