Patterns of brachyury expression in chordomas.

INTRODUCTION: Chordomas are rare malignant midline tumors, presumed to arise from notochordal remnants. This was further suggested by the discovery of the brachyury in chordomas pathogenesis. Its immunohistochemical expression has become the principal adjunct in the diagnosis of chordomas. However, studies about brachyury expression in chordomas are not fully comparable, mainly because they use different primary antibodies. Thus, the aim of this study is to investigate the expression of brachyury expression in a series of chordomas in conjunction to clinicopathological characteristics and to review the relevant literature providing all the details needed in the immunohistochemical study of brachyury. MATERIALS AND METHODS: This is a retrospective study of 62 chordomas, diagnosed over a 22-year period. No dedifferentiated or poorly differentiated cases were included. A monoclonal primary antibody (clone A-4) was used and brachyury expression was evaluated by the H-score. Clinicopathological parameters studied were age, sex, tumor localization, decalcification status and tissue age. Fetal notochords were used for comparison. RESULTS: Mean H-score of nuclear brachyury expression was 129.8. The tissue age significantly influenced brachyury expression, the older samples expressing less brachyury. Decalcification demonstrated a trend to weaken brachyury expression. Clinical characteristics were not correlated with the patterns of brachyury expression. Notochords were negative. Literature review reveals several polyclonal antibodies used and a positivity of 75%-100% in chordomas with even more variable results in notochords. CONCLUSION: In chordomas, as in other tumor types, an uniformization of studies about brachyury expression is needed, by considering the clone used, and the decalcification and the age of the sample, given the growing importance of brachyury in diagnosis and therapeutic steps.

Chordoma: the entity.

Chordomas are malignant tumors of the axial skeleton, characterized by their locally invasive and slow but aggressive growth. These neoplasms are presumed to be derived from notochordal remnants with a molecular alteration preceding their malignant transformation. As these tumors are most frequently observed on the skull base and sacrum, patients suffering from a chordoma present with debilitating neurological disease, and have an overall 5-year survival rate of 65%. Surgical resection with adjuvant radiotherapy is the first-choice treatment modality in these patients, since chordomas are resistant to conventional chemotherapy. Even so, management of chordomas can be challenging, as chordoma patients often present with recurrent disease. Recent advances in the understanding of the molecular events that contribute to the development of chordomas are promising; the most novel finding being the identification of brachyury in the disease process. Here we present an overview of the current paradigms and summarize relevant research findings.

[Chordoma: diagnostic considerations and review of the literature]. / Cordoma: considerazioni diagnostiche e revisione della letteratura.

Chordoma is a rare malignant tumor of the bone; it arises from embryonic remnants of the primitive notochord and occurs along the midline from the skull base to the sacrum. In this article, we reviewed the origin, location, clinical, histopatological and imaging features, treatment, and differential diagnosis of chordoma.

[From bench to bedside for new treatment paradigms in chordomas: An update]. / Depuis la recherche translationnelle jusqu'aux nouveaux paradigmes thérapeutiques : mise à jour des données dans les chordomes.

Chordomas are rare malignant tumours, which typically occur in the axial skeleton and skull base. They arise from embryonic remnants of the notochord. They constitute less than 5 % of primary bone tumours. They are characterised by their locally aggressive potential with high frequency of recurrences and a median overall survival of 6 years. The initial therapeutic strategy must be discussed in an expert centre and may involve surgery, preoperative radiotherapy, exclusive radiotherapy or therapeutic abstention. Despite this, more than 50 % of patients will be facing recurrences with few therapeutic options available at this advanced stage. This review aims to outline current treatment options available in chordomas, as well as discussing potentiality of new therapeutic approaches through their molecular characterization and the comprehension of their immunological environment.

Extraosseous spinal chordoma. Case report.

An extraosseous extradural tumor of the lumbar region with the histological appearance of chordoma produced symptoms in a 58-year-old woman. The tumor occupied the epidural space and produced scalloping of the adjacent vertebral body and pedicle without associated bone destruction. The location of the tumor within Batson's plexus and lack of osseous connection facilitated complete removal. Although the lesion exhibited the classic histological features of a chordoma, it differed significantly in its extraosseous location. Like the rare intradural chordoma arising in the cranium, this tumor presumably represents neoplastic development in an extraosseous notochordal rest.

Sphenooccipital chordoma presenting as a nasopharyngeal mass. A case report.

While the nasopharynx is most commonly regarded by the otolaryngologist as a primary site of neoplastic involvement, it is also an avenue of spread of base-of-the-skull tumors presenting as bulging nasopharyngeal masses. The temporal sequence of clinical signs and symptoms may reliably predict the origin of a ventrally extending sphenooccipital chordoma seen on a nasopharyngeal examination. This tumor may cause extensive bony erosion of the petrous apex, sphenoid sinus, and clivus and may suggest a more rapidly growing and aggressive tumor type. The extent of the tumor may be accurately determined by conventional tomography, computerized axial tomography, and arteriography. Severl surgical approaches including the infratemporal fossa approach, transoral transpalatal approach and rhinoseptal transphenoidal approach may be appropriately utilized singly or in combination to remove this tumor in whole or part; however, the rhinoseptal transphenoidal approach is emphasized and regarded as the most rational treatment plan for subtotal resection, recognizing the usual futility of an en bloc resection with its associated high morbidity.

Skull base chordomas.

Chordomas are rare, benign tumors of the nasopharynx. Because of their location at the skull base, removal of these tumors is usually subtotal. Described is the transcervical-transmandibular approach to the skull base which can be employed in removing these tumors.

[Embryology of the sphenoid bone]. / Développement embryonnaire du sphénoïde.

The sphenoid bone represents a complex structure in terms of anatomy and embryology. Indeed, it is formed by the fusion of different primordia whose embryonic origins are different. In mammals, it is possible to distinguish two components of this bone: the orbitosphenoid and the basi-post-sphenoid derive from the cephalic mesoderm whereas the alisphenoid and the basi-pre-sphenoid are from neural crest cell origin. The genetic control of the development of these two components is different further increasing the heterogeneity of these components. The sphenoid bone has been linked with several developmental diseases: chordomas, tumors arising from notochordal remnants; persistence of the craniopharyngeal canal may result in the occurrence of trans-sphenoidal encephaloceles.

[Massive orbital osteolysis by a chordoma. Report of a case and review of the litterature (author's transl)]. / Envahissement ostéolytique massif de l'orbite par un chordome. Discussion d'une observation privilégiée et revue de la littérature.

Clinical, radiological and anatomical description of sellar chordoma giving, on a sixty seven years old man, an unusually large tumoral exophthalmos, a massive orbito-sphenoidal osteolysis and a chiasmatic syndroma. Discussion stresses the topographic data of chordoma in connection with the embryonal chordal cell rests. Patterns of evolution and neuro-ophthalmologic symptoms of cephalic chordoma are studied with the literature facts. Morphologic criteria, specifical ones and those differential diagnosis, are exactly scheduled.

[Chordoma of the base of the skull. Clinical and histological study. Therapeutic possibilities (author's transl)]. / Chordome de la base du crâne. Etude clinique et histologique. Possibilités thérapeutiques.

A Case of chordoma of the base of the skull is reported. It had been present with minimal symptoms for six years during which the clinical picture was limited to nasal obstruction and headache. Comparison of initial X-rays and the preoperative assessment revealed progressive destruction of the base of the skull which indicated the likelihood of considerable difficulties in excision. Surgical treatment posed the problem of the approach and emphasised the absence of encapsulation and the incomplete nature of the operation. The development of new symptoms (diplopia, dysphagia) resulted in complementary radiotherapy. The authors take the opportunity to point out the polymorphous clinical nature of these tumours in relation to their site and the criteria of the histological diagnosis. The possibilities of treatment are discussed. Abstention from treatment is formally rejected and, on the contrary, the emphasis is placed upon the need for early treatment. The consequences of excision should be limited by using a minimal surgical technique when possible. Complementary radiotherapy is necessary and may be repeated, up to certain limits, in the case of recurrence if the first irradiation is felt to be effective. There is no parallel between histological appearances and the response to treatment. The possibilities of chemotherapy would appear to be limited.

A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12.

Chordoma is a malignant tumor thought to arise from remnants of the embryonic notochord, with its origin in the bones of the axial skeleton. Surgical resection is the standard treatment, usually in combination with radiation therapy, but neither chemotherapeutic nor targeted therapeutic approaches have demonstrated success. No animal model and only few chordoma cell lines are available for preclinical drug testing, and, although no druggable genetic drivers have been identified, activation of EGFR and downstream AKT-PI3K pathways have been described. Here, we report a zebrafish model of chordoma, based on stable transgene-driven expression of HRASV12 in notochord cells during development. Extensive intra-notochordal tumor formation is evident within days of transgene expression, ultimately leading to larval death. The zebrafish tumors share characteristics of human chordoma as demonstrated by immunohistochemistry and electron microscopy. The mTORC1 inhibitor rapamycin, which has some demonstrated activity in a chordoma cell line, delays the onset of tumor formation in our zebrafish model, and improves survival of tumor-bearing fish. Consequently, the HRASV12-driven zebrafish model of chordoma could enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer.

Brachyury and chordoma: the chondroid-chordoid dilemma resolved?

Chordoma, and its relationship to the notochord, has intrigued many researchers over the last two centuries. In particular, the morphological overlap with cartilaginous tumours is striking, and developmental biology has shown a tight relationship between cartilage and the notochord. This is reflected in the expression of common genes in chordoid and chondroid tumours. Wide gene expression analyses have led to the identification of key molecules that might play a crucial role in the pathogenesis of chordoma. Brachyury, a key factor in notochord fate, is significantly differentially expressed in chordoma. This not only gives insight into the histogenesis of this tumour but may also point towards new diagnostic tools in the differential diagnosis between chordoid and chondroid tumours.

Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas.

Chordomas are malignant tumours that occur along the spine and are thought to derive from notochordal remnants. There is significant morphological variability between and within chordomas, with some showing prominent areas of chondroid differentiation. Our microarray data from a broad range of connective tissue neoplasms indicate that, at the transcriptional level, chordomas resemble cartilaginous neoplasms. Here we show that chordomas express many genes known to be involved in cartilage development, but they also uniquely express genes distinguishing them from chondroid neoplasms. The brachyury transcription factor, known to be involved in notochordal development, is only expressed by chordomas. Using a polyclonal antibody, we show that brachyury is expressed in the embryonic notochord and in all 53 chordomas analysed, labelling both chondroid and chordoid areas of these tumours. In contrast, the protein was not detected in over 300 neoplasms, including 163 chondroid tumours. Brachyury was not detected in the nucleus pulposus, arguing against the hypothesis that this tissue derives directly from the notochord. These data provide compelling evidence that chordomas derive from notochord and demonstrate that brachyury is a specific marker for the notochord and notochord-derived tumours.

Three-dimensional reconstruction of human embryonic notochords: clue to the pathogenesis of chordoma.

Three-dimensional reconstruction experiments performed on serial sections of human embryos showed that the anatomy of the caudal and rostral ends of the notochord was complex. Forking of the ends, with separate fragments of chordal tissue, was demonstrated and these provide a way by which notochordal cell rests could be left behind in the basicranial and sacral regions when the notochord involutes elsewhere. Assuming the histogenesis of chordomas from notochordal cell rests, this would furnish an explanation for the observed skeletal distribution of chordomas.