Natural History of a Patient with Sacral Chordoma: Case Report and Literature Review.

BACKGROUND: Chordomas are rare, slow-growing, locally aggressive, malignant tumors of the spine. Chordomas are conventionally treated with surgical resection with or without radiation. There is an absence of literature documenting the natural history of a primary sacral chordoma. CASE DESCRIPTION: A 65-year-old man presented with rectal pain, constipation, urinary and fecal incontinence, S1 radiculopathy, and a palpable rectal mass. A needle biopsy confirmed the pathologic diagnosis of sacral chordoma. The patient declined to have surgery because of the surgical risks involved. He was managed conservatively with supportive care only. The patient was routinely followed in clinic and had a subjective and objective excellent quality of life with adequate pain management. Meanwhile, his neurologic status did not deteriorate. During follow-up, some posterolateral aspects of the chordoma regressed. However, the bulk of the lesion continued to slowly progress. The patient survived for 7.5 years. He eventually succumbed to urosepsis and new-onset peritoneal metastasis. CONCLUSIONS: To our knowledge, the patient is the only documented case in the literature of an untreated biopsy-proven sacral chordoma. The patient's tumor was intended for resection, and therefore comparable with data from treated chordomas. The patient's survival is similar to the median survival in treated chordomas. The patient's survival was despite negative prognosticators, such as advanced age of the patient and high sacral location above S2.

Development of a Novel Orthotopic Primary Human Chordoma Xenograft Model: A Relevant Support for Future Research on Chordoma.

Chordomas are slow-growing rare malignant neoplasms. The aim of this study was to establish a primary model of chordoma in the lumbosacral orthotopic area, to compare the growth rate to the subcutaneous site, and to show that this new graft site optimizes tumor growth and bony invasion. Eleven chordoma samples were transplanted subcutaneously in the flank and/or in contact with the lumbosacral region and grown into nude mice. Engraftment rate was significantly more successful in the lumbosacral environment compared with the flank at P0. Two xenografts from 2 patients showed bone invasion. One tumor was maintained through multiple rounds of serial transplantation, creating a model for study. Histological and immunostaining analysis confirmed that tumor grafts recapitulated the primary tumor from which they were derived, consisting of a myxoid chordoma expressing brachyury, cytokeratin AE1, EMA, and VEGF. Clear destruction of the bone by the tumor cells could be demonstrated. Molecular studies revealed PIK3CA and PTEN mutations involved in PI3K signaling pathway and most of the frequently reported chromosomal alterations. We present a novel orthotopic primary xenograft model of chordoma implanted for the first time in the lumbosacral area showing bone invasion, PIK3CA, and PTEN mutations that will facilitate preclinical studies.

Endoscopic endonasal skull base surgery for pediatric brain tumors.

PURPOSE: The utility of endoscopic endonasal skull base surgery (EES) in various pathologic entities in adults has been published in the literature. However, the role of EES in children has not been clearly elucidated. We evaluated the feasibility of EES in children with brain tumors. METHODS: We retrospectively reviewed clinical features, surgical outcomes, and complications in children who underwent EES for intracranial and skull base tumors at a single institution from July 2010 to October 2018. RESULTS: A total of 82 patients underwent EESs for 77 intracranial and 5 skull base bony tumors. The mean age at diagnosis was 11.4 years (range 4-18 years), and the mean follow-up period was 46.8 months. The most common tumors were craniopharyngioma in the intracranial tumor and chordoma in the skull base. Gross total resection was the goal of surgery in 55 patients and achieved in 90.9%. The vision was improved in 76.1% of patients with visual impairments. Preoperatively, various endocrinological deficiencies were revealed in 73.7% of 76 patients with hypothalamus-pituitary lesions, and the hyposomatotropism was most common. Endocrinological status was improved only in 10. Aseptic or bacterial meningitis (7.3%) was the most common surgical complication, and the cerebrospinal fluid leakage rate was 2.4%. CONCLUSIONS: EES provides favorable neurological outcomes with acceptable risk for children with brain tumors. The high incidence of endocrinological deficits in cases with hypothalamus-pituitary lesions emphasizes the importance of judicious pre- and postoperative evaluation.

A giant lumbar chordoma: A case report.

RATIONALE: Chordomas are malignant neoplasms derived from incomplete regression of notochordal tissue along the craniococcygeal axis.It is rare for Chordoma arising from the lumbar spine and the traditional long-term prognosis is typically poor. PATIENT CONCERNS: The persistent pain in the left side of the waist about 2 years. DIAGNOSES: Chordoma. INTERVENTIONS: The patient was treated with surgical resection of the total tumor, followed by the spinal internal fixation of L1 to L2 with pedicle screws. OUTCOMES: After 5 month follow-up,we find the recurrence in the original lesion.At the 15 month follow-up,the patient was dead after a lot of times revisit by various doctor. LESSONS: So It is suggest that the diagnosis should be carried out accurately at the early stage, the lesions and source of lesions should be cut away as broadly as possible, also the radiation and chemotherapy should be carried out after the operation as necessary.

High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases.

Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome. In contrast to conventional chordomas, PDC show solid growth and increased cellularity, cytologic atypia, and mitotic activity. Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression. Thus PDC joined the expanding family of SMARCB1-deficient tumors characterized by various SMARCB1 structural abnormalities, ranging from large homozygous deletions to small intragenic mutations. In the present study, we investigate the SMARCB1 abnormalities in a group of nine well-characterized PDCs and to establish the sensitivity of the FISH method in detecting these changes in the clinical setting. We further assessed the pathologic features and clinical behavior of this cohort managed at our referral center over a 20-year period. The mean age at diagnosis was 10 years-of-age. All except one case occurred in the cranial region. All demonstrated strong nuclear expression of brachyury and loss of SMARCB1 expression. FISH identified homozygous SMARCB1 deletions in all except one case; additionally two cases revealed a heterozygous EWSR1 locus co-deletion. Clinical follow-up information was available in five patients. Two patients presented with distant metastases at initial diagnosis. Two of the three remaining patients with primary disease failed both locally and distantly after multimodality therapy. We conclude that PDCs are highly aggressive tumors and the dominant mechanism of loss of SMARCB1 expression is through large, homozygous SMARCB1 deletions that can be readily detected by FISH.

Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: an orthotopic spine model.

OBJECTIVE Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat. METHODS Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor-engrafted (n = 11), JHC7 tumor-engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E-based histological examination and immunohistochemistry for brachyury, S100ß, and cytokeratin. RESULTS The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma-engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma-engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor-engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats. CONCLUSIONS The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors' knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

How Does the Level of Nerve Root Resection in En Bloc Sacrectomy Influence Patient-Reported Outcomes?

BACKGROUND: For patients with sacral tumors, who are well enough for surgery, en bloc resection is the preferred treatment. Survival, postoperative complications, and recurrent rates have been described, but patient-reported outcomes often are not included in these studies. QUESTIONS/PURPOSES: The purposes of this study were (1) to compare patient-reported outcomes after en bloc sacrectomy, based on the level of sacral nerve root resection, in terms of mental health, physical health, bowel function, and sexual function; and (2) to assess differences in terms of mental health, physical health, and pain between patients with and without a colostomy. METHODS: A total of 74 patients, of whom 58 (78%) were diagnosed with chordoma, were surveyed between February 2012 and October 2014. This represented 48% of patients with sacral chordoma who were alive and who had been treated with a transverse sacral resection between June 2000 and August 2013 at three institutions with a minimum followup of 6 months (mean, 59 months; range, 6-255 months). We chose 6 months because we believe that neurologic deficits generally are stable by this point and that patients generally have recovered from the operation by this time. Patients were divided into five groups based on the most caudal nerve root spared: L5 (N = 10), S1 (N = 22), S2 (N = 17), S3 (N = 18), and S4 (N = 7). Only postoperative outcomes were collected using the National institute of Health's Patient Reported Measurement Information System (PROMIS) Global Health survey, PROMIS Pain Interference survey, PROMIS Pain Intensity survey, PROMIS Sexual Function survey, and the Modified Obstruction and Defecation Score survey. RESULTS: Differences between two adjacent levels were found in terms of mental health, physical health, and sexual function. Patients in whom the S2 nerve roots were spared had a lower mental health score (median = 44, interquartile range [IQR] = 41-51) than patients in whom the S3 nerve roots were spared (median = 53, IQR = 48-56, q = 0.049). Patients in whom the S2 nerve roots were spared had a slightly lower physical health score (median = 42, IQR = 40-51) than patients in whom the S3 nerve roots were spared (median = 47, IQR = 45-54, q = 0.043). Patients in whom the S1 roots were spared (median = 1.0, range = 1.0-1.0) had a lower orgasm score than patients in whom the S2 nerve roots were spared (median = 3, range = 2-5, q = 0.027). No differences in terms of mental health, physical health, or pain were found between the colostomy group and the no colostomy group. CONCLUSIONS: The combination of our findings can be used to further educate patients and discuss expectations. In an operative setting, these data can be considered when deciding to place a colostomy. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Are the Conditional Survival and Functional Outcomes After Surgical Treatment of 115 Patients With Sacral Chordoma?

BACKGROUND: Conditional survival is a measure of prognosis for patients who have already survived for a specific period of time; however, data on conditional survival after sacrectomy in patients with sacral chordoma are lacking. In addition, because sacral tumors are rare and heterogeneous, classifying them in a way that allows physicians to predict functional outcomes after sacrectomy remains a challenge. QUESTIONS/PURPOSES: (1) What is the overall survival and disease-free survival in patients treated by sacrectomy for chordoma? (2) What is the conditional survival probability and how do prognostic factors change over time in patients undergoing surgical resection for sacral chordoma? (3) What is the local recurrence rate after surgery, how was it treated, and what factors impact on local recurrence? (4) What is the postoperative motor, sensory, bowel, and bladder function by level of resection as determined by using a newly designed scoring method? METHODS: Between 2003 and 2012, our center treated 122 patients surgically for sacral chordoma. Of those, two died and five were lost before a minimum followup of 1 year was achieved, leaving 115 patients available for analysis in this retrospective study at a mean of 4.9 years (range, 1.3-10.8 years). Basically, single posterior or combined approaches were chosen based on the most cephalad extent of the tumor and resection level was normally at half or one sacral vertebrae above the tumor. The 5-year conditional survival rate was calculated based on Kaplan-Meier survival analysis. The effect of prognostic factors on conditional survival was also explored. A newly designed score method was proposed and adopted in the current study to critically evaluate the functional outcome after resection of the sacrum. Inter- and intraobserver reliability was tested by a preliminary study using kappa statistics and Spearman rank correlation coefficients. Significant interobserver (p < 0.01) and intraobserver agreement (κ > 0.75) were found in nine items between each observer. RESULTS: The estimated 5-year overall survival rate was 81% (95% confidence interval [CI], 72%-90%) at diagnosis. The 5-year disease-free survival rate was 52% (95% CI, 43%-63%). The 5-year conditional overall survival decreased with each additional year in the first 4 years (81% at diagnosis versus 60% at the fourth year, p < 0.0001) and increased slightly in the fifth year. Patients with adequate surgical margins displayed a higher 5-year survival than those with an inadequate margin (86% [95% CI, 76%-95%] versus 67% [95% CI, 48%-85%], p = 0.01) at diagnosis. Conditional survival estimates for patients who received operations elsewhere were lower than that of newly diagnosed patients treated by us at diagnosis (64% [95% CI, 46%-83%] versus 90% [95% CI, 82%-99%], p = 0.012), but with the numbers we had, we could not detect a difference in conditional survival between those treated elsewhere first compared with those initially treated by us at 5 years. The proposed score system for function evaluation was able to distinguish different levels of resection. The overall functional results for the preservation of bilateral S1, S2, and S3 were 40 ± 8%, 60 ± 12%, and 82 ± 11%, respectively. Patients who had preservation of only one S3 nerve root had more severe incontinence (1.99 ± 0.79 versus 2.60 ± 0.63, p = 0.01) and more sensory loss (1.88 ± 0.82 versus 2.31 ± 0.59, p = 0.02) than those patients with preservation of bilateral S3 nerve roots. CONCLUSIONS: The 5-year conditional survival for sacral chordoma decreased with each additional year and began to improve after the fourth year. In addition, the effect of the surgical margin and influence of previous surgery on conditional survival were not linear over time. The level of nerve root resections corresponded with the overall function scores according to the proposed scoring method. This information and scoring system should be valuable in discussing outcomes of sacrectomy in patients with chordoma who are considering this operation and serve as the basis for further study. LEVEL OF EVIDENCE: Level III, therapeutic study.

Establishment and characterization of a chordoma cell line from the tissue of a patient with dedifferentiated-type chordoma.

OBJECTIVE Chordoma is a rare bone tumor of the axial skeleton believed to originate from the remnants of the embryonic notochord. The available tumor cells are characteristically physaliferous and express brachyury, a transcription factor critical for mesoderm specification. Although chordomas are histologically not malignant, treatments remain challenging because they are resistant to radiation therapy and because wide resection is impossible in most cases. Therefore, a better understanding of the biology of chordomas using established cell lines may lead to the advancement of effective treatment strategies. The authors undertook a study to obtain this insight. METHODS Chordoma cells were isolated from the tissue of a patient with dedifferentiated-type chordoma (DTC) that had recurred. Cells were cultured with DMEM/F12 containing 10% fetal bovine serum and antibiotics (penicillin and streptomycin). Cell proliferation rate was measured by MTS assay. Cell-cycle distribution and cell surface expression of proteins were analyzed by fluorescence-activated cell sorting (FACS) analysis. Expression of proteins was analyzed by Western blot and immunocytochemistry. Radiation resistance was measured by clonogenic survival assay. Tumor formation was examined by injection of chordoma cells at hindlimb of nude mice. RESULTS The putative (DTC) cells were polygonal and did not have the conventional physaliferous characteristic seen in the U-CH1 cell line. The DTC cells exhibited similar growth rate and cell-cycle distribution, but they exhibited higher clonogenic activity in soft agar than U-CH1 cells. The DTC cells expressed high levels of platelet-derived growth factor receptor-ß and a low level of brachyury and cytokeratins; they showed higher expression of stemness-related and epithelial to mesenchymal transition-related proteins than the U-CH1 cells. Intriguingly, FACS analysis revealed that DTC cells exhibited marginal surface expression of CD24 and CD44 and high surface expression of CXCR4 in comparison to U-CH1 cells. In addition, blockade of CXCR4 with its antagonist AMD3100 effectively suppressed the growth of both cell lines. The DTC cells were more resistant to paclitaxel, cisplatin, etoposide, and ionizing radiation than the U-CH1 cells. Injection of DTC cells into the hindlimb region of nude mice resulted in the efficient formation of tumors, and the histology of xenograft tumors was very similar to that of the original patient tumor. CONCLUSIONS The use of the established DTC cells along with preestablished cell lines of chordoma may help bring about greater understanding of the mechanisms underlying the chordoma that will lead to therapeutic strategies targeting chordomas.

Effective palliative radiofrequency ablation for tumors causing pain, numbness and motor function disorders: case series.

BACKGROUND: We present a case series of a palliative radiofrequency ablation (RFA) for the tumors that lead to the resolution of pain and motor function disorders. RFA is widely used on tumors in various organs and often reported in good outcome. There are some reports that RFA was performed as a palliative treatment but a few reports of RFA that performed for lung tumor as a palliative treatment. This case series includes two cases, palliative RFA for a sacrum and a lung tumor. The results of this case series presented that a palliative RFA is effective in improving the symptoms of patients. CASE PRESENTATION: Case 1. A 64-year-old Japanese woman with a chordoma at her sacrum presented with pain in her left leg and claudication. Though operations, radiation therapy and GS-TAE (gelatin sponge-transarterial embolization, via the L5 lumbar artery) were performed, the size of the tumor leading pain and claudication increased. RFA was performed for the sacral tumor, and these symptoms resolved one year after the procedure. Case 2. A 68-year-old Japanese man with a leiomyosarcoma at the apex of left lung presented with pain and motor function disorders of the left upper limb. Dissemination in the pleura was appeared after the operation for a leiomyosarcoma at the mediastinum. Though radiation therapy and a second operation were performed, the tumor at the apex of the left lung increased and pain and numbness of the left upper limb were appeared after the second operation. RFA was performed for the left lung tumor, and the symptoms resolved 3 months after RFA. CONCLUSION: RFA is effective as a palliative treatment and has a potential to salvage the patients from the symptoms of the tumors when conventional palliative treatments such as surgery, radiation therapy, and chemotherapy are difficult or contraindicated.