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Mesenchymal chondrosarcoma. Typical biphasic appearance (a) with chondroid (lower) and small round cell areas (upper). Round cell component (b) is often rich in vasculature, including some hemangiopericytomatous vessels. (c) Reverse transcription polymerase chain reaction assay with confirmatory Sanger sequencing reveals in-frame fusion between HEY1 and NCOA2 genes diagnostic of mesenchymal chondrosarcoma
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Soft tissue tumors encompass a wide variety of mesenchymal neoplasms exhibiting diverse clinical, pathologic, and molecular features. Among these, osteoid and/or chondroid matrix deposition in some soft tissue tumors represents a noticeable characteristic. Unlike matrices present in bone tumors where they likely reveal the respective cells of origi...
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Introduction The most outstanding aspects of the foot skeleton in relation to the tumoral lesions, refer to the particular characteristics of the bones that compose it and the poor compartmentalization of the middle and hindfoot, which are considered extra compartmental spaces. On the contrary, the forefoot is well compartmentalized in five spaces...
Citations
... FN1 translocations have been reported in a wide variety of neoplasms that share overlapping morphologic features, including cartilaginous matrix production, [2][3][4][5][6] such as synovial chondromatosis, 3 and soft tissue chondroma (particularly with grungy or lacy/chondroblastoma-like calcifications). 7 Phosphaturic mesenchymal tumors (PMTs) frequently demonstrate FN1::FGFR1 or FN1::FGF1 fusions and have variable histology, including chondroid matrix with grungy calcifications, though these commonly produce FGF23 and are associated with osteomalacia in the majority of cases. ...
Calcified chondroid mesenchymal neoplasm is a term proposed for tumors with a spectrum of morphologic features, including cartilage/chondroid matrix formation, that frequently harbor FN1 gene fusions. We report a series of 33 cases of putative calcified chondroid mesenchymal neoplasms, mostly referred for expert consultation out of concern for malignancy. Patients included 17 males and 16 females, with a mean age of 51.3 years. Anatomic locations include the hands and fingers, feet and toes, head and neck, and temporomandibular joint; 1 patient presented with multifocal disease. Radiologic review showed soft tissue masses with variable internal calcification, which occasionally scalloped bone but in all cases appeared indolent/benign. Tumors had a mean gross size of 2.1 cm and a homogenous rubbery to fibrous/gritty tan-white cut surface. Histology demonstrated multinodular architecture with a prominent chondroid matrix and increased cellularity towards the periphery of the nodules. The tumor cells were polygonal with eccentric nuclei and bland cytologic features and showed a variable amount of increased spindled / fibroblastic forms in the perinodular septa. The majority of cases had notable grungy and/or lacy calcifications. A subset of cases demonstrated at least focal areas of increased cellularity and osteoclast-like giant cells. Herein, we confirm the distinct morphologic and clinicopathologic features associated with this entity with the largest series to date, with a focus on practical diagnostic separation from similar chondroid neoplasms. Awareness of these features is critical in avoiding pitfalls, including a malignant diagnosis of chondrosarcoma.
... Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of an uncertain line of differentiation and intermediate risk of malignancy. Up to 85% of OFMT present recurrent rearrangements mostly involving PHD finger protein 1 (PHF1), a Polycomb group protein, but also translocations of other genes related to histone modification functions as well [176,177]. A transcriptome sequencing study assessed the presence of alternate gene fusions in a subset of cases lacking those translocations [126]. ...
The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm.
... Früher ging man davon aus, dass es sich bei der SC um eine Metaplasie der Synoviozyten handelt, also eine reversible Umwandlung einer Zellart in eine andere. In den letzten Jahren wird die primäre SC eher als benigne Neoplasie angesehen [3,4,[18][19][20][21]. ...
... In den letzten Jahren wurden für die SC typische genomische Veränderungen beobachtet [20,21]. Es finden sich in knapp 60 % Gen-Rearrangements, also DNA-Umgruppierungen innerhalb eines Gens, im Fibronektin-1-Gen (FN1) und/oder im Gen für den Activin-A-Typ-II-Rezeptor (ACVR2A). ...
Zusammenfassung
Hintergrund
Die primäre synoviale Chondromatose (SC) ist eine seltene Erkrankung der Synovialmembran unklarer Ätiologie. Der aktuelle Wissensstand zu dieser Erkrankung soll in einer kurzen Übersicht dargestellt werden.
Methoden
Übersichtsarbeiten und rezente Fallberichte zur SC wurden systematisch ausgewertet und mit Daten eigener Fälle in Kontext gesetzt.
Ergebnisse
Auf Grund neuer genomischer Daten wird die SC als benigne Neoplasie eingestuft. In 60 % der Fälle liegen Mutationen im Fibronektin-1-Gen (FN1) und/oder im Gen für den Activin-A-Typ-II-Rezeptor (ACVR2A) vor. Diagnoseweisend ist die Magnetresonanztomographie (MRT) und die meist arthroskopische Biopsie der Synovia. An einem Fallbeispiel soll gezeigt werden, dass die Knorpelaggregate der SC radiologisch nicht immer schattengebend sein müssen. Differenzialdiagnostisch kommen Monarthritiden anderer Ursachen, andere Gelenk- und Muskelerkrankungen mit Mineralisierung sowie weitere von der Synovialmembran ausgehende Erkrankungen in Betracht. Die Entartungsrate liegt bei 2–4 %. Therapeutisch hat sich in den letzten Jahren das arthroskopische Vorgehen durchgesetzt, das an die Ausdehnung der Erkrankung adaptiert wird.
Schlussfolgerung
Genomische Untersuchungen sowie Fallserien und Fallberichte aus jüngerer Zeit werfen ein neues Licht auf die SC. Therapeutisch wird in jüngeren Arbeiten überwiegend arthroskopisch vorgegangen.
... In this study, we analysed in detail an extraskeletal cartilage-forming tumour with highly specific histological features and the FN1-FGFR2 gene fusion. The FN1-FGFR2 fusion was previously described in four cases of a chondroblastoma-like variant of soft tissue chondroma (Amary et al., 2019;Kao et al., 2020). However, no thick perichondrocytic rings were observed in these cases. ...
... There was a fusion between the exon 19 of FN1 and exon 7 of FGFR2 in their cases. However, fusions of FN1 to other receptor tyrosine kinases have also been detected in some other neoplasms of soft tissue tumours, including the FN1-FGFR1 fusion in some chondromas (Amary et al., 2019), FN1-EGF fusion in calcifying aponeurotic fibroma (Puls et al., 2016), FN1-FGFR1 and FN1-FGF1 fusions in phosphaturic mesenchymal tumour (Lee et al., 2016), FN1-AVCR2A fusion in synovial chondromatosis (Amary et al., 2019), FN1-ROS1 fusion in inflammatory myofibroblastic tumour (Kao et al., 2020), FN1-ALK fusion in gastrointestinal leiomyoma and inflammatory myofibroblastic tumour (Panagopoulus, et al., 2016), and FN1-FGFR1 fusion in ALK-negative inflammatory myofibroblastic tumour (Kao et al., 2020). ...
... There was a fusion between the exon 19 of FN1 and exon 7 of FGFR2 in their cases. However, fusions of FN1 to other receptor tyrosine kinases have also been detected in some other neoplasms of soft tissue tumours, including the FN1-FGFR1 fusion in some chondromas (Amary et al., 2019), FN1-EGF fusion in calcifying aponeurotic fibroma (Puls et al., 2016), FN1-FGFR1 and FN1-FGF1 fusions in phosphaturic mesenchymal tumour (Lee et al., 2016), FN1-AVCR2A fusion in synovial chondromatosis (Amary et al., 2019), FN1-ROS1 fusion in inflammatory myofibroblastic tumour (Kao et al., 2020), FN1-ALK fusion in gastrointestinal leiomyoma and inflammatory myofibroblastic tumour (Panagopoulus, et al., 2016), and FN1-FGFR1 fusion in ALK-negative inflammatory myofibroblastic tumour (Kao et al., 2020). ...
This is the first histological and molecular analysis of two chondrosarcomas with target-like chondrocytes that were compared with a group of conventional chondrosarcomas and enchondromas. The unique histological feature of target-like chondrocytes is the presence of unusual hypertrophic eosinophilic APAS-positive perichondrocytic rings (baskets). In the sections stained with Safranin O/Fast green, the outer part of the ring was blue and the material in the lacunar space stained orange, similarly to intercellular regions. Immunohistochemical examination showed strong positivity for vimentin, factor XIIIa, cyclin D1, osteonectin, B-cell lymphoma 2 apoptosis regulator (Bcl-2), p53 and p16. The S-100 protein was positive in 25 % of neoplastic cells. Antibodies against GFAP, D2-40 (podoplanin), CD99, CKAE1.3 and CD10 exhibited weak focal positivity. Pericellular rings/baskets contained type VI collagen in their peripheral part, in contrast to the type II collagen in intercellular interterritorial spaces. Ultrastructural examination revealed that pericellular rings contained an intralacunar component composed of microfibrils with abundant admixture of aggregates of dense amorphous non-fibrillar material. The outer extralacunar zone was made up of a layer of condensed thin collagen fibrils with admixture of non-fibrillar dense material. NGS sequencing identified a fusion transcript involving fibronectin 1 (FN1) and fibroblast growth factor receptor 2 (FGFR2) at the RNA level. At the DNA level, no significant variant was revealed except for the presumably germline variant in the SPTA1 gene.
... Similar situation with hypertrophic chondrocytes surrounded with normal perichondrocytic rings was also described in osteoarthritis 27 . Moreover, mutations in EGFRs cause several skeletal phenotypes such as limb defects, achondroplasia and craniosynostosis or they are associated with the development of some cartilage tumours 28 . ...
Background:
Here we present our experience with the occurrence of neoplastic chondrocytes with target-like appearance surrounded with unusual hypertrophic thick eosinophilic perichondrocytic rings (baskets), sometimes containing two or several layers.
Methods and results:
Pericellular rings (baskets) were positive in APAS and Masson's staining method and showed immunoreactivity with antibody against type IV collagen. Such single cells or small groups of such cells were observed rarely in 3 osteochondromas, 2 skeletal chondromas, 2 extraskeletal chondromas and 2 skeletal and 1 laryngeal chondrosarcomas. Moreover, 1 unusual soft tissue chondrosarcoma was composed entirely of target-like chondrocytes with hypertrophic extremely thick perichondrocytic rings. Such cartilage-forming tumour with target-like cells, which, to the best of our knowledge, is the first such chondrosarcoma reported in the literature. Ultrastructural evidence is presented that perichondrocytic rings have complicated structure.They contained microfibrillar component with abundant admixture of irregular aggregates of dense amorphous non-fibrillar material localised in lacunar spaces. In outer part of the rings predominated microfibrillar structures corresponding to type VI collagen that produced a rather dense capsule-like demarcation line against surrounding intercellular spaces.
Conclusions:
The described unusual changes are probably the result of hyperproduction and remodelation of perichondrocytic matrix by abnormal neoplastic chondrocytes in response to unknown factors. Local vascular and molecular signals, may be supposed as probable causes of this phenomenon.
The clinical, radiological, and histopathological features of chondromyxoid fibroma can sometimes resemble those of other benign or malignant tumors. Recently, recurrent GRM1 rearrangements have been identified in chondromyxoid fibroma, and GRM1 positivity by immunohistochemistry has emerged as a dependable surrogate marker for this molecular alteration. Phosphaturic mesenchymal tumor is a rare tumor that often exhibits overexpression of fibroblastic growth factor 23 (FGF23) through various mechanisms. In this report, we present a case of GRM1-rearranged chondromyxoid fibroma that also exhibited FGF23 expression via in situ hybridization, posing significant diagnostic challenges during workup of the initial core biopsy. We hope that this case can serve as an educational resource, shedding light on a rare diagnostic pitfall.
This is the first histological and molecular analysis of two chondrosarcomas with target-like chondrocytes that were compared with a group of conventional chondrosarcomas and enchondromas. The unique histological feature of target-like chondrocytes is the presence of unusual hypertrophic eosinophilic APAS-positive perichondrocytic rings (baskets). In the sections stained with Safranin O/Fast green, the outer part of the ring was blue and the material in the lacunar space stained orange, similarly to intercellular regions. Immunohistochemical examination showed strong positivity for vimentin, factor XIIIa, cyclin D1, osteonectin, B-cell lymphoma 2 apoptosis regulator (Bcl-2), p53 and p16. The S-100 protein was positive in 25 % of neoplastic cells. Antibodies against GFAP, D2-40 (podoplanin), CD99, CKAE1.3 and CD10 exhibited weak focal positivity. Pericellular rings/baskets contained type VI collagen in their peripheral part, in contrast to the type II collagen in intercellular interterritorial spaces. Ultrastructural examination revealed that pericellular rings contained an intralacunar component composed of microfibrils with abundant admixture of aggregates of dense amorphous non-fibrillar material. The outer extralacunar zone was made up of a layer of condensed thin collagen fibrils with admixture of non-fibrillar dense material. NGS sequencing identified a fusion transcript involving fibronectin 1 (FN1) and fibroblast growth factor receptor 2 (FGFR2) at the RNA level. At the DNA level, no significant variant was revealed except for the presumably germline variant in the SPTA1 gene.
Erratum to this article was published in: Folia Biologica, 2022, 68, (5-6): 211–211. https://doi.org/10.14712/fb2022068050211
Calcifying aponeurotic fibroma (CAF) is a very rare benign entity that principally affects the volar fascia, tendons, and aponeuroses of the hands and feet with a peak incidence of between 5 and 15 years, although there have been cases found for a wide age range and at various anatomical sites. We present ten CAF cases; consisting of eight children and two adults. CAF occurred in the extremities in nine of the cases and in the chest wall in one case. CAF ultrasound and radiological findings are nonspecific but may help orientate diagnosis. Magnetic resonance imaging should be performed when there are doubtful cases, when occurring in nontypical sites, and when there are cases of nontypical clinical presentation. Histologically, all cases showed two components, a fibromatosis-like component and a nodular component. Chondroid areas were present in five cases. Calcifications were observed in nine cases. ERG immunostaining showed the same patterns in all the cases; diffused positivity in pericalcified areas, and patchy positivity in areas away from calcifications. CAF has distinctive histopathological features which should aid in the differential diagnoses with other entities.
Les chordomes sont de rares tumeurs du squelette axial à croissance lente qui sont très agressives localement et ont un potentiel métastatique modéré. Ces tumeurs sont résistantes aux thérapies conventionnelles et restent à ce jour sans traitement spécifique. La prise en charge des patients consiste en une résection chirurgicale de la tumeur avec pour objectif d’obtenir des marges saines, accompagnée de radiothérapie à hautes doses. Malgré cette première ligne de traitement agressive, les récidives locales sont fréquentes et les options de traitement de seconde ligne sont limitées. Les mécanismes de radiorésistance restent à ce jour inconnus. L’étude des chordomes est rendue difficile par sa rareté qui est reflétée par le faible nombre d’analyses omiques réalisées, souvent sur de faibles cohortes, et par le manque de modèles d’étude. Ce projet de thèse avait donc pour objectifs : i) de compléter la signature transcriptomique des chordomes en le comparant aux autres sarcomes, ii) de développer et de caractériser des modèles cellulaires 3D dans le but iii) d’évaluer la faisabilité d’une approche radiosensibilisante dans ces tumeurs. Cette étude a montré que le chordome a un répertoire d’expression génique spécifique, qui repose sur une forte activité des voies de signalisation de l’hypoxie et de la glycolyse. Ces travaux ont également montré que les modèles cellulaires 3D de chordome établis sont représentatifs de la maladie en termes d’d’histologie, d’expression génique et de résistance à la radiothérapie. Enfin, cette étude a montré le bénéfice d’une approche radiosensibilisante dans le chordome par l’inhibition de l’activité aldéhyde déshydrogénase.
Aims:
USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC) and related variants. We characterized UPS6 and fusion partners to delineate the clinicopathologic, genetic, and bone-forming features in such lesions of soft tissue (ST).
Methods and results:
Break-apart FISH validated USP6 rearrangement in 31/35 NFs (containing 3/3 fasciitis ossificans [FO]), 7/8 cellular variants of fibroma of tendon sheath (C-FTSs), 4/6 MOs, 3/3 ST-ABCs, and 2/2 fibro-osseous pseudotumor of digits (FOPD). By FISH and RT-PCR, MYH9-USP6 was the commonest fusion in 4 C-FTSs and 20 NFs, including 1 intravascular and 2 infantile (1 retroperitoneal) cases. MYH9-USP6 fusion confirmed the diagnosis of 2 NFs >5 cm with prominent ischemic necrosis. COL1A1-USP6 fusion was predominant in ossifying lesions, including all FOs, MOs, ST-ABCs, and FOPDs with identified partner genes, and also present in non-ossifying head and neck NFs (HN-NFs) and C-FTSs in 2 cases each. A cervical NF of a 14-month-old girl harbored the novel COL1A2-USP6 fusion. Ossifying lesions exhibited considerable genetic and morphologic overlaps. Sharing COL1A1-USP6 fusion, FO and FOPD exhibited similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, 4 COL1A1-USP6-positive MOs had incipient to sieve-like pseudocysts reminiscent of ST-ABC.
Conclusion:
MYH9-USP6 fusion is present in some C-FTSs and most NFs, including rare variants, but unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NFs and C-FTSs.
