Presumed Lacrimal Gland Pleomorphic Adenoma With Extensive Ossification and Necrosis.

Calcification within pleomorphic adenomas of the lacrimal gland is well recognized but uncommon, being seen more readily in lacrimal gland carcinomas. Bony formation, ossification, in pleomorphic adenomas of the lacrimal glands is even rarer. Together with extensive sclerosis, or "coagulative necrosis," ossification and necrosis should alert the clinician to the risk of malignant transformation. However, both can mimic carcinomatous change, leading to misinterpretation of malignancy in an otherwise benign lacrimal gland neoplasm. We present 2 case reports of patients with clinically presumed pleomorphic adenomas of the lacrimal gland whose histopathology demonstrated lacrimal gland ossification and necrosis without features of malignancy or invasive disease.

Comparison of the Outcomes of Anterior Cervical Discectomy and Fusion and Cervical Disc Replacement for Cervical Disc Disease.

OBJECTIVE: To compare the radiological outcome and development of heterotopic ossification (HO) following single-segment anterior cervical discectomy and fusion (ACDF) and cervical disc replacement (CDR) for cervical disc herniation and evaluate their impact on surgical success. STUDY DESIGN: Descriptive comparative study. Place and Duration of the Study: Neurosurgery Department at Bozyaka Education and Research Hospital, Izmir, Turkiye, between January 2020 and June 2022. METHODOLOGY: Patients aged 18-70 years with radicular neck pain unresponsive to conventional medical treatment and an MRI-confirmed diagnosis were included. Patients with osteoporosis (OP) were excluded. Patients were randomised into two treatment groups (ACDF and CDR) and stratified by age and symptom severity. Radiographic assessments and HO classification according to McAfee were performed. RESULTS: Among the included patients, 56 underwent ACDF and 45 underwent CDR. The mean patient age was 48.29 ± 9.530 and 41.84 ± 7.239 years in the ACDF and CDR groups, respectively (p <0.001). The postoperative disc height increased in both groups. The T1 slope was significantly higher preoperatively and in the early postoperative period in the CDR group than in the ACDF group (p = 0.001). HO was graded as 1, 2, 3, and 4 in 28 (27.7%), 6 (5.9%), 7 (6.9%), and 4 (3%) patients, respectively. CONCLUSION: ACDF and CDR provided similar improvements in radiological measurements and pain relief. Although both procedures significantly enhanced the patient's quality of life and disability scores, HO was more prevalent following CDR during long-term follow-up. KEY WORDS: Cervical disc replacement, Anterior cervical discectomy and fusion, Spinal surgery techniques, Heterotopic ossification.

Vegfc-expressing cells form heterotopic bone after musculoskeletal injury.

Heterotopic ossification (HO) is a challenging condition that occurs after musculoskeletal injury and is characterized by the formation of bone in non-skeletal tissues. While the effect of HO on blood vessels is well established, little is known about its impact on lymphatic vessels. Here, we use a mouse model of traumatic HO to investigate the relationship between HO and lymphatic vessels. We show that injury triggers lymphangiogenesis at the injury site, which is associated with elevated vascular endothelial growth factor C (VEGF-C) levels. Through single-cell transcriptomic analyses, we identify mesenchymal progenitor cells and tenocytes as sources of Vegfc. We demonstrate by lineage tracing that Vegfc-expressing cells undergo osteochondral differentiation and contribute to the formation of HO. Last, we show that Vegfc haploinsufficiency results in a nearly 50% reduction in lymphangiogenesis and HO formation. These findings shed light on the complex mechanisms underlying HO formation and its impact on lymphatic vessels.

"Bone in the penis" or fasciitis ossificans of the penis - a first time description of a pseudo-tumor at an extraordinary site.

BACKGROUND: Fasciitis ossificans is a rare subtype of nodular fasciitis, a benign soft tissue tumor with reactive characteristics. Due to its rapid growth, it is often misdiagnosed as a malignant tumor. While fasciitis ossificans commonly originates from the subcutaneous tissue and can appear throughout the body, it may also arise from extraordinary sites. CASE PRESENTATION: We report the first-ever documented case of fasciitis ossificans arising from the penis in a male patient who presented with a tumor on the glans penis. The tumor was surgically resected due to suspicion of penile cancer. Initial histopathological analysis led to a misdiagnosis of squamous cell carcinoma. However, pathological consultation ultimately confirmed the diagnosis of fasciitis ossificans of the penis originating from the glans penis by demonstrating ossification. CONCLUSION: This case underscores the importance of considering fasciitis ossificans in the differential diagnosis of soft tissue tumors, even in unusual locations such as penile soft tissue.

Cell Senescence in Heterotopic Ossification.

The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.

Neurogenic heterotopic ossification of the hip: Magnetic resonance imaging versus computed tomography for pre-surgical assessment.

PURPOSE: Neurogenic heterotopic ossification (NHO) of the hip is a frequent complication of spinal cord injuries, often requiring surgical management. Pre-surgical imaging assessment is essential, usually with computed tomography (CT)-scan. We aimed to compare magnetic resonance imaging (MRI) and CT for pre-surgical imaging assessment of the NHO, particularly for their relationships with vessels and nerves. METHOD: This prospective study included consecutive patients who underwent surgery for NHO from July 2019 to April 2022. All patients had CT angiography and MRI including Zero Echo Time and TRICKS sequences. Radiologists used standardized reports for CT and MRI to evaluate NHO and their features, bone mineralization, and relation to the arteries, veins and nerves. Agreement between pre-surgical CT and MRI was evaluated. RESULTS: Twenty-four patients (mean age: 53.5 ± 12.2 years) were included, among which 7 had bilateral NHO (31 hips). NHO were anterior in 15/31 hips (48 %), multifragmented in 25/31 hips (81 %). Mild and significant demineralization was most frequent. Gutter and tunnel were reported in 11.1 % of the arteries. Nerves were more often identified in MRI than in CT-scan. Agreement coefficients between CT and MRI were excellent for NHO location (0.95) and implantation (0.92), good for fragmentation (0.70), contact with joint capsule (0.66), bone mineralization (0.74), and relation to arteries (0.85), veins (0.76), sciatic nerve (0.7) and moderate for femoral nerve (0.47). CONCLUSION: MRI exhibited a good agreement with CT for pre-surgical assessment of NHO of the hip, especially to evaluate their relationships with the arteries, veins and sciatic nerve. Femoral nerves were more often identified in MRI than in CT-scan.

KLF5 promotes the ossification process of ligamentum flavum by transcriptionally activating CX43.

BACKGROUND: Ossification of ligamentum flavum (OLF) is a prevalent degenerative spinal disease, typically causing severe neurological dysfunction. Kruppel-like factor 5 (KLF5) plays an essential role in the regulation of skeletal development. However, the mechanism KLF5 plays in OLF remains unclear, necessitating further investigative studies. METHODS: qRT-PCR, immunofluorescent staining and western blot were used to measure the expression of KLF5. Alkaline Phosphatase (ALP) staining, Alizarin red staining (ARS), and the expression of Runt-related transcription factor 2 (RUNX2), osteopontin (OPN), and osteocalcin (OCN) were used to evaluate the osteogenic differentiation. Luciferase activity assay and ChIP-PCR were performed to investigate the molecular mechanisms. RESULTS: KLF5 was significantly upregulated in OLF fibroblasts in contrast to normal ligamentum flavum (LF) fibroblasts. Silencing KLF5 diminished osteogenic markers and mineralized nodules, while its overexpression had the opposite effect, confirming KLF5's role in promoting ossification. Moreover, KLF5 promotes the ossification of LF by activating the transcription of Connexin 43 (CX43), and overexpressing CX43 could reverse the suppressive impact of KLF5 knockdown on OLF fibroblasts' osteogenesis. CONCLUSION: KLF5 promotes the OLF by transcriptionally activating CX43. This finding contributes significantly to our understanding of OLF and may provide new therapeutic targets.

Heterotopic bone formation in a case of clear cell renal cell carcinoma: A case report.

Renal cell carcinoma (RCC) with heterotopic formation has been reported very rarely. We report this rare entity in a 33-year-old female patient who came to the out-patient department after complaining of pain in the lumbar region of the left side for 2 years. A computed tomography scan showed a heterogeneously enhancing lesion originating from the posterior cortex of the left kidney in the upper pole. It had many chunky calcification foci and was treated with left robotic partial nephrectomy. Histo-pathological examination revealed clear cell RCC with the heterotopic bone formation with a tumor size measuring 5 × 4 × 2.5 cm; the tumor was limited to the kidney, and the tumor resection margin were free of tumor, WHO/ISUP Grade 2. The pathological stage (AJCC 8th edition PTNM) was p T1b p NX p MX. The prognostic implications regarding calcification are poorly addressed in the literature. Patients suffering from osseous metaplasia are often in their early stages of the disease and have a favorable prognosis.

Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance.

Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD-like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.

Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.

OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSIONS: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.

iMSC-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP. METHODS: In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc on BMP signaling pathways and HO development, respectively. RESULTS: We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs. CONCLUSIONS: These results offer a new perspective for treating FOP through stem cell therapy.

The significance of heterotopic ossification following total ankle arthroplasty: a systematic review and meta-analysis.

PURPOSE: The purpose of this systematic review and meta-analysis was to evaluate the prevalence and clinical significance of heterotopic ossification (HO) following total ankle replacement (TAR). METHODS: During August 2023, the PubMed, Embase and Cochrane library databases were systematically reviewed to identify clinical studies reporting HO following TAR. Data regarding surgical characteristics, pathological characteristics, subjective clinical outcomes, ankle range of motion, radiographic outcomes, reoperation rates were extracted and analysed. RESULTS: Twenty-seven studies with 2639 patients (2695 ankles) at a weighed mean follow-up time of 52.8 ± 26.9 months were included. The pooled prevalence rate was 44.6% (0.25; 0.66). The implant with the highest rate of HO was the INBONE I (100%) and BOX (100%) implants. The most common modified Brooker staging was grade 1 (132 patients, 27.0%). Random effects models of standardized mean differences found no difference in American orthopedic foot and ankle society (AOFAS) scores, visual analog scale scores (VAS) and ankle range of motion (ROM) between patients with HO and patients without HO. Random effects models of correlation coefficients found no correlation between AOFAS, VAS and ROM and the presence of HO. The surgical intervention rate for symptomatic HO was 4.2%. CONCLUSION: This systematic review and meta-analysis found that HO is a common finding following TAR that is not associated with inferior clinical outcomes. Surgical intervention was required only for moderate-to-severe, symptomatic HO following TAR. This study is limited by the marked heterogeneity and low level and quality of evidence of the included studies. Further higher quality studies are warranted to determine the precise prevalence and impact of HO on outcomes following TAR.

Incidence of heterotopic ossification following total hip arthroplasty by approach: a systematic review.

BACKGROUND: Heterotopic ossification (HO) formation has been increasingly recognized as a complication of major orthopedic surgeries, particularly total hip arthroplasty (THA). Though, the overall incidence of HO following THA has been well-documented, it is often not reported by severity or by surgical approach. QUESTIONS/PURPOSES: (1) What are the demographics of patients with HO? (2) What is the severity of HO following THA using the Brooker classification? (3) What is the incidence and class of HO following different THA approaches (anterior, posterior, posterolateral, anterolateral, superior, lateral, trans-gluteal)? (4) What are the number and training level of surgeons who performed each procedure? METHODS: The PubMed, Embase, and Web of Science databases were queried, and PRISMA guidelines were followed. Qualitative and quantitative analyses were performed using Microsoft Excel. RESULTS: We isolated 26 studies evaluating 6512 total hip arthroplasties (THA). The mean HO percentage overall was 28.8%, mostly Class I (54.2%) or Class II (29.6%). The highest percentage of HO was associated with the modified direct lateral (57.2%) and the traditional lateral (34.6%) approaches. The lowest HO percentages were identified following posterolateral (12.8%) and direct superior approaches (1%). Most studies reported a singular senior surgeon operating within the same approach for all patients. CONCLUSIONS: The traditional lateral and modified direct lateral approaches to THA resulted in the highest percentage of HO postoperatively. However, most ossification cases were not clinically significant and did not strongly affect overall patient morbidity. Further studies are warranted to identify an association between severity of ossification and different arthroplasty approaches.

Trauma patient heterotopic ossification diagnosis is associated with increased hospital length of stay.

BACKGROUND: Traumatic heterotopic ossification (tHO) refers to the development of extra-skeletal bone in muscle and soft tissues following tissue insult secondary to surgery or trauma. This presents a persistent clinical concern associated with significant patient morbidity and expense to diagnose and treat. Traumatic HO is a substantial barrier to rehabilitation for trauma-injured patients. As such, the development of tHO after burn and other trauma is hypothesised to prolong inpatient length of stay (LOS) and thus increase health care costs. OBJECTIVE: To investigate the association between an inpatient tHO diagnosis and hospital LOS in trauma patients. METHODS: A retrospective audit of trauma patients over a 14-year period was completed using data from four WA hospitals. Burn and neurological trauma patients diagnosed with tHO as an inpatient (tHO+) and control subjects (tHO-), matched (1:3) by age, gender, and injury severity factors, were identified using medical diagnostic codes. Data relating to patient and injury-related determinants of LOS from tHO+ and tHO- subjects were analysed to model the association of tHO on total hospital length of stay. RESULTS: 188 identified patients were hospitalised due to traumatic injury; 47 patients with tHO following burn injury (n = 17), spinal cord injury (n = 13) and traumatic brain injury (n = 17), and 141 control patients. Those who developed tHO during hospitalisation had a significantly higher median LOS than matched trauma patients who did not develop tHO (142 days vs. 61 days). Multivariate regression analyses identified the following independent predictive factors of a prolonged hospital LOS: tHO diagnosis, mechanical ventilation hours, injury to the hip region and thigh area, other ossification disorder, pressure injury, admission to intensive care unit and deep vein thrombosis. Trauma patients diagnosed with tHO during their hospital admission stayed 1.6 times longer than trauma patients matched for injury severity without a tHO diagnosis (IRR 1.56, 95% CI 1.35-1.79, p<0.001). CONCLUSION: Traumatic heterotopic ossification is an independent explanatory factor for increased hospital LOS in patients following burns, spinal cord, and traumatic brain injury. Early diagnosis may assist in reducing the impact of tHO on acute hospital stay after trauma.

Heterotopic mineralization (ossification or calcification) in aged musculoskeletal soft tissues: A new candidate marker for aging.

Aging can lead to various disorders in organisms and with the escalating impact of population aging, the incidence of age-related diseases is steadily increasing. As a major risk factor for chronic illnesses in humans, the prevention and postponement of aging have become focal points of research among numerous scientists. Aging biomarkers, which mirror molecular alterations at diverse levels in organs, tissues, and cells, can be used to monitor and evaluate biological changes associated with aging. Currently, aging biomarkers are primarily categorized into physiological traits, imaging characteristics, histological features, cellular-level alterations, and molecular-level changes that encompass the secretion of aging-related factors. However, in the context of the musculoskeletal soft tissue system, aging-related biological indicators primarily involve microscopic parameters at the cellular and molecular levels, resulting in inconvenience and uncertainty in the assessment of musculoskeletal soft tissue aging. To identify convenient and effective indicators, we conducted a comprehensive literature review to investigate the correlation between ectopic mineralization and age-related changes in the musculoskeletal soft tissue system. Here, we introduce the concept of ectopic mineralization as a macroscopic, reliable, and convenient biomarker for musculoskeletal soft tissue aging and present novel targets and strategies for the future management of age-related musculoskeletal soft tissue disorders.

Differences in the Demographics and Clinical Characteristics between the Ossification of the Posterior Longitudinal Ligament and Ossification of the Ligamentum Flavum in Patients Who Underwent Thoracic Spinal Surgery for Compressive Myelopathy.

Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) are related diseases associated with the ossification of spinal ligaments that can occasionally lead to thoracic myelopathy. We retrospectively analyzed the clinical data of 34 consecutive patients who underwent thoracic spinal surgeries for OPLL and/or OLF at our hospital between July 2010 and June 2022, and statistically compared data between patients with thoracic OPLL (TOPLL; n = 12) and those with thoracic OLF (TOLF; n = 22). The mean age of the TOPLL group was significantly lower than that of the TOLF group (53.7 vs. 68.4 years). The TOPLL group exhibited a greater female predominance than the TOLF group (58.3% vs. 18.2%). The median body mass index of the TOPLL group was significantly higher than that of the TOLF group (33.0 vs. 26.0 kg/m2). Patients with TOPLL significantly required instrumented fusion and repetitive surgical intervention more than those with TOLF (83.3% vs. 9.1%; 50.0% vs. 0.0%). Although neurological deterioration just after the intervention was more common in patients with TOPLL (41.7% vs. 4.6%), no difference was observed in thoracic Japanese Orthopaedic Association score and recovery rate in the chronic phase between TOPLL and TOLF. The TOPLL group had a younger onset, female dominance, and a greater degree of obesity when compared with the TOLF group. The surgery for TOPLL is challenging, considering that it requires long-range decompression and fusion, subsequent operations, careful management, and long-term follow-up, when compared to TOLF, which necessitates only simple decompression.

Heterotopic ossification, osteolysis and implant failure following cervical total disc replacement with the M6-C™ artificial disc.

INTRODUCTION: A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the prevalence, risk factors, and radiographic characteristics of periprosthetic bony changes and implant failure of the M6-C™ artificial disc. METHODS: We retrospectively analysed radiographic (conventional X-ray, CT scan) and clinical outcomes (EQ-5D-5L, Neck Disability Index (NDI), and Visual Analog Scale (VAS) for neck and arm pain) data collected during routine follow-up of patients who underwent CTDR with the M6-C™ between 2011 and 2015. RESULTS: In total, 85 patients underwent CTDR with the M6-C™. Follow-up data were available for 43 patients (54% female, mean age 44 years) with 50 implants and a mean follow-up of 8.1 years (6.5-11 years). Implant failure with the presence of severe osteolysis was identified in 5 (12%) patients who were all male (p = 0.016) and implanted at the C5/6 level (p = 0.11). All failed implants required revision surgery. The overall prevalence of osteolysis was 44% (22/50 implants) and 34% (17/50 implants) for significant heterotopic ossification. Patients with high-grade osteolysis showed higher VAS arm pain (p = 0.05) and lower EQ-5D-VAS health VAS (p = 0.03). CONCLUSION: We report a lower reoperation rate for failed M6-C™ implants than previously published, but confirmed that osteolysis and heterotopic ossification are common following CTDR with the M6-C™ and may be asymptomatic. Therefore, we strongly recommend ongoing clinical and radiographic monitoring after CTDR with the M6-C™, particularly for male patients implanted at the C5/6 level.