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Background Chordomas are relatively rare lesions of the bones. About 30% occur in the sacrococcygeal region. Surgical resection is still the standard treatment. Due to the size, proximity to neurovascular structures and the complex anatomy of the pelvis, a complete resection with adequate safety margin is difficult to perform. A radical resection with safety margins often leads to the loss of bladder and rectal function as well as motoric/sensoric dysfunction. The recurrence rate after surgery alone is comparatively high, such that adjuvant radiation therapy is very important for improving local control rates. Proton therapy is still the international standard in the treatment of chordomas. High-LET beams such as carbon ions theoretically offer biologic advantages in slow-growing tumors. Data of a Japanese study of patients with unresectable sacral chordoma showed comparable high control rates after hypofractionated carbon ion therapy only. Methods and design This clinical study is a prospective randomized, monocentric phase II trial. Patients with histologically confirmed sacrococcygeal chordoma will be randomized to either proton or carbon ion radiation therapy stratified regarding the clinical target volume. Target volume delineation will be carried out based on CT and MRI data. In each arm the PTV will receive 64 GyE in 16 fractions. The primary objective of this trial is safety and feasibility of hypofractionated irradiation in patients with sacrococygeal chordoma using protons or carbon ions in raster scan technique for primary or additive treatment after R2 resection. The evaluation is therefore based on the proportion of treatments without Grade 3–5 toxicity (CTCAE, version 4.0) up to 12 months after treatment and/or discontinuation of the treatment for any reason as primary endpoint. Local-progression free survival, overall survival and quality of life will be analyzed as secondary end points. Discussion The aim of this study is to confirm the toxicity results of the Japanese data in raster scan technique and to compare it with the toxicity analysis of proton therapy given in the same fractionation. Using this data, a further randomized phase III trial is planned, comparing hypofractionated proton and carbon ion irradiation. Trial registration ClinicalTrials.gov Identifier: NCT01811394 .

Chordoma is a rare malignant tumor of bone with high morbidity and mortality. Recently, aggressive pediatric poorly differentiated chordoma with SMARCB1 loss has been described. This study summarizes the clinicopathologic features of poorly differentiated chordoma with SMARCB1 loss in the largest series to date. A search of records between 1990–2017 at MGH identified 19 patients with poorly differentiated chordoma. Immunohistochemical stains were evaluated. Kaplan–Meier survival statistics and log-rank (Mantel Cox) tests compared survival with other subtypes. The patients ( n  = 19) were diagnosed at a median age of 11 years (range: 1–29). Tumors arose in the skull base and clivus ( n  = 10/19; 53%); cervical spine ( n  = 6/19; 32%); and sacrum or coccyx ( n  = 3/19; 16%). The clinical stage of these patients (AJCC 7e) was stage 2A ( n  = 7/16; 44%); stage 2B (n = 6/16; 38%); stage 4A ( n  = 1/16; 6%); and stage 4B ( n  = 2/16; 13%). The tumors were composed of sheets of epithelioid cells with nuclear pleomorphism, abundant eosinophilic cytoplasm, and increased mitoses. Tumors were positive for cytokeratin ( n  = 18/18; 100%) and brachyury ( n  = 18/18; 100%). Patients were treated with a combination of excision, radiation therapy, and chemotherapy. No difference in overall survival, progression free survival, local control time, and metastasis free survival was identified between poorly differentiated chordoma of the skull base and of the spine. Compared to other chordoma subtypes, poorly differentiated chordoma has a significantly decreased mean overall survival after stratification by site ( p  = 0.037). Pediatric poorly differentiated chordoma has a distinct clinical and immunohistochemical profile, with characteristic SMARCB1 loss and decreased survival compared to conventional/chondroid chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy.

Background Chordoma is a rare and aggressive primary bone sarcoma. En-block resection remains the primary treatment, but some patients are unable to undergo it due to the location and potential complications. Currently, there is no direct comparison of the effects of radiotherapy (RTH) and surgical treatment. However, retrospective analyses indicate the potential benefits of using RTH. Methods A retrospective analysis was conducted on 48 patients with sacral chordoma who were treated with surgery and/or radiotherapy between 2001-2020. Among those, 22 were initially treated with surgery, 19 with definitive radiotherapy, and 7 received combined treatment. The outcomes of the treatment of recurrence in 16 patients were considered. The resection margins were defined according to R classification, and the Kaplan-Meier method was employed to calculate disease-free survival (DFS) and overall survival (OS). Results The median (mOS) for the entire cohort was 80.6 months (95% CI: 62.3-NA), and the median (mDFS) was 40.4 months (95% CI: 35-69.5). Patients who underwent radical surgery of the primary tumor did not achieve the mOS (mean 68), while patients treated only with RTH for the primary tumor achieved an mOS of 62.3 months (95% CI: 52.1-NA). This resulted in a significant advantage of surgery over RTH in terms of OS (P = 0.01). This was not observed for DFS. The 3-year DFS rates were 65% in the surgical treatment group and 53.3% in the RTH group. The 3-year OS rates were 96% in the surgery group and 88.9% in the RTH group. In the treatment of recurrence, there were no statistically significant differences between RTH and surgery, for OS (P = 0.76). Conclusions Radical surgery remains the optimal treatment for sacral chordoma. For patients who are not candidates for surgical intervention, RTH offers excellent long-term outcomes. The treatment of recurrence remains a significant challenge. Comparing modern RTH techniques and surgical procedures could provide further insights.

The research retrospectively analyzed cases of spinal chordoma and chondrosarcoma involving patients who received treatment at the two hospitals between 2001 and 2023. Among the 48 patients studied (39 chordoma and 9 chondrosarcoma cases), the average age was 53.9 ± 15.8 years, with a range of 17 to 86 years. Out of these patients, 43 underwent excision surgery and were categorized based on tumor margin into negative (R0) or microscopically positive (R1) margin ( n  = 14) and macroscopically positive (R2) margin ( n  = 29) groups. The mean overall survival (OS) for R0/R1 and R2 groups was 156.5 ± 19.3 and 79.2 ± 11.9 months, respectively ( p value = 0.012). The mean progression-free survival (PFS) for R0/R1 and R2 was 112.9 ± 24.4 and 25.5 ± 5.5 months ( p value < 0.001). The study showed that regardless of whether patients in the R0/R1 or R2 groups received radiation therapy (RT) or not, there was no significant improvement in OS or PFS. Specifically, the OS and PFS for the RT only group were 75.9 ± 16.6 and 73.3 ± 18.0 months. In conclusion, the recommended treatment approach for spinal chordoma and chondrosarcoma remains en bloc resection surgery with an appropriate margin. Patients who are unsuitable for or decline surgery may find a beneficial disease control rate with traditional external beam photon/proton therapy.

CD3L1 (ITPRIPL1), a natural ligand of CD3ε, is implicated in tumor-immune interactions and is overexpressed in several solid tumors. However, its expression and functional significance in osteosarcoma and chordoma remain uncharacterized. This study aimed to evaluate CD3L1 expression in osteosarcoma and chordoma and assess its association with clinical features and outcomes. Formalin-fixed, paraffin-embedded tissue samples from 42 osteosarcoma and 20 chordoma patients were analyzed for CD3L1 expression using immunohistochemistry. Multiplex immunofluorescence staining was performed to evaluate immune cell infiltration in chordoma. Associations between CD3L1 expression and clinicopathological parameters were examined using chi-square tests, Fisher’s exact test, and Kaplan-Meier survival analysis. CD3L1 was detected in 62.9% (39/62) of cases, with positivity rates of 59.6% in osteosarcoma and 70.0% in chordoma. CD3L1 expression was independent of patient age, sex, or tumor location but was significantly associated with chondroid stroma and prior PD-1 immunotherapy in osteosarcoma. In chordoma, higher CD3L1 expression correlated with increased infiltration of CD8 + T cells, B cells, and M2 macrophages. CD3L1 is expressed in osteosarcoma and chordoma and is associated with features of the tumor immune microenvironment, including markers of macrophage infiltration. As a potential therapeutic target, CD3L1 warrants further functional and clinical investigation.

Purpose Chordomas are rare malignant tumors that occur primarily in the axial skeleton. We seek to analyze trends affecting five-year overall survival (5y OS) among patients with primary spinal chordomas (PSC) of the vertebrae and sacrum/pelvis. Methods The Surveillance, Epidemiology, and End Results (SEER) Program was used to identify patients with PSC (ICD-O-3 histology codes 9370/3, 9371/3, and 9372/3) of the spine or sacrum/pelvis. Multivariate and univariate survival analyses were conducted to assess demographic, disease, or treatment characteristic trends. Results Eight-hundred-ninety-six patients diagnosed with PSC were identified. Patients 0–54 years at diagnosis had improved 5y OS compared to those either 55–69 years (HR = 1.78; p  = 0.046) or those between 70 and 85 + years (HR = 3.92; p  < 0.001). Histology impacted 5y OS: Cox regression demonstrated variance among the three histologies assessed ( p  < 0.001), while univariate analysis demonstrated patients with dedifferentiated chordoma (1.0% of cohort; 33.3% [1.9,64.7]) and chondroid chordoma (2.0% of cohort; 52.5% [26.1,78.9]) had decreased 5y OS compared to those with general chordoma (72.2% [68.8,75.6]; p  < 0.001). Nonmarried patients had decreased 5y OS on univariate analysis (65.2% [59.4,71.0] versus 76.2% [72.0,80.4]), with widowed patients being the primary driver of this on subanalysis. Treatment with gross total resection was associated with increased 5y OS (HR = 0.22, p  < 0.001), as was treatment with radiotherapy (HR = 0.69, p  = 0.030). Conclusion Patient age and marital status were significant demographic factors associated with changes in 5y OS among those with PSC. PSC histology is a potentially important prognostic factor in the management of disease.

Purpose Spinal chordomas are aggressive tumors that rarely occur in the pediatric population. Demographics and post-treatment outcomes in this select group of patients is poorly studied. We hence aimed to analyze the clinical characteristics, demographics, and survival outcomes of pediatric patients with spinal chordomas, in contrast to the adult population. To address this, the literature was reviewed to evaluate the coverage on spinal chordomas of the pediatric population, and the National Cancer Database (NCDB) was analyzed to provide insights into the US experience over the past two decades. Methods A search of the literature was performed leveraging the MEDLINE and Web of Science electronic databases from inception until March 2024, using the keywords “spinal,” “chordoma,” and “pediatric”. Additionally, the NCDB was queried for pediatric patients (≤ 21 years) with chordoma treated between 2004 and 2017. Baseline characteristics, tumor specifics, treatment details, and survival outcomes were collected and analyzed. Results From the literature, 45 pediatric chordoma patients were identified, with a median age of 7 years. Most chordomas were in the cervical spine (40%), and 93% of the patients received surgical treatment. Gross total resection was achieved in 59% of cases, and 49% received adjuvant radiotherapy. Recurrence, metastasis, and mortality rates were 7%, 18%, and 24%, respectively at a median follow-up of 12 months. In the NCDB cohort, 53 pediatric patients (≤ 21 years) and 980 adults (> 21 years) were compared. Despite having smaller tumors in size, pediatric patients presented with more advanced tumors with a higher proportion of stage 4 tumors. They had more mobile spine chordomas (83% vs. 51%) and traveled further for treatment (57 vs. 27 miles). Pediatric patients also received higher radiation doses (5420 vs. 5049 cGy). Surgical resection and adjuvant radiotherapy were common treatments in both groups. After matching, outcomes, including survival rates and early mortality, were similar between age groups. Kaplan-Meier analysis showed no difference in overall survival probabilities between the age groups both prior to and after matching. Conclusion While pediatric patients with spinal chordomas present with more advanced stage tumors, they demonstrate similar overall survival outcomes when compared to adults. The current literature is mainly composed of single cases and other reports of low evidence levels.

Abstract BACKGROUND Currently, little is known about the clinical relevance of tumor-stroma ratio (TSR) in chordoma and data discussing the relationship between TSR and immune status of chordoma are lacking. OBJECTIVE To characterize TSR distribution in spinal chordoma, and investigated its correlation with clinicopathologic or immunological features of patients and outcome. METHODS TSR was assessed visually on hematoxylin and eosin-stained sections from 54 tumor specimens by 2 independent pathologists. Multiplex immunofluorescence was used to quantify the expression levels of microvessel density, Ki-67, Brachyury, and tumor as well as stromal PD-L1. Tumor immunity status including the Immunoscore and densities of tumor-infiltrating lymphocytes (TILs) subtypes were obtained from our published data and reanalyzed. RESULTS Bland-Altman plot showed no difference between mean TSR derived from the two observers. TSR was positively associated with stromal PD-L1 expression, the Immunoscore and CD3+ as well as CD4+ TILs density, but negatively correlated with tumor microvessel density, Ki-67 index, surrounding muscle invasion by tumor and number of Foxp3+ and PD-1+ TILs. Low TSR independently predicted poor local recurrence-free survival and overall survival. Moreover, patients with low TSR and low Immunoscore chordoma phenotype were associated with the worst survival. More importantly, combined TSR and Immunoscore accurately reflected prognosis and enhanced the ability of TSR or Immunoscore alone for outcome prediction. CONCLUSION These data reveal the significant impact of TSR on tumor progression and immunological response of patients. Subsequent use of agents targeting the stroma compartment may be an effective strategy to treat chordoma especially in combination with immune-based drugs.

ABSTRACT BACKGROUND: Clival chordomas frequently recur because of their location and invasiveness. OBJECTIVE: To investigate clinical, operative, and anatomic factors associated with clival chordoma recurrence. METHODS: Retrospective review of clival chordomas treated at our center from 1993 to 2013. RESULTS: Fifty patients (56% male) with median age of 59 years (range, 8–76) were newly diagnosed with clival chordoma of mean diameter 3.3 cm (range, 1.5-6.7). Symptoms included headaches (38%), diplopia (36%), and dysphagia (14%). Procedures included transsphenoidal (n = 34), transoral (n = 4), craniotomy (n = 5), and staged approaches (n = 7). Gross total resection (GTR) rate was 52%, with 83% mean volumetric reduction, values that improved over time. While the lower third of the clivus was the least likely superoinferior zone to contain tumor (upper third = 72%/middle third = 82%/lower third = 42%), it most frequently contained residual tumor (upper third = 33%/middle third = 38%/lower third = 63%; P < .05). Symptom improvement rates were 61% (diplopia) and 53% (headache). Postoperative radiation included proton beam (n = 19), cyberknife (n = 7), intensity-modulated radiation therapy (n = 6), external beam (n = 10), and none (n = 4). At last follow-up of 47 patients, 23 (49%) remain disease-free or have stable residual tumor. Lower third of clivus progressed most after GTR (upper/mid/lower third = 32%/41%/75%). In a multivariate Cox proportional hazards model, male gender (hazard ratio [HR] = 1.2/P = .03), subtotal resection (HR = 5.0/P = .02), and the preoperative presence of tumor in the middle third (HR = 1.2/P = .02) and lower third (HR = 1.8/P = .02) of the clivus increased further growth or regrowth, while radiation modality did not. CONCLUSION: Our findings underscore long-standing support for GTR as reducing chordoma recurrence. The lower third of the clivus frequently harbored residual or recurrent tumor, despite staged approaches providing mediolateral (transcranial + endonasal) or superoinferior (endonasal + transoral) breadth. There was no benefit of proton-based over photon-based radiation, contradicting conventional presumptions.

Sacral chordoma is a rare primary bone neoplasm associated with high morbidity. The aim of this study is to identify demographic and clinicopathological characteristics of this tumor and evaluate their impact on survival outcomes. The Surveillance, Epidemiology and End Results (SEER) database collecting data between 2000 and 2018 was searched for all cases of sacral chordoma. We analyzed demographic aspects, cancer stage and treatment patterns. Overall survival was calculated using the Kaplan-Meier method and compared between subgroups using the log-rank test. A multivariate Cox hazard regression analysis was conducted to identify independent predictors of overall survival. Four hundred and forty-two patients were identified with a mean age of 62.7 years. Most tumors presented regional invasion at diagnosis (43.2%). Mean overall survival was 124.7 months. No significant difference in terms of overall survival was found between surgery alone and surgery associated with radiotherapy. Both options provided a significantly increased survival than radiotherapy alone. Age of less than 50 years or between 50 and 69 correlated significantly with improved survival. Age and stage at diagnosis impact significantly survival outcomes. Surgery remains the mainstay treatment with the highest overall survival. Its association with radiotherapy is currently questionable and needs further research.