Trovarelli Giulia, Sbaraglia Marta, Angelini Andrea, Bellan Elena, Pala Elisa, Belluzzi Elisa, Pozzuoli Assunta, Borga Chiara, Dei Tos Angelo Paolo, Ruggieri Pietro
Department of Orthopedics and Orthopedic Oncology, University of Padua, Padua, Italy.
Department of Surgery, Oncology and Gastroenterology of University of Padova, Padua, Italy.
Clin Orthop Relat Res. 2024 Jan 3;482(6):947-56. doi: 10.1097/CORR.0000000000002960.
Because chondrosarcomas vary widely in their behavior, and because anticipating their behavior based on histology alone can be challenging, genetic markers represent an appealing area of inquiry that may help us refine our prognostic approaches. Isocitrate dehydrogenase (IDH) mutations are involved in the pathogenesis of a variety of neoplasms, and recently, IDH1/2 mutations have been found in the tissue of benign cartilage tumors as well as in conventional chondrosarcomas and highly aggressive dedifferentiated chondrosarcomas. However, their association with patient survival is still controversial.
QUESTIONS/PURPOSES: (1) What proportion of patients with chondrosarcomas carry IDH mutations, and which IDH mutations can be found? (2) Are any specific IDH mutations associated with poorer overall survival, metastasis-free survival, or local recurrence-free survival?
Between April 2017 and December 2022, we treated 74 patients for atypical cartilaginous tumors or chondrosarcomas in a musculoskeletal tumor referral center. Patients were considered potentially eligible for the present study if the histologic diagnosis was confirmed by two expert soft tissue and bone pathologists following the current WHO classification, complete preoperative imaging and follow-up data were available, surgical excision was performed by sarcoma orthopaedic surgeons directed by a team leader, and the minimum follow-up was 2 years after surgical treatment unless the patient died. Data including sex, age, diagnosis, grade, type of operation, local recurrence, metastasis, and oncologic follow-up were recorded. Forty-one patients (55%) were eligible for the study. For each patient, DNA was extracted and quantified from paraffin-embedded sections of tumor tissue, and the mutational status of IDH1 (codons 105 and 132) and IDH2 (codons 140 and 172) genes was assessed. Of those, 56% (23 of 41) of patients had adequate DNA for analysis of IDH mutations: 10 male and 13 female patients, with a median age of 59 years (range 15 to 98 years). There were 22 conventional chondrosarcomas (8 atypical cartilaginous tumors, 11 Grade 2, and 3 Grade 3) and 1 dedifferentiated chondrosarcoma. Stage was IA in 3 patients, IB in 5, IIA in 1, IIB in 13, and III in 1, according to the Musculoskeletal Tumor Society classification. At a median follow-up of 3.5 years (range 4 months to 5.6 years), 14 patients were disease-free, 2 were alive with disease, and 7 died (3 within 2 years from surgery). Eight patients had metastases, and 7 developed local recurrence. We determined the proportion of patients who carried IDH mutations, and compared patients with and without those mutations in terms of overall survival, metastasis-free survival, and local recurrence-free survival using Kaplan-Meier curves.
Six patients showed wild-type IDH genes, and 17 had IDH mutations (12 had IDH1 R132, 3 had IDH1 G105, and 2 had IDH2 R172). Overall survival at 2 years using the Kaplan-Meier estimator was lower in patients with an IDH mutation than in those with the wild-type gene (75% [95% confidence interval 50% to 99%] versus 100% [95% CI 100% to 100%]; p = 0.002). Two-year metastasis-free survival was also lower in patients with an IDH mutation than in those with the wild-type gene (33% [95% CI 7% to 60%] versus 100% [95% CI 100% to 100%]; p = 0.001), as was 2-year local recurrence-free survival (70% [95% CI 42% to 98%] versus 100% [95% CI 100% to 100%]; p = 0.02).
We found that IDH1 R132 mutations were negatively associated with the prognosis of patients with bone chondrosarcomas. Nevertheless, more extensive studies (such as multicenter international studies) are needed and advisable to confirm our observations in this preliminary small series. Moreover, evaluating mutational status in fresh samples instead of in paraffin-embedded sections could help to increase the number of patients with adequate DNA for analysis. If our findings will be confirmed, the evaluation of IDH mutational status in biopsy samples or resection specimens could be considered when stratifying patients, highlighting those who may benefit from more aggressive treatment (such as adjuvant chemotherapy) or closer follow-up.
Level III, prognostic study.
由于软骨肉瘤的行为差异很大，而且仅根据组织学来预测其行为具有挑战性，因此基因标志物是一个有吸引力的研究领域，可能有助于我们改进预后方法。异柠檬酸脱氢酶（IDH）突变参与多种肿瘤的发病机制，最近，在良性软骨肿瘤组织以及传统软骨肉瘤和高度侵袭性去分化软骨肉瘤中均发现了IDH1/2突变。然而，它们与患者生存的关联仍存在争议。
问题/目的：（1）软骨肉瘤患者携带IDH突变的比例是多少，能发现哪些IDH突变？（2）是否有特定的IDH突变与较差的总生存、无转移生存或无局部复发生存相关？
2017年4月至2022年12月期间，我们在一家肌肉骨骼肿瘤转诊中心治疗了74例非典型软骨肿瘤或软骨肉瘤患者。如果两名专家软组织和骨病理学家根据当前WHO分类确诊组织学诊断，有完整的术前影像学和随访数据，由肉瘤骨科医生在团队负责人指导下进行手术切除，且除非患者死亡，手术治疗后最短随访2年，则认为这些患者可能符合本研究条件。记录包括性别、年龄、诊断、分级、手术类型、局部复发、转移和肿瘤学随访等数据。41例患者（55%）符合研究条件。对每位患者，从肿瘤组织石蜡包埋切片中提取并定量DNA，评估IDH1（密码子105和132）和IDH2（密码子140和172）基因的突变状态。其中，56%（41例中的23例）患者有足够的DNA用于IDH突变分析：10例男性和13例女性患者，中位年龄59岁（范围15至98岁）。有22例传统软骨肉瘤（8例非典型软骨肿瘤、11例2级和3例3级）和1例去分化软骨肉瘤。根据肌肉骨骼肿瘤学会分类，3例患者为IA期，5例为IB期，1例为IIA期，13例为IIB期，1例为III期。中位随访3.5年（范围4个月至5.6年），14例患者无疾病，2例带瘤生存，7例死亡（3例在术后2年内死亡）。8例患者发生转移，7例出现局部复发。我们确定了携带IDH突变的患者比例，并使用Kaplan-Meier曲线比较了有和没有这些突变的患者在总生存、无转移生存和无局部复发生存方面的情况。
6例患者显示IDH基因野生型，17例有IDH突变（12例为IDH1 R132，3例为IDH1 G105，2例为IDH2 R172）。使用Kaplan-Meier估计法，IDH突变患者的2年总生存率低于野生型基因患者（75%[95%置信区间50%至99%]对100%[95%CI 100%至100%]；p = 0.002）。IDH突变患者的2年无转移生存率也低于野生型基因患者（33%[95%CI 7%至60%]对100%[95%CI 100%至100%]；p = 0.001），2年无局部复发生存率也是如此（70%[95%CI 42%至98%]对100%[95%CI 100%至100%]；p = 0.02）。
我们发现IDH1 R132突变与骨软骨肉瘤患者的预后呈负相关。尽管如此，仍需要并建议进行更广泛的研究（如多中心国际研究）来证实我们在这个初步小系列中的观察结果。此外，评估新鲜样本而非石蜡包埋切片中的突变状态可能有助于增加有足够DNA用于分析的患者数量。如果我们的发现得到证实，在对患者进行分层时，可以考虑评估活检样本或切除标本中的IDH突变状态，突出那些可能从更积极的治疗（如辅助化疗）或更密切的随访中获益的患者。
III级，预后研究。
