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Heterotopic Ossification: Two Rare Forms and What They Can Teach Us.

Heterotopic ossification is characterized by the formation of normal bone at ectopic soft-tissue locations. Regardless of the etiology of heterotopic ossification, requisite pathogenetic conditions include an inductive signal capable of stimulating morphogenesis, a population of inducible osteoprogenitor cells, and a heterotopic environment conducive to osteogenesis. Two rare heritable and developmental forms of heterotopic ossification, fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, provide valuable clinical and pathogenetic insights into heterotopic ossification in humans. A fundamental understanding of the developmental and molecular pathology of these disorders may lead to more effective strategies for preventing and treating heterotopic ossification in humans.

Journal Article↗

[Atypical ossification of anomalous ribs].

Atypical ossifications of anomalous ribs were found in 22 cases of 400.000 fluorograms with rentgenological control (0,005% or 1:18.000). Among them there were 15 cases on the right side, 6--on the left and one bilateral case in the third ribs. The fourth ribs were altered more frequently (12) and the fifth one--less frequently (9). Atypical ossifications were observed only in forked bifurcations of anterior ends which may serve as one of differential diagnostical signs for distinguishing them from other pathological changes.

Humans↗

[Clinical aspects, differential diagnosis and histogenesis of heterotopic ossification].

Investigations regarding proliferation behaviour, histogenesis and bone transformation were carried out on soft tissue samples with 133 heterotopic ossifications (HO), collected from the surgical material of the Institute of Pathology, Berufsgenossenschaftliche Kliniken Bergmannsheil, using methods of conventional histology, histochemistry, immunohistochemistry, electron microscopy and molecular biology, yielding the following results: 1. There is only a limited pathognomonic growth pattern for the variant of non-traumatic heterotopic ossification. Basically, the ossification foci may be divided into central, intermediate and peripheral zones. Expression intensities of the proliferation markers PCNA and MIB-1 show the proliferation behaviour in peripheral areas of osteogenesis to be similar to that found in autonomous osseous neoplasias. The phenotypical picture of zonal architecture found in HO can be seen by the simultaneous demonstration of variable image sequences of multifocally arising ectopic formations of new bone with varying degrees of maturation. 2. Vascular endothelium and pericytes are integrated into the formal histogenesis of heterotopic ossification and belong to osteoprogenitor cells as "stem cells" of heterotopic ossification. 3. The histochemically established expression pattern of alkaline phosphatasis is in good correlation with the degree of activity of the step-by-step development of heterotopic ossification. The intracellular demonstration of alkaline phosphatasis is an indicator for the transformation towards an osteogenic direction. In HO, the enzyme is a major characteristic of osteoprogenitor cells. 4. According to our immunohistochemical results, the proteoglycanes Decorin and PG 100-osteogenic matrix proteins-show a phase-like expression and are involved in osteoneogenesis. They are predominantly found in the area of mineralization. The proteoglycane 100 experiences a "modulation" and can be demonstrated almost selectively in osteoclasts in advanced stages of osteodevelopment. 5. Using in situ hybridization-with digoxigenin labeled cDNA probes- and a propidium iodide counterstaining a co-expression of collagene types I, II and III-mRNA could be demonstrated in samples of ossification. The expression pattern is similar to the collagen expression I. in early phases of embryonal bone development II. with callus proliferation and shows III. also similarities to chondral neoplasias. The results underline the reactive-neoplastic character of heterotopic ossification. 6. TGF-beta 1 mRNA shows a polytopic expression pattern with accumulation in areas of osteogenesis. TGF-beta 1 was found mostly in cartilage cells of heterotopic ossifications, as were collagene types I (alpha 1) and III (alpha 1) mRNAs. In sum, our in situ hybridization results underline the central part of cartilage cells in the ossification process in ectopic osteoneogenesis. This is also indicated by a phenotypical alteration of collagen expression as well as by an accumulation of TGF-beta 1 in chondral ossification areas. In situ hybridization propidium iodide counterstaining offers a reproducable image of morphological structures in the histological slide sample by means of fluorescence microscopy. 7. Phenotyping of osteroclasts in HO revealed their derivation from mature local macrophages. The immunohistochemical characterization with the demonstration of the vitronectin receptor classified the multinucleate giant cells of HO as original osteoclasts. Their origin is in accordance with the histogenetical concept of original bone. 8. Summarizing, the results characterize heterotopic ossification as a reactive proliferative and reversible neoplasia in chronically damaged soft tissue. From the formal pathogenetical point of view, relations could be established to orthotopic osteoneogenesis as well as to impaired proliferation kinetics, similar to osseous autonomous neoplastic lesions. (ABSTRACT TRUNCATED)

Biomarkers↗

Heterotopic ossification: a case report and immunohistochemical observations.

This report describes the case of a 69-year-old man with adenocarcinoma of the transverse colon who developed heterotopic ossification in a metastatic axillary lymph node. The areas of pathologic bone formation were characterized by the appearance of osteoblast-like cells at the surfaces of the mineral deposits. Immunostaining for alkaline phosphatase revealed a significant concentration of this enzyme in these cells and, to a lesser degree, on the apical membrane of the glandular cells of the adenocarcinoma adjacent to the ossification centers. Proliferating mesenchymal cells in close proximity to the areas of osteogenesis also showed significant immunolabeling. We conclude that metastatic colonic carcinoma can promote heterotopic ossification, and that alkaline phosphatase is intimately associated with bone formation under these pathologic conditions.

Adenocarcinoma↗

Ultrasonography as a diagnostic modality in Osgood-Schlatter disease. A clinical study and review of the literature.

Sonographic examination of the knee has been proposed by several authors in the past as a simple and reliable method to diagnose Osgood-Schlatter disease (OSD). Ultrasound was used to compare the knees of 25 boys and 10 girls with typical OSD with 35 symptom-free knees of an aged-matched group of children. Based on recorded data, patients were categorized (one affected knee in each individual) according to the classification system proposed by De Flaviis et al. in 1989. The results included the following pathological findings: pretibial swelling, fragmentation of the ossification center, insertional thickening of the patellar tendon, and excessive fluid collection in the infrapatellar bursa. Of our patients, 26% fell into the type 1 category, 43% were type 2, 20% type 3, and 11% type 4. This distribution of cases was found to be statistically similar to the initial findings reported by De Flaviis and colleagues. This study therefore supports the validity and reproducibility of their classification method for the ultrasonographic evaluation of children with OSD. This is only the first step, and further assessment of this classification is still required to elucidate its clinical as well as its prognostic value.

Adolescent↗

Effect of ultralow doses of antibodies to erythropoietin on antenatal and postnatal development of the offspring.

We studied the effects of ultralow doses of antibodies to erythropoietin on antenatal and postnatal development of rat offspring. Daily administration of the preparation on days 1-6, 6-16, and 16-19 of pregnancy did not increase embryonic mortality and was not associated with congenital malformations, fetal growth retardation, high incidence of pathological changes in fetal organs, and delayed ossification (compared to control and intact animals). For evaluation of their embryotoxic effect manifested in the postnatal period ultralow doses of antibodies to erythropoietin were administered throughout pregnancy. The offspring of treated and intact rats did not differ in physical development, appearance of sensory and locomotor reflexes, locomotor, exploratory, and emotional behavior, and learning and adaptive capacities.

Animals↗

Fibrodysplasia ossificans progressiva: CT appearance.

Twelve patients with fibrodysplasia ossificans progressiva were studied with computed tomography (CT). Characteristic swelling of the muscular fascial planes could be identified on CT scans prior to the development of ectopic ossification. Ossification could be seen on CT scans before it was apparent on plain radiographs. The pattern of ossification was similar to that seen at pathologic study, with multifocal sites developing adjacent to and extending around muscles. The appearance on CT scans confirms the hypothesis that the initial focus in fibrodysplasia ossificans progressiva is in the connective tissue.

Adolescent↗

Lectin-binding histochemistry of non-decalcified growth plate cartilage: a postembedment method for light microscopy of epon-embedded tissue.

A postembedment method for the localization of lectin-binding glycoconjugates was developed using Epon-embedded growth plate cartilage from Yucatan miniature swine. By testing a variety of etching, blocking, and incubation procedures, a standard protocol was developed for 1 micron thick sections that allowed visualization of both intracellular and extracellular glycoconjugates with affinity for wheat germ agglutinin and concanavalin A. Both fluorescent and peroxidase techniques were used, and comparisons were made between direct methods and indirect methods using the biotin-avidin bridging system. Differential extracellular lectin binding allowed visualization of interterritorial , territorial, and pericellular matrices. Double labeling experiments showed the precision with which intracellular binding could be localized to specific cytoplasmic compartments, with resolution of binding to the Golgi apparatus, endoplasmic reticulum, and nuclear membrane at the light microscopic level. This method allows the localization of both intracellular and extracellular lectin-binding glycoconjugates using fixation and embedment procedures that are compatible with simultaneous ultrastructural analysis. As such it should have applicability both to the morphological analysis of growth plate organization during normal endochondral ossification, as well as to the diagnostic pathology of matrix abnormalities in disease states of growing cartilage.

Animals↗

Angiogenesis in the pathogenesis of inflammatory joint and lung diseases.

This paper reviews hypotheses about roles of angiogenesis in the pathogenesis of inflammatory disease in two organs, the synovial joint and the lung. Neovascularisation is a fundamental process for growth and tissue repair after injury. Nevertheless, it may contribute to a variety of chronic inflammatory diseases, including rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis. Inflammation can promote angiogenesis, and new vessels may enhance tissue inflammation. Angiogenesis in inflammatory disease may also contribute to tissue growth, disordered tissue perfusion, abnormal ossification, and enhanced responses to normal or pathological stimuli. Angiogenesis inhibitors may reduce inflammation and may also help to restore appropriate tissue structure and function.

Arthritis↗

[Neurology in Paris hospitals, particularly the Salpêtrière before Charcot: Rostan on brain softening].

In the beginning of the 19th century, many studies were devoted to the diseases of the nervous system in France, long before the work of Charcot. The researches of Léon Rostan on the cerebral softening (1819, 1823) were based on the anatomoclinic method developed by the School of Paris whose most famous representatives were Corvisart and Laennec for the study of heart and lung diseases. The researches of Rostan were performed in the Salpêtrière hospital which was, at this time, an hospice for old women. Rostan was appointed Inspector of the Health service in the Salpêtrière hospital in 1812 then Head of a department in 1818. He was 28 year old when he published his book "Researches on the cerebral softening" in 1819. Rostan was the first to describe the spontaneous cerebral softening as a special anatomoclinic entity distinct from encephalitis and apoplexy. He compared this entity to the senile gangrene and stated that it was related to the ossification of cerebral arteries. He described the pathologic features of the brain softening and also its clinical symptomatology in opposition to that of apoplexy. The concept of brain softening according to Rostan was harshly fought by the followers of the Broussais's physiological medicine (from Lallemand, 1830 to Calmeil, 1859) who claimed that all brain softenings were due to the inflammation process and thus should be described as encephalitis. In opposite, the ideas of Rostan were accepted and developed by others such as Carswell in England (1835), Abercrombie in Scotland (1836) and Andral in France (1827, 1840). These authors agreed that some type of cerebral softening was related to a disease of the arterial system. Nevertheless, the modern concept of brain softening was not definitively accepted before the description of the thromboembolic mechanisms by Virchow in Germany (1856) with the help of the microscope, and the anatomoclinic studies of Proust, Laborde and Prevost and Cottard in France (1866). The book of Rostan was dedicated to the "Conseil Général des Hospices" which was created in 1801 to unify the administration of the hospitals in Paris and became the "Administration Générale de l'Assistance Publique à Paris" in 1849. One hundred and fifty years after its publication, the work of Léon Rostan was outstanding by its modernity of the form as well as the substance.

Cerebrovascular Circulation↗

Ankylosing spondylitis: what remains of the standard radiography anno 2004?

In this review, the radiographic features of ankylosing spondylitis of the axial skeleton will be discussed shortly. Three pathologic processes, including inflammation, bony repair and ossification occurring consecutively or simultaneously, will contribute to the radiographic picture of ankylosing spondylitis. Typical target sites at which these processes take place are the synovial joints, discovertebral joints and ligamentous attachments or entheses of the axial skeleton.

Humans↗

[Arthroscopic evaluation of the mobility of the meso-acromion].

OBJECTIVES: Failure of fusion of the secondary centers of ossification of the acromial apophyses is a pathology that should be included in the differential diagnosis of shoulder pain and subacromial impingement syndrome. Mobility of the meso-acromion is of particular importance in choosing the appropriate treatment. This study presents a new arthroscopic method to evaluate the mobility of os acromiale. METHODS: We presented the arthroscopic evaluation and surgical treatment of three women (mean age 43.3 years; range 34 to 53 years) with shoulder pain and a radiographically confirmed meso-acromiale. The Neer and Hawkins impingement signs were positive and palpation over the acromion gave rise to pain. Axillary radiographs showed a meso-acromion in all the affected shoulders. Magnetic resonance imaging showed a rotator cuff tear in one patient. During arthroscopic examination the motility of the meso-acromion was dynamically observed in the subacromial region and the rotator cuff tear was repaired. Acromioplasty was not performed. Following removal of pseudarthrotic areas, the mobile meso-acromion was fixed with a cerclage wire, two cannulated screws and bone grafting, followed by a tension-band configuration. The mean follow-up was five years (range 3 to 6 years). RESULTS: Union occurred in all the patients. None of the patients had shoulder pain at rest or during activities. When compared with the normal side, the range of motion and the strength of the shoulder were normal in all the patients, with Constant scores being 89, 96, and 98, respectively. CONCLUSION: Identification of the type of os acromiale is important for the treatment plan. The meso-acromion is particularly important because of its greater size and its role in narrowing the subacromial space. It is necessary to determine whether the meso-acromion fragment is mobile. Dynamic arthroscopic examination offers significant help in this respect.

Acromion↗

[Disseminated ossification of the lung].

Disseminated pulmonary ossification is a rather rare finding. Two classical cases of the dendriform and seven of the nodular one, even if with minimal aspects, were reported. They were found through a revision of 720 postmortem registers and a reexamination of their histological specimens. A typical morphologic picture was observed. About formal genesis of the bone we emphasized the possibility that the ossification occurred in the dendriform also through a cartilaginous phase in addition to a connective one. Various pathological forms of the lung or other organs, that on the basis of the literature are considered responsible or associated with pulmonary ossification, were listed. Eventually, we pointed out that dendriform could be a pathological picture by itself and not a secondary one, that is to say a real idiopathic ossification.

Aged↗

Heterotopic ossification in the orbit.

BACKGROUND: While calcification of orbital hemangiomas has been reported previously, no reports exist of heterotopic ossifications occurring within the orbit. CASE DESCRIPTION: A 30-year-old male presented with spontaneous onset of painless progressive proptosis of the left eye, with diplopia. The preoperative radiologic findings are presented. The lesion was excised completely. The pathologic features and probable causes are discussed. CONCLUSIONS: Heterotopic ossification of the orbit should be considered in the differential diagnosis of an orbital lesion showing radiologic features of calcification or ossification.

Adult↗

Does increased signal intensity of the spinal cord on MR images due to cervical myelopathy predict prognosis?

We examined whether or not high signal intensity change on magnetic resonance imaging of the spinal cord of patients with cervical myelopathy is related to the clinical symptoms and prognosis. Twenty-five patients with cervical myelopathy were treated by decompressive surgery which involved laminoplasty or decompressive anterior interbody fusion. The pathological conditions were cervical disc herniation (n = 8), ossification of the posterior longitudinal ligament in the cervical spine (n = 7), and cervical spondylotic myelopathy (n = 10). The spinal cord compression and the intramedullary signal intensity at the site of maximum compression were evaluated pre- and postoperatively using T1- and T2-weighted images. There was no significant relationship between spinal cord compressive change and clinical symptoms. Patients in whom the high signal change of the spinal cord on T2-weighted sequence recovered after decompressive surgery had better recovery from clinical symptoms, but a statistical significance was not found. We suggest that signal changes on T2-weighted images may reflect pathological changes but cannot be used to predict prognosis at present.

Adult↗

Clinical and prognostic analysis of ossified ligamentum flavum in a Chinese population.

OBJECT: The authors performed a retrospective study of clinical and radiological data obtained in 27 Chinese patients with myelopathy induced by ossification of the ligamentum flavum (OLF) who underwent surgery between March 1990 and March 2002. The factors related to surgical outcome of thoracic OLF-induced myelopathy were also assessed. METHODS: The preoperative clinical features and radiological findings were reviewed retrospectively. Preoperative and postoperative neurological status was assessed using the Japanese Orthopaedic Association (JOA) scoring system and the Nurick Scale. The ossified lesions were classified into five types (lateral, extended, enlarged, fused, and tuberous). Multiple linear regression and logistic regression analyses were performed to establish the factors affecting surgical outcome. The patients' chief complaints were lower-limb weakness and gait disturbance (93%), numbness and sensory deficit (89%), and low-back pain (48%). The coexisting pathological entities were disc herniation, canal stenosis, and ossification of posterior longitudinal ligament. The ossified ligamentum flavum was mainly located at the T10-12 (67%) and T1-3 (15%) levels. Symptoms in 26 patients improved but resolved completely in only 14 after surgery. The mean overall JOA score was 5.3 +/- 1.9 preoperatively and 7.9 +/- 2.3 postoperatively. There is a significant difference between the pre- and postoperative neurological status (p < 0.05) determined by the Student t-test. The recovery rate was 46.3 +/- 9.4%. Multiple regression analysis revealed negative correlation between the duration of preoperative symptoms and surgical outcome as well as a positive correlation between the preoperative JOA score and surgical outcome. Logistic regression analysis demonstrated that fecal and/or urinary incontinence, positive patellar and/or ankle clonus, and intramedullary high T2-weighted magnetic resonance (MR) imaging signal change had negative effects on the surgical outcome. CONCLUSIONS: The clinical and radiological features of OLF in the Chinese population are similar to those observed in the Japanese population. The duration of preoperative symptoms and JOA score are the most important predictors of the postoperative JOA score and recovery rate. The patients with fecal and/or urinary incontinence, positive patellar and/or ankle clonus, and intramedullary high T2-weighted MR imaging signal change were at higher risk of poor outcome after surgery.

Adult↗

The significance of sinonasal radiodensities: ossification, calcification, or residual bone?

PURPOSE: To determine whether very radiodense material within a sinonasal soft-tissue mass on CT can be differentiated as calcification, ossification, or residual bone. METHODS: We retrospectively described the radiodensities within 235 sinonasal soft-tissue masses as discrete, solitary or multiple, or as a diffuse process with either a well-defined or poorly defined margin. They were also classified as calcification, ossification, or residual bone. Findings were correlated with pathologic specimens. RESULTS: Residual bone was underdiagnosed; calcification was overdiagnosed. A solitary discrete density was most likely to be calcification within an inflammatory mass. However, multiple discrete densities were as likely to be in a tumor as in an inflammatory lesion. If the process was diffuse with a well-defined margin, it was most likely to be a benign fibroosseous lesion. If the process was diffuse with a poorly defined margin, it was most likely to be a high-grade sarcoma. Densities within inverted papillomas were shown to be residual bone, not calcifications; densities within esthesioneuroblastomas were calcifications. CONCLUSION: Radiodensities may help in refining a CT diagnosis, but one may not know based on CT whether the density is a calcification, ossification, or residual bone.

Calcinosis↗

A review of factors predictive of surgical outcome for ossification of the ligamentum flavum of the thoracic spine.

OBJECT: Ossification of the ligamentum flavum (OLF) is a pathological condition that affects the ligament and causes slowly progressive myeloradiculopathy in adults. Although OLF has been regarded as endemic to East Asian countries, studies from outside these areas have increasingly been reported. Because of long-standing compression of the spinal cord by OLF, a patient's functional prognosis may not always be favorable, and attempts have been made in recent studies to identify clinical factors that are predictive of the surgical outcome of patients with thoracic OLF. METHODS: The authors conducted a review of the literature published in the English, Japanese, and Korean languages. They examined studies in which correlation between clinical factors and outcome was statistically evaluated. The clinical factors included sex, age, level of the ossified ligamentum flavum, number of segments affected by OLF, coexisting ossification of the posterior longitudinal ligament (OPLL) or other spinal disorders, preoperative duration of symptoms, preoperative neurological score, computed tomography (CT)-based classification, and the presence of intramedullary high signal intensity on T2-weighted magnetic resonance images. CONCLUSIONS: The clinical factors that are unlikely to be predictive of outcome include sex, age, level of the ossified lesion, number of OLF-affected segments, coexisting OPLL, CT classification, and the presence of high signal intensity. It is unclear whether the preoperative duration of symptoms or neurological score is predictive of outcome because the results have been inconsistent among the studies. Analysis of the more recent literature, however, suggests that these two factors are predictive of outcome. The use of a neurological score should be standardized so that compilation and comparison of data can be facilitated.

Humans↗