Underlying synovial sarcoma undiagnosed for more than 20 years in a patient with regional pain: a case report.

Synovial sarcoma (SS) is a malignant tumor comprising 5-10% of all soft tissue sarcomas. SS has distinct characteristics, such as a predilection for young adults and relatively slow growth compared to other soft tissue sarcomas. Some patients with SS experience long-standing pain at the tumor site before the development of a palpable mass. Herein, we report the case of a 39-year-old woman with SS in the upper arm who presented with pain for > 20 years. The tumor detected on magnetic resonance imaging at 17 years was an SS. To the best of our knowledge, no English-language reports on imaging study-based identification of SS, which was undiagnosed for > 20 years, are known in the literature. This report discusses the imaging features of this latent lesion and the volume-doubling time of this unusual tumor.

Diagnostic accuracy of fine needle aspiration cytology and core needle biopsy in bone and soft tissue tumor: A comparative study of the image-guided and blindly performed procedure.

INTRODUCTION: Fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) can provide tissue samples for the diagnoses of bone and soft tissue tumors. We evaluated the diagnostic accuracy of FNAC and CNB, the usefulness of the image-guided needle procedures, and assessed whether a discordance can influence the prognosis. PATIENTS AND METHODS: We retrospectively examined the accuracy rates of FNAC and CNB procedures by analyzing results of 405 specimens of 389 patients. We evaluated the diagnostic accuracy of FNAC and CNB, compared the clinical effectiveness between the image-guided procedures and the blind procedures, and also compared survival rates between the true positive and the false negative cases for patients with high-grade malignant tumors. RESULTS: The accuracy rates of FNAC were 86.6% and 93.8% for CNB. In cases with non-palpable masses, there were significantly low sampling error rates in the image-guided procedure. There were no significant differences in progression-free-survival and overall survival rates in patients between the false negative and true positive cases. CONCLUSION: Both FNAC and CNB procedures had high accuracy rates. Limited to cases with no palpable masses, the image-guided procedure had a low sampling error rate and was an effective method for obtaining tissue samples.

Human leukocyte antigen I is significantly downregulated in patients with myxoid liposarcomas.

The characteristics of the tumor immune microenvironment remains unclear in liposarcomas, and here we aimed to determine the prognostic impact of the tumor immune microenvironment across separate liposarcomas subtypes. A total of 70 liposarcoma patients with three subtypes: myxoid liposarcoma (n = 45), dedifferentiated liposarcoma (n = 17), and pleomorphic liposarcoma (n = 8) were enrolled. The presence of tumor infiltrating lymphocytes (CD4+ , CD8+ , FOXP3+ lymphocytes) and CD163+ macrophages and expression of HLA class I and PD-L1 were assessed by immunohistochemistry in the diagnostic samples; overall survival and progression-free survival were estimated from outcome data. For infiltrating lymphocytes and macrophages, dedifferentiated liposarcoma and pleomorphic liposarcoma patients had a significantly higher number than myxoid liposarcoma patients. While myxoid liposarcoma patients with a high number of macrophages were associated with worse overall and progression-free survival, dedifferentiated liposarcoma patients with high macrophage numbers showed a trend toward favorable prognosis. Expression of HLA class I was negative in 35 of 45 (77.8%) myxoid liposarcoma tumors, whereas all dedifferentiated liposarcoma and pleomorphic liposarcoma tumors expressed HLA class I. The subset of myxoid liposarcoma patients with high HLA class I expression had significantly poor overall and progression-free survival, while dedifferentiated liposarcoma patients with high HLA class I expression tended to have favorable outcomes. Only four of 17 (23.5%) dedifferentiated liposarcomas, two of eight (25%) pleomorphic liposarcomas, and no myxoid liposarcoma tumors expressed PD-L1. Our results demonstrate the unique immune microenvironment of myxoid liposarcomas compared to other subtypes of liposarcomas, suggesting that the approach for immunotherapy in liposarcomas should be based on subtype.

Minimally Invasive Spinal Stabilization with Denosumab before Total Spondylectomy for a Collapsing Lower Lumbar Spinal Giant Cell Tumor.

A 21-year-old man consulted our hospital for treatment of a spinal giant cell tumor (GCT) of Enneking stage III. Lower lumbar-spine tumors and severe spinal canal stenosis are associated with high risk for surgical mor-bidity. Stability was temporarily secured with a percutaneous pedicle screw fixation in combination with deno-sumab, which shrank the tumor. Total en bloc spondylectomy was then performed 6 months after initiation of denosumab, and the patient was followed for 3 years. There was no local recurrence, and bony fusion was obtained. Minimally invasive surgery and denosumab allowed safer and easier treatment of a collapsing lower lumbar extra-compartmental GCT.

Expression Profiling of Receptor-Activator of Nuclear Factor-Kappa B Ligand in Soft Tissue Tumors.

Bone and soft tissue tumors are derived from mesenchymal cells, and they are hard to treat. Receptor-activator of nuclear factor-kappa B ligand (RANKL) is an essential cytokine for osteoclast differentiation and activation and is expressed on the surface of osteoblasts or stromal cells. In this study, to explore the potential of denosumab treatment for soft tissue tumors, we analyzed the expression profiles of RANKL mRNA in 425 tumor specimens of 33 histological types by real-time RT-PCR. Denosumab is a monoclonal antibody that prevents the binding of RANKL to receptor-activator of nuclear factor-kappa B (RANK). For comparison, the relative expression levels of RANK and osteoprotegerin (OPG) mRNAs were also measured. OPG functions as a soluble decoy receptor for RANKL. Higher expression levels of RANKL mRNA were detected in calcifying aponeurotic fibroma, fibrosarcoma, calcifying epithelioma, myositis ossificans, heterotopic calcification, giant cell tumor of the tendon sheath (GCTTS), and pigmented villonodular synovitis (PVNS), compared with the levels of other tumor types. Moreover, the expression levels of RANK mRNA were highest in GCTTS, followed by myositis ossificans and PVNS, whereas the expression levels of OPG mRNA were greatly varied among these histological types. We then analyzed RANKL protein expression by immunohistochemistry in 57 tumor specimens with higher expression levels of RANKL mRNA. RANKL-positive cells were detected in GCTTS, PVNS, myositis ossificans, heterotopic calcification, and calcifying aponeurotic fibroma. In conclusion, RANKL is expressed in subsets of soft tissue tumors with calcification, and denosumab is a potential therapeutic option for soft tissue tumors expressing RANKL.

Prognostic impact of the tumor immune microenvironment in synovial sarcoma.

The association between the immune status within the tumor microenvironment and prognosis in synovial sarcoma is not well understood. We aimed to investigate the tumor immune microenvironment and analyze its prognostic impact for patients with synovial sarcoma. A total of 36 primary patients who were treated in our institution were retrospectively evaluated. Infiltration of lymphocytes (CD4+, CD8+, and FOXP3+), CD163+ macrophages, and expression of human leukocyte antigen (HLA) class I and programmed death ligand 1 (PD-L1) were evaluated by immunohistochemistry. Moreover, we investigated PD-L1 and programmed death ligand 2 (PD-L2) mRNA expression in 19 of the 36 cases, using real-time PCR. The Kaplan-Meier method was used to estimate overall survival and progression-free survival. Infiltration of lymphocytes and macrophages varied among the patients. Furthermore, the expression of HLA class I was negative or downregulated in 11 specimens. No PD-L1 expression was observed using immunohistochemistry. Moreover, although PD-L1 mRNA expression was observed in 18 of 19 specimens, the expression level was low. A higher infiltration of CD8+ or FOXP3+ lymphocytes in patients was associated with a favorable overall survival. In addition, a higher infiltration of CD163+ macrophages indicated a significantly worse overall and progression-free survival. Infiltration of CD4+ lymphocytes, HLA class I, PD-L1, and PD-L2 expression were not associated with patient prognosis. This represents the first report investigating the tumor immune microenvironment as a prognostic factor in synovial sarcoma, indicating that CD163+ macrophages are associated with tumor progression. Our results underscore the clinical significance of the tumor immune microenvironment in synovial sarcoma.

A malignant solitary fibrous tumour arising from the first lumbar vertebra and mimicking an osteosarcoma: a case report.

BACKGROUND: A solitary fibrous tumour (SFT) is an unusual neoplasm typically found in soft tissues. Although SFTs can arise in the bones, they very rarely arise in the vertebral arch. Here, we describe a case of a SFT that arose in the vertebral arch of the first lumbar (L1) spinal vertebrae and mimicked osteosarcoma. CASE PRESENTATION: A 49-year-old woman presented with a 2-month history of lower back pain and a lumbar region mass. Magnetic resonance imaging demonstrated a heterogeneously enhanced mass in the L1 vertebral arch. The patient received neoadjuvant chemotherapy, followed by a surgical procedure comprising an anterior spinal fusion and en bloc resection. Histologically, our initial diagnosis was osteosarcoma. The postoperative course was uneventful, and the patient received adjuvant chemotherapy. However, the tumour metastasised to the lung 5 years after the first surgery, and a second surgery was performed for lung tumour resection. The histology of the metastatic lung tumour appeared similar to that of the malignant SFT, and the specimen from the first surgery was re-examined. Immunohistochemically, the tumour was positive for STAT6. Reverse transcription-polymerase chain reaction revealed a NAB2-STAT6 fusion gene, thus confirming our final diagnosis of malignant SFT. The patient died of disease progression 8 years after the first surgery; however, there was no evidence of local recurrence. CONCLUSIONS: Malignant SFT in the vertebral arch is extremely rare and very difficult to distinguish histologically an osteoid from lace-like collagen. STAT6 immunostaining is useful for distinguishing malignant SFTs from other neoplasms. Although it is difficult to completely resect a SFT arising from the spine, we demonstrated the feasibility of an en bloc resection of spinal tumours arising from posterior elements, without local recurrence.

＜Editors' Choice＞ Stanniocalcin-1 mRNA expression in soft-tissue tumors.

Stanniocalcin-1 (STC1) is a glycoprotein that was originally identified as a calcium-regulating hormone in bony fish, and that has been shown to also critically mediate cell growth, proliferation and differentiation, etc. in humans. Increased STC1 expression levels have been previously detected in different human cancer samples, such as those isolated from lung, breast, ovary, colon, pancreas, and liver tumors; thus, the present study evaluated STC1 expression in various soft-tissue tumors. STC1 mRNA isolated from 16 cell lines and 186 clinical soft-tissue tumor specimens were analyzed via quantitative real-time PCR, and the calculated expression levels were normalized to those exhibited by STC1-expressing MDA-MB-231 cells. The results of these analyses did not reveal any specific histological tumor types that displayed significantly increased STC1 expression; however, they did not indicate that STC1 expression was significantly higher in malignant compared to benign soft-tissue tumors. Furthermore, in adipocytic tumors, STC1 expression in dedifferentiated liposarcomas was found to be highest and lowest in lipoma tissues, respectively, suggesting that adipocytic tumors may express increasely high levels of STC1 mRNA as they become histologically more advanced. STC1 expression correlates with the malignancy grade in soft-tissue tumors.

Reconstruction of knee extensor with patellar tendon autograft following intraoperative radiotherapy.

BACKGROUND: Patellar tendon autograft after intraoperative extracorporeal radiotherapy has been used for reconstruction of the extensor mechanism following limb-sparing wide tumor resection around the knee. The purpose of this study was to determine the clinical outcome of this reconstruction technique. METHODS: We retrospectively reviewed six consecutive patients with peripatellar tendon and proximal tibial sarcoma who underwent reconstruction of the knee extensor mechanism. The resection area was planned to be contained with the patellar tendon in order to obtain a wide margin. First, the patella was osteotomized at the midline, and the inferior half of patella, patellar tendon, and tibial tuberosity were excised en bloc. The resected segments were devitalized with intraoperative extracorporeal radiotherapy and reimplanted into the original site. A follow-up evaluation included an assessment of the range of motion, extensor lag, the International Society of Limb Salvage score, and complications. RESULTS: Six patients were followed up for 121-270 months. One patient underwent an additional reconstruction with total knee arthroplasty due to a collapse of the tibial subchondral bone. A supracondylar fracture of the femur occurred in two patients, and a delayed union of the osteosynthesis site of the tibial shaft was observed in one patient. At the latest follow up, extensor lag had a median of five degrees, and International Society of Limb Salvage scores had a median of 83%. No local recurrence or rupture of the patellar tendon was observed. CONCLUSIONS: Reconstruction of the knee extensor mechanism using a patellar tendon treated with intraoperative radiotherapy is a reliable and successful method.

Symptom Burden and End-of-Life Palliative Treatments during the Last Two Weeks of Life in Patients with Advanced Musculoskeletal Sarcoma.

Background: Musculoskeletal sarcomas (MSSs) are rare cancers and often aggressive tumors that originate from mesenchymal tissue. Patients with advanced MSS often report difficulties with symptom burden, which can reduce their health-related quality-of-life. Objective: The aim of this study was to describe the patterns of the physical symptoms of MSS patients in the palliative setting and to detail the palliative treatment used in the last two weeks of life. Design: Retrospective study using the electronic patient records from a single institution. Setting/Subjects: A retrospective study was carried out in a sample of 46 consecutive MSS patients with locally advanced/metastatic disease, who were hospitalized and died in our department. The median age of these patients was 56 years at death. Measurements: Symptom burden and medical intervention during the last two weeks of life were collected. Results: The most frequent physical symptoms were pain and dyspnea in 93% and 78% of patients, respectively, while only 17% of patients suffered from nausea. A total of 98% of patients required opioids, and most patients were treated with morphine through either subcutaneous or intravenous continuous injection. Nonsteroidal anti-inflammatory drugs and acetaminophen were administered to 79% of patients. Corticosteroids were administered for the relief of dyspnea to 83% of patients. Of the patients, 46% received palliative chemotherapy within the last two weeks of life, and the oral treatment was continued until a median of 5.6 days before death. In addition, 39% of patients received a sedative treatment during the last two weeks of life for uncontrolled refractory symptoms. Conclusions: The symptom burden experienced by advanced MSS patients is profound at the end of life for all palliative approaches. Therefore, palliative medicine is an important and even crucial component of the continuum of care, allowing for aggressive symptom management with a variety of medical interventions, including palliative sedation.

The natural history of incidental retroperitoneal schwannomas.

The natural history of asymptomatic retroperitoneal schwannomas is poorly understood. This study aimed at investigating the natural history of incidental retroperitoneal schwannomas. The medical charts and imaging studies of 22 asymptomatic patients under observation for at least 12 months for retroperitoneal schwannomas were reviewed. The duration of follow-up ranged between 13 and 176 months (mean 48 months). In the 22 patients managed by the "wait and see" approach, the average tumor size at initial presentation was 51 mm, which increased to 57 mm at final follow-up. During the final follow-up, 2 patients required surgical treatment for tumor enlargement, while the remaining patients remained asymptomatic without surgery. The average growth rate of the tumors was 1.9 mm/year (range: -1.9 to 8.7 mm/year). The majority of asymptomatic retroperitoneal schwannomas demonstrate minimal growth and may be suitable for management with the "wait and see" approach.

Prolonged Myelosuppression due to Progressive Bone Marrow Fibrosis in a Patient with Acute Promyelocytic Leukemia.

A 34-year-old woman was diagnosed with acute promyelocytic leukemia. Chemotherapy was administered following the JALSG APL204 protocol. Induction therapy with all-trans retinoic acid resulted in complete remission on day 49. She developed coccygeal pain from day 18, which spread to the spine and cheekbones and lasted 5 weeks. She had similar bone pain on days 7-10 of the first consolidation therapy and on days 4-12 of the second consolidation therapy. Oral loxoprofen was prescribed for pain relief. On day 33 of the third consolidation, white blood cell and neutrophil counts were 320/µL and 20/µL, respectively. After she developed epigastralgia and hematemesis, she developed septic shock. Gastroendoscopy revealed markedly thickened folds and diffusely damaged mucosa with blood oozing. Computed tomography revealed thickened walls of the antrum and the pylorus. Despite emergency treatments, she died. Bacterial culture of the gastric fluid yielded Enterobacter cloacae and enterococci growth. Collectively, she was diagnosed with phlegmonous gastritis. Retrospective examination of serial bone marrow biopsy specimens demonstrated progressive bone marrow fibrosis, which may have caused prolonged myelosuppression. Thus, evaluation of bone marrow fibrosis by bone marrow biopsy after each treatment cycle might serve as a predictor of persistent myelosuppression induced by chemotherapy.

Denosumab as a potential therapeutic option for leiomyosarcoma with osteoclast-like giant cells: A case report.

Bone leiomyosarcoma is a rare primary osseous malignant tumor with a high metastatic potential. Similar to other bone sarcomas, high histological grade and tumor stage are predictive of a poor outcome. We herein present our experience with treating a 64-year-old woman with bone leiomyosarcoma accompanied by multiple bone metastases. A biopsy revealed occasional osteoclast-like giant cells. In addition to radiation therapy, the osteoclastogenesis inhibitor denosumab was administered but the patient did not undergo adjuvant chemotherapy or surgery. Good clinical and short-term radiological responses to denosumab have been observed for 2 years. Therefore, denosumab may represent a viable treatment option without the need for adjuvant chemotherapy.

Extensor reconstruction of the knee using the fibular transposition technique after proximal tibial resection.

BACKGROUND: Reconstruction of the extensor mechanism after resection of the proximal tibia is challenging, and several surgical procedures are available. The purpose of this study was to determine the outcome of the fibular transposition technique for reconstruction of the extensor mechanism of the knee after proximal tibial resection. METHODS: We retrospectively reviewed five consecutive patients who underwent resection of the proximal tibia with prosthetic reconstruction and reconstruction of the extensor using fibular transposition between 1997 and 2011. There were two female and three male patients with a mean age of 50years (range, 27 to 76years). A follow-up evaluation included both passive and active range of motion, extensor lag, the MSTS score and complications. RESULTS: Patients were followed up for 93months (range, 44 to 160months). The mean extensor lag and active flexion were four degrees (range, 0 to 10°) and 103° (range, 85 to 110°), respectively. The mean MSTS score was 80% (range, 73 to 90%). All patients were able to ambulate without crutches at the latest follow-up. CONCLUSIONS: The utilization of the fibular transposition technique is a simple, reliable, and successful procedure for extensor reconstruction after proximal tibial resection.

Frequent expression of human leukocyte antigen class I and the status of intratumoral immune cells in alveolar soft part sarcoma.

The prognosis of alveolar soft part sarcoma is poor, despite the slow growth of the tumor. A number of cases with spontaneous regression of this rare tumor have been reported. Although the mechanisms underlying spontaneous regression remain uncertain, local immune reaction may be a possible contributing factor. Immunohistochemical expression of human leukocyte antigen (HLA) class I, cluster of differentiation (CD) 3, CD4, CD8, CD20, CD45, CD56, CD68, CD138 and CD163 were assessed in a series of 10 alveolar soft part sarcomas, and the expression profiles were associated with patients' clinicopathological parameters. Expression of HLA class I was observed in almost all the tumor cells of all cases. CD8(+) cells were identified in all tumors with varying densities. Moderate infiltration of CD8(+) cells was detected in three patients; one of these patients survived with long-term tumor remission. Infiltration of CD10(+), CD20(+), CD56(+) or CD138(+) cells was not revealed in all tumors. Moderate-diffuse infiltration of CD163(+) cells was observed in all tumors. To the best of our knowledge, the present study represents the first report of intratumoral immune cells in alveolar soft part sarcoma. Frequent expression of HLA class I in tumor cells was observed. CD8(+) cells were identified at various densities and CD163(+) cells were observed in alveolar soft part sarcoma. Moderate infiltration of CD8(+) cells in patients with a good prognosis may indicate the antitumor effects of immune cells in alveolar soft part sarcoma.

Disappearance of giant cells and presence of newly formed bone in the pulmonary metastasis of a sacral giant-cell tumor following denosumab treatment: A case report.

A giant-cell tumor of the bone (GCTB) is a benign but locally aggressive bone tumor. Recently, the receptor activator of nuclear factor κB (RANK) ligand inhibitor, denosumab, has demonstrated activity against giant-cell tumors. The current study reports a case of a sacral GCTB with lung metastasis. A 19-year-old male patient presented with right buttock pain and right lower leg pain, and a sacral GCTB was diagnosed based on the histological analysis of a biopsy specimen. The patient was successfully treated with neoadjuvant denosumab therapy, which allowed curettage. In addition, the pulmonary nodule reduced in size following denosumab administration, and surgical resection was performed. Since the operation, the patient has been managed with the continued use of denosumab with no sign of recurrence. Microscopic findings from the surgical specimen following denosumab treatment revealed that the giant cells had disappeared and woven bone had formed. The specimen from the pulmonary nodule exhibited similar findings to the surgical specimen. It was reported that denosumab treatment was able to reduce the number of giant cells and RANK-positive stromal cells, and cause the formation of new bone in the primary lesion. The present study reports the first case to demonstrate the efficiency of denosumab in treating pulmonary metastasis of GCTB.

Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors.

The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts.