Snezana Popovic

Evidence for the role of matrix metalloproteinase-13 in bone resorption by giant cell tumor of bone☆☆☆

Giant cell tumor of bone (GCT) is an aggressively osteolytic primary bone tumor that is characterized by the presence of abundant multinucleated osteoclast-like giant cells, hematopoietic monocytes, and a distinct mesenchymal stromal cell component. Previous work in our laboratory has shown that matrix metalloproteinase (MMP)-13 is the principal proteinase expressed by the stromal cells of GCT. The release of cytokines, particularly interleukin-1beta, by the giant cells of GCT acts on stromal cells to stimulate a surge in MMP-13 secretion. The purpose of this study was to determine the bone resorption capabilities of the cellular elements of GCT and the significance of the MMP-13 expression involved in GCT bone resorption. We present a 3-dimensional histomorphometric technique developed to analyze resorption pit depth and yield an accurate measurement of bone resorption with a direct physical view of lacunae on bone slices. In this study, we demonstrate that the mesenchymal stromal cells and the multinucleated giant cells of GCT are independently capable of bone resorption. However, coculture of these 2 cell fractions shows a synergistic increase in bone resorption. In addition, inhibition of MMP-13 reduces resorptive activity of the cells indicating that MMP-13 likely plays an important role in this tumor. This cell-cell cooperation involves giant cell-derived cytokine up-regulation of MMP-13 in the stromal cells, which in turn assists the giant cells in bone resorption. Future research will involve elucidation of the role of cell-cell/matrix communication pathways in bone resorption and tumorigenesis in GCT.

A blinded study of bone marrow examinations in patients with primary immune thrombocytopenia

The role of bone marrow examinations in patients with primary immune thrombocytopenia (ITP) is uncertain. The objectives of this study were to determine the inter‐rater reliability of bone marrow examinations and to identify distinguishing morphological features of ITP bone marrows under controlled conditions.

Angiosarcoma of the adrenal gland with concurrent contralateral advanced renal cell carcinoma: A diagnostic and management dilemma.

Angiosarcoma is a rare high-grade malignant neoplasm with poor clinical outcome and survival rates, occurring most commonly in the skin and soft tissue. It is composed of neoplastic cells that demonstrate endothelial differentiation. The diagnosis of angiosarcoma can be difficult due to its pathohistologic presentation as a poorly differentiated neoplasm with associated secondary changes. We report a case of angiosarcoma of the adrenal gland with concurrent contralateral renal cell carcinoma (RCC) and renal vein thrombus. The presumptive clinical diagnosis was metastatic renal cell carcinoma to the contralateral adrenal gland. Pathohistologic evaluation demonstrated massive hematoma associated with intravascular papillary endothelial hyperplasia (IPEH)-like features. We discuss the pathohistological features used to ascertain a diagnosis of angiosarcoma in the presence of IPEH-like changes and differentiate it from reactive vascular proliferation seen in IPEH (Massons tumour).

Aneurysmal Bone Cyst of the Temporal Bone Presenting with Headache and Partial Facial Palsy.

Background Aneurysmal bone cysts (ABCs) are benign bony lesions that rarely affect the skull base. Very few cases of temporal bone ABCs have been reported. We describe the first case of a temporal bone ABC that was thought to be consistent with a meningioma based on preoperative magnetic resonance imaging (MRI) findings. Clinical Presentation An otherwise healthy 23-year-old woman presented with a pulsatile noise in her left ear and a 4-week history of throbbing headache with nausea. There was no associated emesis, visual or auditory changes, or other neurologic features. Neurologic examination revealed a left lower motor neuron facial paresis. Computed tomography and MRI studies demonstrated a large lesion in the left middle cranial fossa skull base with erosion of the petrous temporal bone. Based on the presence of a “dural tail” on preoperative contrast-enhanced T1-weighted imaging, the lesion was interpreted to likely be consistent with a meningioma. An orbitozygomatic approach was utilized for surgical excision. Histopathologic evaluation was consistent with an ABC. Conclusion Postoperatively the patient had improvement in the lower motor neuron facial paresis. It is important to consider ABC in the differential diagnosis of intracranial lesions accompanied by the dural tail sign on MRI.

Radiologic and Histopathologic Features of Calcifying Pseudoneoplasm of the Neural Axis

Aim To describe the radiologic and corresponding histopathologic features of calcifying pseudoneoplasms of the neural axis. Methods Two cases of calcifying pseudoneoplasm of the neural axis were retrospectively reviewed. The first case was documented in a 64-year-old woman, who presented with lower back pain with radiation to her left leg. The second case was documented in a 70-year-old man, who presented with headaches. Medical records, radiologic and histologic findings, and related literature were reviewed. Results In the first case, imaging of the lumbar spine revealed a 3.8 × 2.2-cm calcified lesion at the level of vertebrae L5 and S1. A subsequent excision exposed an extradural lesion at L5. Histopathologic examination showed amorphous and granular calcifying material with occasional fibrohistiocytic and giant cell reaction, consistent with calcifying pseudoneoplasm of the neural axis. In the second case, imaging of the head revealed a 2.4 × 2.6-cm well-circumscribed, lobulated, calcified lesion within the basal frontal lobe. Subsequent resection exposed an intradural mass with a nodular arrangement of amorphous and granular calcifying material associated with fibrohistiocytic and giant cell reaction. Both patients had a favorable postoperative course and failed to show any clinical or radiologic sign of recurrence. Conclusion Calcifying pseudoneoplasm of the neural axis is an uncommon condition with an excellent prognosis but is often misdiagnosed due to its nonspecific clinical presentation and varied findings on radiology.

Functional effects of TrkA inhibition on system xC−-mediated glutamate release and cancer-induced bone pain:

Breast cancer cells release the signalling molecule glutamate via the system xC− antiporter, which is upregulated to exchange extracellular cystine for intracellular glutamate to protect against oxidative stress. Here, we demonstrate that this antiporter is functionally influenced by the actions of the neurotrophin nerve growth factor on its cognate receptor tyrosine kinase, TrkA, and that inhibiting this complex may reduce cancer-induced bone pain via its downstream actions on xCT, the functional subunit of system xC−. We have characterized the effects of the selective TrkA inhibitor AG879 on system xC− activity in murine 4T1 and human MDA-MB-231 mammary carcinoma cells, as well as its effects on nociception in our validated immunocompetent mouse model of cancer-induced bone pain, in which BALB/c mice are intrafemorally inoculated with 4T1 murine carcinoma cells. AG879 decreased functional system xC− activity, as measured by cystine uptake and glutamate release, and inhibited nociceptive and physiologically relevant responses in tumour-bearing animals. Cumulatively, these data suggest that the activation of TrkA by nerve growth factor may have functional implications on system xC−-mediated cancer pain. System xC−-mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.

Early Occurrence of Angiosarcoma in a Woman With a BRCA2 Gene Variation of Unknown Significance Treated With Breast-Conserving Therapy for Bilateral Ductal Carcinoma: A Case Report

Radiation-associated angiosarcoma (RAAS) develops in the setting of lymphedema or previous radiation; patients typically present with cutaneous lesions rather than parenchymal lesions. RAAS can present as early as 6 months after completion of radiotherapy, and skin punch biopsy of suspicious cutaneous lesions should be performed. BRCAmutations may play a role in in the development of breast RAAS. However, this still requires further study.

Intra-articular solitary fibrous tumor of the knee

A rare case of intra-articular solitary fibrous tumor of the knee in an 84-year-old man is presented. This case report illustrates that solitary fibrous tumor should be included in the extended differential diagnosis of an intra-articular soft tissue mass.

Molecular analyses in the diagnosis and prediction of prognosis in non-GIST soft tissue sarcomas: A systematic review and meta-analysis

BACKGROUND The molecular pathogenesis of many forms of soft tissue sarcomas (STS) have been rigorously characterized in the medical literature, which may be particularly important for the diagnosis and prediction of prognosis in STS. METHODS Electronic databases (2005 to October 2016) were searched. Gastrointestinal stromal tumor and pediatric sarcomas were excluded. The eligible individual studys risk of bias and the quality of aggregate evidence were assessed. Meta-analyses were performed. RESULTS Of 6674 identified articles, 70 were eligible and analyzed, covering 13 types of STS. Meta-analyses showed that the test of detecting MDM2 amplification by fluorescence in situ hybridization was accurate in differentiating atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma from benign tumors (N = 971; sensitivity = 95%, 95% confidence interval [CI] 89-98; specificity = 100%, CI 89-100) or from other STS (N = 347; sensitivity = 99%, CI 72-100; specificity = 90%, CI 78-95); that the test of detecting SS18-SSX fusion by reverse transcription polymerase chain reaction (PCR) was accurate in differentiating synovial sarcoma from other STS (N = 532; sensitivity = 93%, CI 85-96; specificity = 99%, CI 96-100). The presence of a CTNNB1 S45F mutation detected by PCR was a risk factor for decreased recurrence-free survival in desmoid tumors (N = 418; hazard ratio from 3.50 [CI 1.51-8.14] to 6.20 [CI 2.24-17.15]). CONCLUSIONS Sarcomas are rare cancers whose molecular pathogenesis is becoming increasingly understood. The current evidence demonstrates that molecular analyses are useful in the diagnosis and prediction of prognosis in some STS.

Oncodynamic Changes in Skeleton

When cancers are present in bone, a number of complex changes occur that can alter the physiology and structure of the skeleton. To properly understand these oncodynamic processes—how the bone changes in response to cancer cell invasion—it is necessary to define the types of cells that are present in normal bone, to explore the main physiological functions of these cells and of the bone itself, and to describe the types of cancers that often grow in bone. To properly characterize the functional and anatomical responses of bone cells, a broader definition of what cell types are present in bone is required. Using a more comprehensive and inclusive definition of bone cells, adaptations that result from cancer cell invasion can be categorized on the basis of the signalled functional and structural changes that occur between all involved cells in the bone environment. These pathological responses will be integrated with what is known about the chemical mediators that may be involved. This analysis of the normal signalling environment in bone and the potential interactions between cell types will help to better characterize the complex oncodynamic processes that can occur when cancer invades bone and disrupts this carefully balanced microenvironment.