Extremity gossypiboma mimicking sarcoma: case report and review.

A 70-year-old man with a history of bladder and colon cancer presented with an enlarging mass in his right lower extremity. Forty years before presentation, he had injured his right lower extremity in a motor vehicle accident. Imaging findings indicated suspected sarcoma, which led to biopsy. Biopsy and further surgical exploration revealed the presence of a surgical sponge and surrounding local inflammatory reaction. No neoplasm was found, and the sponge and involved tissues were removed. Gossypiboma is exceedingly rare in the extremities. Imaging of retained foreign material can appear suggestive of sarcoma because of strong inflammatory responses and local tissue mass-like derangement resulting in heterogeneous signal changes. Ultimately, biopsy must be performed to ensure that no oncological pathological condition is present.

Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.

The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease. Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (MET(Δ14)) lacking a cytoplasmic juxtamembrane domain. Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization. In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the MET(Δ14) mutations, had a stabilizing effect on the mature protein. Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone.

Extra-Axial Chordoma of the Hand.

Chordomas are low-grade malignant tumors that are locally aggressive and have the potential to metastasize. They most often occur in the sacrococcygeal and spheno-occipital portions of the vertebral column. Morphologically similar tumors have been found outside the axial skeleton and are referred to as extra-axial chordomas. Several case reports have described the radiologic, microscopic, and immunologic profiles of these tumors and their similarities to axial chordomas. The authors report a 24-year-old man who presented with a mass in his left hand and underwent surgical excision. Specimens stained positive for pancytokeratin, S100, and brachyury. Brachyury is a protein that is present during embryogenesis and is expressed by chordomas. This is the first report of an extra-axial chordoma within the interosseous muscle compartment of the hand in a young patient.

Primary rhabdomyosarcoma of the distal femoral diaphysis: a case report and review of the literature.

Primary rhabdomyosarcoma of the bone is an extremely rare condition with few examples reported in the literature. We present the case of a 34-year-old male who presented with a lesion in the distal femur with initial imaging features consistent with Ewing sarcoma. Histologically, the lesion consisted of atypical pleomorphic polygonal rhabdomyoblasts demonstrating focal desmin and myogenin expression. A diagnosis of pleomorphic rhabdomyosarcoma was rendered. Despite systemic treatment and surgery, this patient experienced a rapidly progressive disease course. We believe this is only the second report in the orthopedic literature of a case of primary pleomorphic rhabdomyosarcoma of the bone. The key imaging, pathologic, and clinical findings are discussed.

PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment.

Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.

TrkA + sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression.

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

Conventional Chondrosarcoma with Clear Cell Features in the Rib: Report of Two Cases and Review of the Literature.

A subset of clear cell chondrosarcomas may contain focal areas of low-grade conventional chondrosarcoma; however, it is rare to find foci resembling clear cell chondrosarcoma admixed with areas otherwise typical conventional chondrosarcoma. We report two patients with conventional chondrosarcoma with clear cell features occurring in the rib, one in the setting of multiple hereditary exostoses (MHE) and the other without MHE. Both patients were found to have a destructive rib mass with a soft tissue component and underwent en bloc resection. Histologic examination revealed predominantly grade 2 conventional chondrosarcomas; however, multiple foci containing large cells with pale eosinophilic to clear cytoplasm, distinct cell borders, centrally located nuclei, and conspicuous nucleoli, resembling clear cell chondrosarcoma were identified throughout the specimen. The significance of clear cell features in an otherwise typical conventional chondrosarcoma, to our knowledge, is unknown and deserves recognition. Finally, these tumors highlight the need for careful histologic examination and proper classification as unexpected findings may impact management.

CNTNAP4 signaling regulates osteosarcoma disease progression.

Improved treatment strategies for sarcoma rely on clarification of the molecular mediators of disease progression. Recently, we reported that the secreted glycoprotein NELL-1 modulates osteosarcoma (OS) disease progression in part via altering the sarcomatous extracellular matrix (ECM) and cell-ECM interactions. Of known NELL-1 interactor proteins, Contactin-associated protein-like 4 (Cntnap4) encodes a member of the neurexin superfamily of transmembrane molecules best known for its presynaptic functions in the central nervous system. Here, CRISPR/Cas9 gene deletion of CNTNAP4 reduced OS tumor growth, sarcoma-associated angiogenesis, and pulmonary metastases. CNTNAP4 knockout (KO) in OS tumor cells largely phenocopied the effects of NELL-1 KO, including reductions in sarcoma cell attachment, migration, and invasion. Further, CNTNAP4 KO cells were found to be unresponsive to the effects of NELL-1 treatment. Transcriptomic analysis combined with protein phospho-array demonstrated notable reductions in the MAPK/ERK signaling cascade with CNTNAP4 deletion, and the ERK1/2 agonist isoproterenol restored cell functions among CNTNAP4 KO tumor cells. Finally, human primary cells and tissues in combination with sequencing datasets confirmed the significance of CNTNAP4 signaling in human sarcomas. In summary, our findings demonstrate the biological importance of NELL-1/CNTNAP4 signaling axis in disease progression of human sarcomas and suggest that targeting the NELL-1/CNTNAP4 signaling pathway represents a strategy with potential therapeutic benefit in sarcoma patients.

Interobserver reliability in the histopathological diagnosis of cartilaginous tumors in patients with multiple osteochondromas.

The distinction between benign and malignant cartilaginous tumors located peripherally in the bone may be a challenging task in surgical pathology. The aim of this study was to investigate interobserver reliability in histological diagnosis of cartilaginous tumors in the setting of multiple osteochondromas and to evaluate possible histological parameters that could differentiate among osteochondroma, low- and high-grade secondary peripheral chondrosarcoma. Interobserver reliability was assessed by 12 specialized bone-tumor pathologists in a set of 38 cases. Substantial agreement on diagnosis among all the reviewers was observed (intraclass correlation coefficient=0.78). Our study confirmed that mitotic figures and nuclear pleomorphism are hallmarks of high-grade secondary peripheral chondrosarcoma. However, despite the substantial agreement, we demonstrated that histology alone cannot distinguish osteochondroma from low-grade secondary peripheral chondrosarcoma in the setting of multiple osteochondromas, as nodularity, the presence of binucleated cells, irregular calcification, cystic/mucoid changes and necrosis were not helpful to indicate malignant transformation of an osteochondroma. On the other hand, among the concordant cases, the cartilage cap in osteochondroma was significantly less thicker than in low- and high-grade secondary peripheral chondrosarcoma. Therefore, our study showed that a multidisciplinary approach integrating clinical and radiographical features and the size of the cartilaginous cap in combination with a histological assessment are crucial to the diagnosis of cartilaginous tumors.

NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression.

Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improving survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phosphoproteomic analyses demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and signaling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall survival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression. SIGNIFICANCE: NELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell-ECM interactions in sarcomagenesis and disease progression.

NGF-p75 signaling coordinates skeletal cell migration during bone repair.

Bone regeneration following injury is initiated by inflammatory signals and occurs in association with infiltration by sensory nerve fibers. Together, these events are believed to coordinate angiogenesis and tissue reprogramming, but the mechanism of coupling immune signals to reinnervation and osteogenesis is unknown. Here, we found that nerve growth factor (NGF) is expressed following cranial bone injury and signals via p75 in resident mesenchymal osteogenic precursors to affect their migration into the damaged tissue. Mice lacking Ngf in myeloid cells demonstrated reduced migration of osteogenic precursors to the injury site with consequently delayed bone healing. These features were phenocopied by mice lacking p75 in Pdgfra+ osteoblast precursors. Single-cell transcriptomics identified mesenchymal subpopulations with potential roles in cell migration and immune response, altered in the context of p75 deletion. Together, these results identify the role of p75 signaling pathway in coordinating skeletal cell migration during early bone repair.

Imaging features of chondrosarcoma.

Chondrosarcomas are malignant neoplasms of mesenchymal origin and represent a heterogeneous group of tumors ranging from indolent, low-grade lesions to aggressive, high-grade neoplasms. The early diagnosis and treatment of chondrosarcomas is paramount to achieving a better prognosis. Multiple imaging modalities have been used for the purpose of initial detection, characterization, and staging, as well as for the performance of image-guided biopsies. As imaging techniques continue to evolve, radiologists are assuming an increasingly important role in the management of chondrosarcomas. This review describes the imaging characteristics of chondrosarcomas on multiple modalities and emphasizes the imaging features that may assist in differentiating these tumors from their benign counterparts, enchondromas and osteochondromas, which frequently still pose challenging diagnostic dilemmas.

Genetic diseases of bones and joints.

Genetic factors play roles in many diseases. Often these factors are ill defined and unpredictable. Other diseases are caused by specific single gene mutations and are passed to offspring in Mendelian inheritance patterns. There are over 5000 documented Mendelian disorders; over 500 of these affect bones and joints. Some of these single gene disorders affect many tissues, and the skeletal system is one of many organ systems involved. The surgical pathologist must often diagnose these disorders. Important examples are neurofibromatosis, Gaucher's disease, and alkaptonuria. Other single gene disorders almost exclusively affect the skeleton. These disorders are the skeletal dysplasias and 372 have been documented. These disorders are classified using radiographic, clinical, and molecular data. The most common dysplasias are osteogenesis imperfecta, achondroplasia, and osteopetrosis. The surgical pathologist usually does not play a role in the diagnosis of skeletal dysplasias. However, histologic studies often elucidate the pathophysiologic basis of these diseases and proper collection of tissues is important for the evolving understanding of the molecular basis of these disorders.

Chronic expanding hematoma of the lateral thigh and massive bony destruction after a failed total hip arthroplasty.

Pseudotumors have been described around both stable and failed total hip arthroplasties. The causes are varied and include polyethylene debris and masses associated with metal-on-metal bearings. We present a patient with a massive tumor of the thigh that grossly and pathologically was associated with recurrent bleeding and extensive bony destruction. The characteristics of this tumor most resemble those of a chronic expanding hematoma. To our knowledge, this has not previously been reported in association with a total hip arthroplasty.

Intravascular Mesenchymal Chondrosarcoma of the Femoral Vein: A Case Report.

CASE: A 30-year-old man presented with progressive lower right extremity pain and swelling, initially diagnosed as a deep venous thrombosis. He returned 18 months later after 2 episodes of gross hemoptysis, with chest computed tomography angiography findings concerning for tumor thrombus in the left pulmonary artery. Subsequent advanced imaging showed a lesion arising from his right femoral vein, which open biopsy revealed to be a primary intravascular mesenchymal chondrosarcoma. He underwent medical therapy, with improvement of pain and swelling and successful return to work. CONCLUSION: Mesenchymal chondrosarcoma is a rare pathology, and its intravascular origin makes this case extraordinarily uncommon.

Clinicopathologic Analysis of Chondroblastoma in Adults: A Single-Institution Case Series.

Chondroblastoma is a rare benign tumor of immature cartilage cells that generally occurs in an epiphyseal location of skeletally immature individuals. However, a few studies have reported cases in older patients. The purpose of this study was to evaluate the clinical, radiographic, and pathologic features of chondroblastoma in an adult population. The pathology archives of our institution were searched for cases of chondroblastoma diagnosed in patients ≥25 years of age. Of 14 patients identified, 8 were male and 6 were female with a median age of 34 years (range = 29-54 years). Most lesions occurred in short bones of hands and feet (N = 7, 50%), followed by the long tubular bones (N = 4, 28%). All demonstrated typical histologic features of chondroblastoma, but more extensive calcification, necrosis, and degenerative changes were also seen. At follow-up (median = 73.5 months), 2 patients (17%) had local recurrence. None had metastasis. In summary, chondroblastoma in adults tends to involve the short bones of the hands and feet and demonstrate histologic changes associated with long-standing growth of a benign tumor.

Chondrosarcoma of the spine: a narrative review.

Chondrosarcoma is an uncommon primary bone tumor with an estimated incidence of 0.5 per 100,000 patient-years. Primary chondrosarcoma of the mobile spine and sacrum cumulatively account for less than 20% of all cases, most .commonly causing patients to present with focal pain with or without radiculopathy, or myelopathy secondary to neural element compression. Because of the rarity, patients benefit from multidisciplinary care at academic tertiary-care centers. Current standard-of-care consists of en bloc surgical resection with negative margins; for high grade lesions adjuvant focused radiation with ≥60 gray equivalents is taking an increased role in improving local control. Prognosis is dictated by lesion grade at the time of resection. Several groups have put forth survival calculators and epidemiological evidence suggests prognosis is quite good for lesions receiving R0 resection. Future efforts will be focused on identifying potential chemotherapeutic adjuvants and refining radiation treatments as a means of improving local control.

Chordoma of the sacrum and mobile spine: a narrative review.

Chordoma is a notochord-derived primary tumor of the skull base and vertebral column known to affect 0.08 to 0.5 per 100,000 persons worldwide. Patients commonly present with mechanical, midline pain with or without radicular features secondary to nerve root compression. Management of these lesions has classically revolved around oncologic resection, defined by en bloc resection of the lesion with negative margins as this was found to significantly improve both local control and overall survival. With advancement in radiation modalities, namely the increased availability of focused photon therapy and proton beam radiation, high-dose (>50 Gy) neoadjuvant or adjuvant radiotherapy is also becoming a standard of care. At present chemotherapy does not appear to have a role, but ongoing investigations into the ontogeny and molecular pathophysiology of chordoma promise to identify therapeutic targets that may further alter this paradigm. In this narrative review we describe the epidemiology, histopathology, diagnosis, and treatment of chordoma.