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Archives of Pathology & Laboratory... Mar 2022Chordomas are uncommon malignant neoplasms with notochordal differentiation encountered by neuropathologists, bone/soft tissue pathologists, and general surgical... (Review)
Review
CONTEXT.—
Chordomas are uncommon malignant neoplasms with notochordal differentiation encountered by neuropathologists, bone/soft tissue pathologists, and general surgical pathologists. These lesions most commonly arise in the axial skeleton. Optimal therapy typically involves complete surgical resection, which is often technically difficult owing to the anatomic location, leading to a high rate of recurrence. Lesions have been generally resistant to radiation and chemotherapy; however, experimental studies involving targeted therapy and immunotherapy are currently underway.
OBJECTIVE.—
To summarize the clinical and pathologic findings of the various types of chordoma (conventional chordoma, dedifferentiated chordoma, and poorly differentiated chordoma), the differential diagnosis, and recent advances in molecular pathogenesis and therapeutic modalities that are reliant on accurate diagnosis.
DATA SOURCES.—
Literature review based on PubMed searches containing the term "chordoma" that address novel targeted and immunomodulatory therapeutic modalities; ongoing clinical trials involved in treating chordoma with novel therapeutic modalities identified through the Chordoma Foundation and ClinicalTrials.gov; and the authors' practice experience combined with various authoritative texts concerning the subject.
CONCLUSIONS.—
Chordoma is a clinically and histologically unique malignant neoplasm, and numerous diagnostic considerations must be excluded to establish the correct diagnosis. Treatment options have largely been centered on surgical excision with marginal results; however, novel therapeutic options including targeted therapy and immunotherapy are promising means to improve prognosis.
Topics: Chordoma; Diagnosis, Differential; Humans
PubMed: 34319396
DOI: 10.5858/arpa.2020-0258-RA -
International Journal of Molecular... May 2024Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their... (Review)
Review
Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.
Topics: Humans; Chordoma; Prognosis; Biomarkers, Tumor; Mutation; T-Box Domain Proteins; Disease Management; Fetal Proteins; Brachyury Protein
PubMed: 38892063
DOI: 10.3390/ijms25115877 -
Journal For Immunotherapy of Cancer Apr 2023Chordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic...
BACKGROUND
Chordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic strategies for chordoma. Herein, we aimed to explore cellular interactions within the chordoma immune microenvironment and provide new therapeutic targets.
METHODS
Spectrum flow cytometry and multiplex immunofluorescence (IF) staining were used to investigate the immune microenvironment of chordoma. Cell Counting Kit-8, Edu, clone formation, Transwell, and healing assays were used to validate tumor functions. Flow cytometry and Transwell assays were used to analyze macrophage phenotype and chemotaxis alterations. Immunohistochemistry, IF, western blot, PCR, and ELISA assays were used to analyze molecular expression. An organoid model and a xenograft mouse model were constructed to investigate the efficacy of maraviroc (MVC).
RESULTS
The chordoma immune microenvironment landscape was characterized, and we observed that chordoma exhibits a typical immune exclusion phenotype. However, macrophages infiltrating the tumor zone were also noted. Through functional assays, we demonstrated that chordoma-secreted CCL5 significantly promoted malignancy progression, macrophage recruitment, and M2 polarization. In turn, M2 macrophages markedly enhanced the proliferation, invasion, and migration viability of chordoma. CCL5 knockdown and MVC (CCL5/CCR5 inhibitor) treatment both significantly inhibited chordoma malignant progression and M2 macrophage polarization. We established chordoma patient-derived organoids, wherein MVC exhibited antitumor effects, especially in patient 4, with robust killing effect. MVC inhibits chordoma growth and lung metastasis in vivo.
CONCLUSIONS
Our study implicates that the CCL5-CCR5 axis plays an important role in the malignant progression of chordoma and the regulation of macrophages, and that the CCL5-CCR5 axis is a potential therapeutic target in chordoma.
Topics: Humans; Animals; Mice; Tumor-Associated Macrophages; Chordoma; Macrophages; Maraviroc; Disease Models, Animal; Tumor Microenvironment; Chemokine CCL5
PubMed: 37185233
DOI: 10.1136/jitc-2023-006808 -
Neuro-oncology Feb 2024With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and...
BACKGROUND
With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression.
METHODS
Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma.
RESULTS
We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes.
CONCLUSIONS
These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.
Topics: Humans; Chordoma; Cancer-Associated Fibroblasts; Gene Expression Profiling; RNA-Seq; Endoplasmic Reticulum Stress; Tumor Microenvironment
PubMed: 37772937
DOI: 10.1093/neuonc/noad173 -
Cell Reports. Medicine Oct 2024Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular...
Chordoma is a rare and heterogeneous mesenchymal malignancy, with distinct clinical and biological behaviors. Till now, its comprehensive clinical-molecular characteristics and accurate molecular classification remain obscure. In this research, we enroll 102 patients with chordoma and describe their clinical, imageological, and histopathological features. Through tandem mass tag-based proteomic analysis and nonnegative matrix factorization clustering, we classify chordoma into three molecular subtypes: bone microenvironment-dominant, mesenchymal-derived, and mesenchymal-to-epithelial transition-mediated pattern. The three subtypes exhibit discrete clinical prognosis and distinct biological attributes of osteoclastogenesis and immunogenicity, oxidative phosphorylation, and receptor tyrosine kinase activation, suggesting targeted therapeutic strategies of denosumab, S-Gboxin, and anlotinib, respectively. Notably, these approaches demonstrate positive treatment outcomes for each subtype in vitro and in vivo. Altogether, this work sheds light on the clinical-proteomic characteristics of chordoma and provides a candidate precision treatment strategy for chordoma according to molecular classification, underscoring their potential for clinical application.
Topics: Humans; Chordoma; Proteomics; Male; Female; Middle Aged; Animals; Precision Medicine; Adult; Epithelial-Mesenchymal Transition; Tumor Microenvironment; Aged; Mice; Prognosis; Denosumab
PubMed: 39368483
DOI: 10.1016/j.xcrm.2024.101757 -
Nature Communications Sep 2024Skull-base chordoma is a rare, aggressive bone cancer with a high recurrence rate. Despite advances in genomic studies, its molecular characteristics and effective...
Skull-base chordoma is a rare, aggressive bone cancer with a high recurrence rate. Despite advances in genomic studies, its molecular characteristics and effective therapies remain unknown. Here, we conduct integrative genomics, transcriptomics, proteomics, and phosphoproteomics analyses of 187 skull-base chordoma tumors. In our study, chromosome instability is identified as a prognostic predictor and potential therapeutic target. Multi-omics data reveals downstream effects of chromosome instability, with RPRD1B as a putative target for radiotherapy-resistant patients. Chromosome 1q gain, associated with chromosome instability and upregulated mitochondrial functions, lead to poorer clinical outcomes. Immune subtyping identify an immune cold subtype linked to chromosome 9p/10q loss and immune evasion. Proteomics-based classification reveals subtypes (P-II and P-III) with high chromosome instability and immune cold features, with P-II tumors showing increased invasiveness. These findings, confirmed in 17 paired samples, provide insights into the biology and treatment of skull-base chordoma.
Topics: Humans; Chordoma; Skull Base Neoplasms; Chromosomal Instability; Proteogenomics; Male; Female; Middle Aged; Prognosis; Adult; Gene Expression Regulation, Neoplastic; Chromosomes, Human, Pair 1; Aged; Proteomics
PubMed: 39333076
DOI: 10.1038/s41467-024-52285-7 -
Sovremennye Tekhnologii V Meditsine 2023Chordomas and chondrosarcomas of the skull base are rare tumors. They are located in close proximity to critical structures, which poses a serious problem in the... (Review)
Review
Chordomas and chondrosarcomas of the skull base are rare tumors. They are located in close proximity to critical structures, which poses a serious problem in the treatment of these tumors. Despite advances in surgery, radical resection is often not possible. Radiation therapy for chordomas and chondrosarcomas of the skull base is able to improve overall survival and local control. is to analyze the literature data and evaluate the efficacy of radiation therapy techniques for chordomas and chondrosarcomas of the skull base. The most promising methods of radiation therapy for chordomas and chondrosarcomas of the skull base have been shown to be pencil-beam scanning proton therapy with intensity modulation and carbon ion therapy. These techniques have demonstrated high local control and overall survival with a low incidence of severe radiation-induced toxicity, which confirms their clinical benefits. It has also been found that stereotactic radiosurgery can be effectively used for small tumors (less than 7 cm).
Topics: Humans; Chordoma; Chondrosarcoma; Skull Base Neoplasms; Radiosurgery; Proton Therapy; Treatment Outcome
PubMed: 39967912
DOI: 10.17691/stm2023.15.5.05 -
Archives of Pathology & Laboratory... Dec 2006Chordomas are low-grade malignant tumors of bone that occur almost exclusively in the axial skeleton. Other neoplasms with a similar histologic picture but an...
Chordomas are low-grade malignant tumors of bone that occur almost exclusively in the axial skeleton. Other neoplasms with a similar histologic picture but an extra-axial location have been described, including parachordoma, myxoid chondrosarcoma, and extra-axial chordoma. We herein present another case of the rare extra-axial chordoma. A 41-year-old woman developed an 8.3 cm mass in the pubic bone. The gross, microscopic, and immunohistochemical findings were identical to those of a classic chordoma. Parachordoma and myxoid chondrosarcoma were excluded from the differential diagnosis. Five previously reported cases of extra-axial chordoma were reviewed and found also to demonstrate clinical and pathologic features specific to chordoma, despite arising in an extra-axial location. Although rare, extra-axial chordoma does exist and should be recognized and managed in a similar fashion to its well-described counterpart. It must be differentiated from other histologic mimics, because the treatment and prognosis can differ significantly.
Topics: Adult; Biomarkers, Tumor; Bone Neoplasms; Chordoma; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Pubic Bone; Radiotherapy, Adjuvant; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography
PubMed: 17149966
DOI: 10.5858/2006-130-1871-EC -
Science Advances Feb 2022Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Chordomas are considered insensitive to conventional chemotherapy,...
Chordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective treatments. Therefore, there is a need for discovery of novel therapeutic approaches. Patient-derived organoids can accelerate drug discovery and development studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter- as well as intrapatient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-κB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.
Topics: Antineoplastic Agents; Chordoma; Drug Discovery; Humans; Organoids; Treatment Outcome
PubMed: 35171675
DOI: 10.1126/sciadv.abl3674 -
British Journal of Hospital Medicine... Dec 2023
Topics: Humans; Chordoma; Neck; Cervical Vertebrae; Spinal Neoplasms
PubMed: 38153021
DOI: 10.12968/hmed.2023.0285