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Expression of osteocalcin, osteonectin, osteopontin, osterix and collagen type 1 RNA transcripts by cultured osteofibrous dysplasia/adamantinoma (OFD/ALB) stromal cells. Data normalised to osteoblast control. Mean ± s.d.
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Adamantinoma of long bones and osteofibrous dysplasia are rare, osteolytic primary bone tumours of uncertain origin containing areas of fibrous and fibro-osseous proliferation. We investigated the nature of the stromal cells in adamantinoma of long bones and osteofibrous dysplasia, and determined cellular and molecular mechanisms of osteolysis in t...
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... dysplasia but not adamantinoma stro- mal cells expressed alkaline phosphatase, an osteo- blast marker; both osteofibrous dysplasia and adamantinoma cells when cultured in the presence of b glycerophosphate and ascorbate, did not form RT-PCR studies showed expression of RNA tran- scripts in cultured osteofibrous dysplasia and adamantinoma stromal cells for the osteoblast products osteocalcin, osteonectin, osteopontin, osterix and collagen type 1 ( Figure 5). ...
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... Some authors supported the hypothesis of congenital epithelial cell implantation, others argued for traumatic implantation or articular origin, while recent studies indicate the role of mesenchymal-toepithelial transformation, leading to the origin of the epithelial component. [10][11][12][13] Similar clinical, radiological, histological and molecular features of AD and OFD suggest a relationship between the two. [14][15][16][17][18][19] Despite these similarities, the treatment and prognosis differ significantly; therefore, the establishment of diagnosis should be performed precisely. ...
Adamantinoma (AD) is a rare, slow-growing primary malignant bone tumor characterized by a biphasic morphology of clusters of epithelial cells and spindle cell osteofibrous components. A strong relationship between AD and osteofibrous dysplasia (OFD) has been proposed, while fibrous dysplasia (FD) has been rarely associated with AD. We present an AD case that was followed and histologically evaluated 3 times over 6 years with different morphological patterns. The tumor in the primary biopsy and after complete resection showed classical features of AD and osteofibrous-like pattern, while the recurrent lesion presented with exclusively spindle cell morphology and was thus diagnosed as FD. However, the extensive immunohistochemical analysis in all 3 lesions revealed strong reactivity for pancytokeratin, vimentin, p63, and podoplanin, which are characteristic for AD. Although, in the FD-like section of the tumor from the first recurrence the positivity of podoplanin was stronger than pancitokeratin, which was variably positive on spindle cells. The present case highlights the problem of diagnosing AD based on a single biopsy with one tumor’s component predominating over the other, and at the same time emphasizes the importance of using immunohistochemical staining for keratin and podoplanin when the histopathological features of (osteo)fibrous lesion can be linked to AD.
... P-63 is also a reliable marker in adamantinomas [35]. E-, P-and N-cadherin, as well as osteonectin are expressed in classical subtype whereas in OFD adamantinoma expression of nuclear factor kB ligand, macrophage cerebrospinal fluid and osteoclastogenic factors are seen [29,36]. Trisomies of chromosomes 7, 8, 12, 19 and 21 have been demonstrated through GTG-banding in both classical and OFD adamantinomas substantiating the common histological origins, findings of translocations, deletions and inversions are only present in adamantinomas [1,8,33,37]. ...
Adamantinoma is a rare primary low-grade malignant tumour of the appendicular skeleton most commonly found in the tibia. It has an indolent course, with local recurrences and lung metastases occurring over a protracted duration. There have been several suggestions pertaining to a vascular origin in the literature, however, histogenesis remains unclear. Currently, guidelines are not available pertaining to clinical management.
This paper presents an overview of the current literature regarding this unusual malignancy. It also explores disease etiology and acknowledges the benefits and challenges of investigations pertaining to diagnosis. It recognizes a paucity of recommendations regarding appropriate surveillance and follow up. This review aims to assist clinicians in the building of a consensus opinion for optimal adamantinoma case management under current circumstances where formal guidelines do not exist.
... In classic adamantinoma, immunochemistry can also detect E-, P-and N-cadherin, as well as osteonectin, but not osteopontin and osteocalcin (45). As is also seen in osteofibrous dysplasia, adamantinoma cells immunohistochemically express receptor activator of nuclear factor ĸB ligand, macrophage colony-stimulating factor and osteoclastogenic factors, which may be responsible for the osteolysis which is described in the referred lesions (46). Other researchers studied the proliferation marker Ki67, epidermal growth factor, epidermal growth factor receptor and fibroblast growth factor type 2 and concluded that the epithelial component is the primary proliferating tumor cell population capable of stimulating reactive fibrous growth (47). ...
Adamantinoma is a biphasic tumor, with a low potential for malignancy, characterized by clusters of epithelial cells surrounded by a relatively bland spindle-cell osteofibrous component. The aim of the present study was to review the updated data regarding epidemiology; pathogenesis; clinical presentation; radiological, histopathological and ultrastructural findings; and treatment options of adamantinoma. In X-ray, it is usually seen as an eccentric and sometimes central, lobular, lytic lesion with sclerotic margins of overlapping radiolucency, and a characteristic 'soap-bubble' appearance. Magnetic resonance imaging seems to be the most appropriate examination for differential diagnosis between adamantinoma and other skeletal tumors. Histologically, adamantinoma is identified as classic adamantinoma or osteofibrous-like adamantinoma. Classic adamantinoma is classified into four patterns of growth: Basaloid, tubular, spindle cell, and squamous. The preferable treatment of this tumor type is en bloc resection within wide operative margins, which may include suspicious regional lymph nodes, with limb reconstruction and limb salvage.
... Adamantinoma [3,[112][113][114][115][116] Progressive complexity of cytogenetic alterations including increased copy number of chromosomes 7, 8, 12, 19, and 21, KMT2D alterations and rare gene fusions ...
The diagnosis of primary tumors of bone relies heavily on clinicopathological and radiological correlation and is often best performed in a multidisciplinary setting. Bone tumors comprise a heterogenous category of human lesions ranging from benign to malignant neoplasms. These tumors affect a wide age range and can become problematic for diagnosis when less common entities are encountered. Traditionally the pathological diagnosis of many bone tumors has been based primarily on the evaluation of hematoxylin and eosin-stained glass slides, sometimes combined with ancillary diagnostic techniques such as immunohistochemistry, conventional cytogenetics, fluorescence in situ hybridization, and polymerase chain reaction-based assays. More recently, the advent of massively parallel sequencing-based techniques has opened new avenues for diagnostic testing in bone tumors; however, these new testing modalities are sensitive to traditional decalcification procedures that are commonly used in the routine processing of bony specimens. Herein we provide a focused review concentrating on the molecular genetic features of bone tumors with specific, recurrent genetic alterations that make them appealing targets for directed ancillary testing by conventional or molecular techniques. In addition, specimen handling with regards to decalcification procedures are discussed and the different types of testing modalities available are reviewed.
... Upon cell culture, tumour manifests macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL), molecules which engender osteolysis [1,2]. Differential Diagnosis Adamantinoma requires segregation from conditions such as •osteofibrous dysplasia is devoid of aggregates of epithelial cells and is immune reactive to keratin [7,8]. •metastatic carcinoma within the bone generally displays a diffuse dissemination of malignant cells. ...
... Vascular invasion is associated with extensively malignant cellular component. Osteofibrous dysplasia-like stroma is usually absent [7,8]. •adamantinoma like Ewing's sarcoma is associated with significant epithelial differentiation. ...
... Pertinent chromosomal rearrangements such as genomic fusions between EWSR1 gene situated upon chromosome 22 and ETS family of transcription factors are observed. However, FUS gene situated upon chromosome 16 is uncommonly substituted for EWSR1 gene [7,8]. ...
Adamantinoma is an exceptional, primary, malignant, low-grade bone, biphasic, fibro-osseous bone neoplasm of uncertain origin typically constituted of epithelial articulations embedded within a mesenchymal or osteofibrous dysplasia-like stroma. Adamantinoma commonly arises within diaphysis and metaphysis of tibia in addition to ulna, femur, fibula, humerus, radius, ribs, tarsal and metatarsal bones. Adamantinoma depicts a repetitive mutation of KMT2D (MLL2) gene along with fusion of somatic gene EPHB4-MARCH10. Expression of DLK1 gene is enhanced. Adamantinoma is subdivided into diverse categories such as classic subtype, osteofibrous dysplasia-like or differentiated adamantinoma and dedifferentiated adamantinoma. The neoplasm is comprised of epithelial cells with minimal atypia disseminated within an osteofibrous dysplasia -like stroma. Solid nests of basaloid cells with peripheral palisading, tubular structures, clusters of keratinized squamous epithelium or fascicles of spindle-shaped cells are exemplified.
... 4 The tumor is characterized histologically by a variety of morphologic patterns, consisting of both dominant epithelial component and areas of osteofibrous dysplasia-like fibro-osseous tissue. 5 Adamantinoma commonly occurs in the second to fifth decade of life (median age: 25 to 35 y) and a slight male predominance is noted. 3 The initial symptoms are often indolent and nonspecific; however, the majority of patients present with swelling, symptoms may last > 30 years before diagnosis. ...
Adamantinoma and osteofibrous dysplasia (OFD)-like adamantinoma are rare primary bone tumors that are predominantly confined to the tibia. These 2 entities show similarities in location, histology, and radiologic appearance; however, adamantinoma is malignant and therefore differentiating between these bone tumors is essential for optimal patient care. To elucidate their genomic and transcriptomic alteration profiles and expand their etiological mechanisms, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were conducted on adamantinoma and OFD-like adamantinoma tumors. Copy number variation analysis using WES data revealed distinct chromosomal alteration profiles for adamantinoma tumors compared with OFD-like adamantinomas, allowing molecular differentiation between the 2 tumor subtypes. Combining WES and copy number variation analyses, the chromatin remodelling-related gene KMT2D was recurrently altered in 3/8 adamantinoma tumors (38%), highlighting the potential involvement of deregulated chromatin structure and integrity in adamantinoma tumorigenesis. RNA-Seq analysis revealed a novel somatic gene fusion (EPHB4-MARCH10) in an adamantinoma, the gene fusion was fully characterized. Hierarchical clustering analysis of RNA-Seq data distinctly clustered adamantinoma tumors from OFD-like adamantinomas, allowing to molecularly distinguish between the 2 entities. David Gene Ontology analysis of differentially expressed genes identified distinct altered pathways in adamantinoma and OFD-like adamantinoma tumors, highlighting the different histopathologic characteristics of these bone tumor subtypes. Moreover, RNA-Seq expression profiling analysis identified elevated expression of DLK1 gene in adamantinomas, serving as a potential molecular biomarker. The present study revealed novel genetic and transcriptomic insights for adamantinoma and OFD-like adamantinoma tumors, allowing to differentiate genetically and transcriptomically between the 2 lesions and identifying a potential diagnostic marker for adamantinomas.
... It has also been recognized that recurrences and metastases more frequently show the spindle cell pattern though it is not clear whether it represents a more aggressive variant [5]. Recent evidence supports a pathogenetic relationship between osteofibrous dysplasia and adamantinoma but only the latter has malignant potential [6,7]. On conventional radiographs, adamantinoma involves the tibia or fibula diaphysis and produces multiple lucencies with interspersed sclerosis of the cortex with an overall destructive appearance [8]. ...
... Aneuploidy has been identified in the epithelial component [9]. Recurrent numerical abnormalities of chromosomes 2,7,8,10,11,12,19 and/or 21 have been reported [1]. Isolated cases with translocations involving chromosomes 1,8,9,16,17,19 and 21 have also been identified [10,11]. ...
Adamantinoma represents a distinct group of bone tumors showing both mesenchymal and epithelial differentiation most commonly involving the tibial diaphysis. Most adamantinomas contain a fibro-osseous component and an epithelial component consisting of squamous or basaloid cells. Adamantinomas are considered malignant neoplasms requiring en bloc excision that frequently recur locally and can rarely metastasize. Rare adamantinomas show an epithelial component consisting predominantly of monomorphic spindle cells, which, combined with an epithelial immunophenotype, can mimic monophasic synovial sarcoma. Synovial sarcoma is very rare in bone. It is considered a high-grade sarcoma that typically necessitates chemotherapy. However, the relationship between spindle cell adamantinoma and intraosseous synovial sarcoma has not been investigated. The current study was prompted by identification of a presumed spindle cell adamantinoma of the tibia with diffuse keratin expression that harbored a SS18 gene region rearrangement. FISH of eight additional bone tumors initially classified as spindle cell adamantinoma based on clinicoradiopathologic findings revealed one additional case with SS18 rearrangement. Histologically, both intraosseous synovial sarcoma and spindle cell adamantinoma demonstrated uniform fusiform nuclei with scant cytoplasm, short fascicles and low mitotic activity. The adamantinomas, but not the synovial sarcomas, were more likely to show overt epithelial differentiation in the form of pseudoglands or squamous nests. Immunohistochemistry of all cases, irrespective of SS18 status, showed diffuse keratin positivity in the spindle cell component, and less consistent EMA positivity. Clinical follow-up was available in both intraosseous synovial sarcomas, one of which recurred and the other metastasized. Two of the six spindle cell adamantinomas with follow-up metastasized. The above findings highlight the morphologic and immunophenotypic overlap between spindle cell adamantinoma and intraosseous synovial sarcoma of the tibia. Investigation of SS18 status to exclude synovial sarcoma is suggested prior to rendering a diagnosis of spindle cell adamantinoma.
... Histologically, OFD lesions exhibit ''zonal architecture'' characterized by spindle-shaped fibroblastlike cells in the center of the lesions that are progressively replaced with peripherally located, more differentiated cells from the osteoblastic lineage ( Figure 1B). 5 The cells lying at the center of the lesions stain for markers of undifferentiated mesenchymal cell states, whereas bridging zones of osteoid with surface osteoblasts and embedded osteocytic cells are interspersed between the lesions. 5,6 In OFD, the unossified zones eventually mineralize after replacement with normal osteoid and, finally, bone. ...
... 5 The cells lying at the center of the lesions stain for markers of undifferentiated mesenchymal cell states, whereas bridging zones of osteoid with surface osteoblasts and embedded osteocytic cells are interspersed between the lesions. 5,6 In OFD, the unossified zones eventually mineralize after replacement with normal osteoid and, finally, bone. This histological progression corresponds with the clinical and radiographic resolution of the lesions, although some affected bones exhibit residual bowing ( Figure 1A). ...
... Osteoclasts staining for tartrate resistant acid phosphatase (TRAP) were also prominent at the periphery of the lesions ( Figure S1). On the basis of these and previous observations 5 demonstrating that the centrally located cells stained positively for markers that are associated with undifferentiated mesenchymal cells, we hypothesized that the pathogenesis of familial OFD was related to a delay in osteogenesis, with lesions resolving at the margins through the action of rimming osteoblasts and osteoclasts. ...
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 (METΔ14) 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 METΔ14 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.
... A functional interaction between RANKL and RANK is necessary for osteoclast differentiation, survival, and activation. In addition, the up-regulation of RANKL-RANK signaling also plays an important role in other osteolysis-related diseases such as osteoporosis [12] and osteofibrousdysplasia [13], as well as bone metastasis [14]. Recent findings have revealed a number of transcription factors that regulate RANKL expression, such as parathyroid hormone (PTH) [15] and vitamin D3 [16]. ...
Giant cell tumor (GCT) of bone consists of three major cell types: giant cells, monocytic cells, and stromal cells. From microarray analysis, we found that miR-106b was down-regulated in GCT clinical samples and further determined by fluorescence in situ hybridization. In addition, the expression of novel potential target of miR-106b, RANKL, was elevated in GCT along with previously determined targets in other tumors such as IL-8, MMP2 and TWIST. In a RANKL 3'UTR luciferase reporter assays, agomiR-106b repressed the luciferase activity and the effect was eliminated when the targeting site in the reporter was mutated, suggesting a direct regulation of miR-106b on RANKL mRNA. Moreover, overexpression of miR-106b in GCTSCs through TALEN-mediated site-specific knockin clearly inhibited osteoclastogenesis and osteolysis. By grafting the GCT onto the chick CAM, we confirmed the inhibitory effect of miR-106b on RANKL expression and giant cell formation. Furthermore, in an OVX mouse model, silencing of miR-106b increased RANKL protein expression and promoted bone resorption, while up-regulation of miR-106b inhibited bone resorption. These results suggest that miR-106b is a novel suppressor of osteolysis by targeting RANKL and some other cytokines, which indicates that miR-106b may be a potential therapeutic target for the treatment of GCT.
... However, osteofibrous dysplasia always present as a palpable mass with bone deformities. Furthermore, a number of cases present with pathologic fractures and high alkali phosphatase levels (13). Additional differential diagnoses include osteoblastic sarcoma and aneurysmal bone cysts. ...
Focal fibrocartilaginous dysplasia (FFCD) is a rare, paraneoplastic disease that often presents in children and teenagers. Previous studies have reported cases of lesions in the proximal tibia and distal femur, as well as lesions in the upper extremities. The present study describes a case of FFCD on the transverse process and the rib. The imaging findings were found to correspond with the typical observations of FFCD and a biopsy from the nidus revealed pathological results similar to those of previous reports. Thus, the present study demonstrated that FFCD affects tubular bones as well as flat bones. Further studies are required to investigate the underlying mechanism and treatment of FFCD.
