Michelle A. Scott

Brief Review of Models of Ectopic Bone Formation

Ectopic bone formation is a unique biologic entity--distinct from other areas of skeletal biology. Animal research models of ectopic bone formation most often employ rodent models and have unique advantages over orthotopic (bone) environments, including a relative lack of bone cytokine stimulation and cell-to-cell interaction with endogenous (host) bone-forming cells. This allows for relatively controlled in vivo experimental bone formation. A wide variety of ectopic locations have been used for experimentation, including subcutaneous, intramuscular, and kidney capsule transplantation. The method, benefits and detractions of each method are summarized in the following review. Briefly, subcutaneous implantation is the simplest method. However, the most pertinent concern is the relative paucity of bone formation in comparison to other models. Intramuscular implantation is also widely used and relatively simple, however intramuscular implants are exposed to skeletal muscle satellite progenitor cells. Thus, distinguishing host from donor osteogenesis becomes challenging without cell-tracking studies. The kidney capsule (perirenal or renal capsule) method is less widely used and more technically challenging. It allows for supraphysiologic blood and nutrient resource, promoting robust bone growth. In summary, ectopic bone models are extremely useful in the evaluation of bone-forming stem cells, new osteoinductive biomaterials, and growth factors; an appropriate choice of model, however, will greatly increase experimental success.

Current Methods of Adipogenic Differentiation of Mesenchymal Stem Cells

There has been a recent increase in our understanding in the isolation, culture, and differentiation of mesenchymal stem cells (MSCs). Concomitantly, the availability of MSCs has increased, with cells now commercially available, including human MSCs from adipose tissue and bone marrow. Despite an increased understanding of MSC biology and an increase in their availability, standardization of techniques for adipogenic differentiation of MSCs is lacking. The following review will explore the variability in adipogenic differentiation in vitro, specifically in 3T3-L1 and primary MSCs derived from both adipose tissue and bone marrow. A review of alternative methods of adipogenic induction is also presented, including the use of specific peroxisome proliferator-activated receptor-gamma agonists as well as bone morphogenetic proteins. Finally, we define a standard, commonly used adipogenic differentiation medium in the hopes that this will be adopted for the future standardization of laboratory techniques--however, we also highlight the essentially arbitrary nature of this decision. With the current, rapid pace of electronic publications, it becomes imperative for standardization of such basic techniques so that interlaboratory results may be easily compared and interpreted.

Clinical and Histopathological Diagnosis of Glomus Tumor: An Institutional Experience of 138 Cases

Background. Glomus tumors are relatively uncommon subcentimeteric benign perivascular neoplasms usually located on the fingers. With their blue-red color and common subungual location, they are commonly confused for vascular or melanocytic lesions. To date there is no comprehensive review of an institutional experience with glomus tumors. Methods. A 14-year retrospective review of all cases within University of California, Los Angeles, with either a clinical or pathological diagnosis of glomus tumor was performed. Data obtained included demographic information, tumor description, pathological diagnoses, immunohistochemical studies, radiographic and treatment information, and clinical course. Rates of concordance between clinical and pathological diagnoses and an evaluation of overlap with other entities were assessed. Results. Clinical diagnosis of glomus tumor showed concordance with a histopathological diagnosis (45.4% of cases). The most common alternate clinical diagnoses included lipoma, cyst, or angioma. A pathological diagnosis of glomus tumor was most common in the fourth to seventh decades of life. The most common presentation was a subcentimeter lesion on the digit. Deep-seated tumors had a strikingly increased risk for malignancy (33%). Radiological studies were not relied on frequently (18.2% of cases). Immunohistochemical analysis showed diffuse αSMA and MSA expression in nearly all cases (99% and 95%, respectively), with focal to diffuse CD34 immunostaining in 32% of cases. Discussion. Our study illustrates trends in the clinical versus pathologic diagnoses of glomus tumor, common competing diagnoses, a difference in demographics than is commonly reported (older age groups most commonly affected), and important differences in the use adjunctive diagnostic tools including radiology and immunohistochemistry.

Current Status of Surgical Planning for Orthognathic Surgery: Traditional Methods versus 3D Surgical Planning

Background: Orthognathic surgery has traditionally been performed using stone model surgery. This involves translating desired clinical movements of the maxilla and mandible into stone models that are then cut and repositioned into class I occlusion from which a splint is generated. Model surgery is an accurate and reproducible method of surgical correction of the dentofacial skeleton in cleft and noncleft patients, albeit considerably time-consuming. With the advent of computed tomography scanning, 3D imaging and virtual surgical planning (VSP) have gained a foothold in orthognathic surgery with VSP rapidly replacing traditional model surgery in many parts of the country and the world. What has yet to be determined is whether the application and feasibility of virtual model surgery is at a point where it will eliminate the need for traditional model surgery in both the private and academic setting. Methods: Traditional model surgery was compared with VSP splint fabrication to determine the feasibility of use and accuracy of application in orthognathic surgery within our institution. Results: VSP was found to generate acrylic splints of equal quality to model surgery splints in a fraction of the time. Drawbacks of VSP splint fabrication are the increased cost of production and certain limitations as it relates to complex craniofacial patients. Conclusions: It is our opinion that virtual model surgery will displace and replace traditional model surgery as it will become cost and time effective in both the private and academic setting for practitioners providing orthognathic surgical care in cleft and noncleft patients.

Review of microRNA in osteosarcoma and chondrosarcoma

MicroRNAs (miRNAs) are small noncoding RNAs, which play a complex role in posttranscriptional gene expression and can theoretically be used as a diagnostic or prognostic tool, or therapeutic target for neoplasia. Despite advances in the diagnosis and treatment of skeletal sarcomas, including osteosarcoma and chondrosarcoma, much remains unknown regarding their underpinning molecular mechanisms. Given the recent increasing knowledge base of miRNA roles in neoplasia, both as oncogenes and tumor suppressor genes, this review will focus on the available literature regarding the expression profiles and potential roles of miRNA in skeletal sarcomas. Although this is an emerging field, miRNA profiling may be of use in clarifying competing diagnoses of skeletal sarcomas and possibly indicate patient risk of resistance to traditional chemotherapeutic agents. While detecting and targeting miRNAs is currently limited to experimental investigations, miRNA may be utilized for future clinical management of skeletal sarcomas.

Roles of bone morphogenetic protein signaling in osteosarcoma

PurposeSince the original extraction of bone morphogenetic proteins (BMPs) from bovine bone, research interest and clinical use has increased exponentially. With this, a concomitant analysis of BMP expression in bone tumours has been performed. BMP ligands, receptors, and signaling activity have been observed in diverse benign and malignant bone tumours. However, the reported expression, function, and importance of BMPs in bone tumours, and specifically osteosarcomas, have been far from uniform. This review highlights recent advances in understanding the role of BMP signaling in osteosarcoma biology, focusing on the sometimes divergent findings by various researchers and the challenges inherent in the study of osteosarcoma.MethodsWe performed a literature review of all studies examining BMP signaling in osteosarcoma.ResultsOverall, multiple BMP ligands and receptors are expressed in most osteosarcoma cell lines and subtypes, although BMP signaling may be reduced in comparison with benign bone-forming tumours. Studies suggest that osteosarcomas with different lineages of differentiation may have differential expression of BMP ligands. Although significant disagreement in the literature exists, the presence of BMP signaling in osteosarcoma may impart a worse prognosis. On the cellular level, BMP signaling appears to mediate promigratory effects in osteosarcoma and chondrosarcoma cell types, possibly via interaction and activation of Integrin β1.ConclusionsBMP signaling has clear biologic importance in osteosarcoma, although it is not yet fully understood. Future questions for study include assessing the utility of BMP signaling in prognostication of osteosarcoma and the potential modulation of BMP signaling for inhibition of osteosarcomagenesis, growth and invasion.

The pericyte antigen RGS5 in perivascular soft tissue tumors

Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear lineage of differentiation, although most are presumed to originate from or differentiate to pericytes or a modified perivascular cell. Among these, glomus tumor, myopericytoma, and angioleiomyoma share a spectrum of histologic findings and a perivascular growth pattern. In contrast, solitary fibrous tumor was once hypothesized to have pericytic differentiation--although little bona fide evidence of pericytic differentiation exists. Likewise the perivascular epithelioid cell tumor (PEComa) family shares a perivascular growth pattern, but with distinctive dual myoid-melanocytic differentiation. RGS5, regulator of G-protein signaling 5, is a novel pericyte antigen with increasing use in animal models. Here, we describe the immunohistochemical expression patterns of RGS5 across perivascular soft tissue tumors, including glomus tumor (n = 6), malignant glomus tumor (n = 4), myopericytoma (n = 3), angioleiomyoma (n = 9), myofibroma (n = 4), solitary fibrous tumor (n = 10), and PEComa (n = 19). Immunohistochemical staining and semi-quantification was performed, and compared to αSMA (smooth muscle actin) expression. Results showed that glomus tumor (including malignant glomus tumor), myopericytoma, and angioleiomyoma shared a similar diffuse immunoreactivity for RGS5 and αSMA across all tumors examined. In contrast, myofibroma, solitary fibrous tumor and PEComa showed predominantly focal to absent RGS5 immunoreactivity. These findings further support a common pericytic lineage of differentiation in glomus tumors, myopericytoma and angioleiomyoma. The pericyte marker RGS5 may be of future clinical utility for the evaluation of pericytic differentiation in soft tissue tumors.

Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor ☆ ☆☆

Pericytes are modified smooth muscle cells that closely enwrap small blood vessels, regulating and supporting the microvasculature through direct endothelial contact. Pericytes demonstrate a distinct immunohistochemical profile, including expression of smooth muscle actin, CD146, platelet-derived growth factor receptor β, and regulator of G-protein signaling 5. Previously, pericyte-related antigens have been observed to be present among a group of soft tissue tumors with a perivascular growth pattern, including glomus tumor, myopericytoma, and angioleiomyoma. Similarly, malignant tumor cells have been shown to have a pericyte-like immunoprofile when present in a perivascular location, seen in malignant melanoma, glioblastoma, and adenocarcinoma. Here, we examine well-differentiated liposarcoma specimens, which showed some element of perivascular areas with the appearance of smooth muscle (n = 7 tumors). Immunohistochemical staining was performed for pericyte antigens, including smooth muscle actin, CD146, platelet-derived growth factor receptor β, and regulator of G-protein signaling 5. Results showed consistent pericytic marker expression among liposarcoma tumor cells within a perivascular distribution. MDM2 immunohistochemistry and fluorescence in situ hybridization for MDM2 revealed that these perivascular cells were of tumor origin (7/7 tumors), whereas double immunohistochemical detection for CD31/CD146 ruled out an endothelial cell contribution. These findings further support the concept of pericytic mimicry, already established in diverse malignancies, and its presence in well-differentiated liposarcoma. The extent to which pericytic mimicry has prognostic significance in liposarcoma is as yet unknown.

Presurgical Dentofacial Orthopedic Management of the Cleft Patient

Over the last decade, presurgical orthopedic molding for the patient with cleft lip and palate has become much more common; it is even reasonable to assume it may be the standard of care for those wide unilateral and bilateral clefts with substantial dentofacial deformities. In 2013, there was a comparative study of nasoalveolar molding methods, comparing the Grayson-NAM device and DynaCleft. The results showed the 2 to be equivocal with both methods significantly reducing the cleft width and improving the nasal asymmetry.

Corrigendum to “Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor” (Hum Pathol 2016;54:92–99)

School of Dentistry, University of California, Los Angeles, CA 90095 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine,University of California, Los Angeles, CA 90095 Nationwide Childrens Hospital, Columbus, OH 43205 Orthopedic Hospital Research Center, University of California, Los Angeles, CA 90095 Department of Surgery, University of California, Los Angeles, Los Angeles, CA 90095 Center for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom