R. Nakayama, N. Asano, Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
K. Hayakawa, Department of Orthopaedic Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Clin Orthop Relat Res. 2020 Nov;478(11):2537-2547. doi: 10.1097/CORR.0000000000001266.
Clear cell chondrosarcoma is an extremely rare chondrosarcoma subtype; thus, its treatment outcomes and associated factors have not been widely studied. Knowing more about it is potentially important because clear cell chondrosarcomas are often misdiagnosed as other benign lesions and subsequently treated and followed inappropriately.
QUESTIONS/PURPOSES: (1) What are the patient- and tumor-related characteristics of clear cell chondrosarcoma? (2) What proportion of patients with clear cell chondrosarcoma initially had a misdiagnosis or a misleading initial biopsy result? (3) What is the survivorship of patients with clear cell chondrosarcoma free from death, local recurrence, and distant metastasis, and what factors are associated with greater survivorship or a reduced risk of local recurrence?
Between 1985 and 2018, 12 Japanese Musculoskeletal Oncology Group (JMOG) hospitals treated 42 patients with a diagnosis of clear cell chondrosarcoma. All 42 patients had complete medical records at a minimum of 1 year or death, and were included in this multicenter, retrospective, observational study. No patients were lost to follow-up within 5 years of treatment but four were lost to follow-up greater than 5 years after treatment because their physicians thought their follow-up was sufficient. Clinical data were collected by chart review. The median (range) follow-up period was 69 months (2 to 392). In general, when a possibly malignant bone tumor was found on imaging studies, the histological diagnosis was made by biopsy before initiating treatment. Once the diagnosis had been made, the patients were treated by surgery only, complete resection if technically possible, because chondrosarcomas are known to be resistant to chemotherapy and radiotherapy. Unresectable tumors were treated with particle-beam radiation therapy. When patients with chondrosarcoma were referred after unplanned surgical procedures with inadequate surgical margins, immediate additional wide resection was considered before local recurrence developed. This diagnostic and treatment strategy is common to all JMOG hospitals and did not change during the study period. Primary wide resection was performed in 79% (33 of 42) patients, additional wide resection after initial inadequate surgery in 12% (five of 42), curettage and bone grafting in 5% (two of 42) patients, and radiotherapy was administered to 5% (two of 42). Surgical margins among the 40 patients who underwent surgery at JMOG hospitals were no residual tumor in 93% (37 of 42) of patients, microscopic residual tumor in 2% (one of 42), and macroscopic residual tumor or state after curettage or intralesional excision in 5% (two of 42). The oncological endpoints of interest were 5- and 10- year overall survival, disease-free survival, survival free of local recurrence, and survival free of distant metastases; these were calculated using the Kaplan-Meier method and compared using the log-rank test. Risk ratios with their respective 95% confidence intervals (CIs) were estimated in a Cox regression model. The Bonferroni adjustment was used for multiple testing correction.
The sex distribution was 74% men and 26% women (31 and 11 of 42, respectively), with a mean age of 47 ± 17 years. Eighty one percent (34 of 42) of tumors occurred at the ends of long bones, and the proximal femur was the most common site accounting for 60% (25 of 42). The mean size of the primary tumors was 6.3 ± 2.7 cm. Definite pathologic fractures were present in 26% (10 of 42) and another 26% (10 of 42) had extraskeletal involvement. None had metastases at presentation. Twenty four percent (six of 25) tumors in the proximal femur were misdiagnosed as benign lesions and treated inadequately without biopsy. Twenty nine percent (10 of 35) patients had initial misdiagnoses by biopsy and core needle biopsies had a greater risk of resulting in inaccurate histological diagnoses. The study patients' 5- and 10-year overall survival rates were 89% (95% CI 74 to 96) and 89% (95% CI 74 to 96), respectively; 5- and 10- year disease-free survival rates 77% (95% CI 58 to 89) and 57% (95% CI 36 to 75), respectively; 5- and 10-year local recurrence-free survival rates 86% (95% CI 68 to 95) and 71% (95% CI 49 to 86), respectively; and 5- and 10-year distant metastasis-free survival rates 84% (95% CI 67 to 93) and 74% (95% CI 53 to 88), respectively. Notably, bone metastases (17%, seven of 42) were as common as pulmonary metastases (14%, six of 42); four patients developed both bone and pulmonary metastases. The difference between 10-year overall survival rates and 10-year disease-free survival indicated very late recurrence more than 5 years after the initial treatment. After controlling for multiple comparisons, the only factor we found that was associated with local recurrence-free survival was initial treatment (positive margin versus primary wide resection) (risk ratio 8.83 [95% CI 1.47 to 53.1]; p = 0.022 after the Bonferroni adjustment). Additional wide resection reduced the risk of local recurrence.
The femoral head was the most common location of clear cell chondrosarcoma and had a high risk of misdiagnosis as common benign lesions that resulted in initial inadequate surgery and a consequent high risk of local recurrence. Immediate additional wide resection should be considered in patients who had initial inadequate surgery to reduce the risk of local recurrence. Because clear cell chondrosarcoma can recur locally or distantly in the bones and lungs in the long term, patients should be informed of the risk of very late recurrence and the necessity of decades-long with surveillance for local recurrence and lung and bone metastases.
Level IV, therapeutic study.
透明细胞软骨肉瘤是一种极为罕见的软骨肉瘤亚型；因此，其治疗结果和相关因素尚未得到广泛研究。了解更多这方面的知识可能很重要，因为透明细胞软骨肉瘤常被误诊为其他良性病变，随后进行不适当的治疗和随访。
问题/目的：(1)透明细胞软骨肉瘤患者的临床和肿瘤特征有哪些？(2)有多少透明细胞软骨肉瘤患者最初存在误诊或误导性的初始活检结果？(3)透明细胞软骨肉瘤患者的无死亡、局部复发和远处转移生存率是多少，哪些因素与生存率更高或局部复发风险降低相关？
1985 年至 2018 年，日本肌肉骨骼肿瘤学会（JMOG）的 12 家医院共收治了 42 例透明细胞软骨肉瘤患者。所有 42 例患者均至少有 1 年或死亡的完整病历，并纳入这项多中心、回顾性、观察性研究。在治疗后 5 年内，没有患者失访，但有 4 例患者在治疗后 5 年以上失访，因为他们的医生认为他们的随访已经足够。通过病历回顾收集临床数据。中位（范围）随访时间为 69 个月（2 至 392 个月）。一般来说，当影像学检查发现可能为恶性骨肿瘤时，在开始治疗前通过活检做出组织学诊断。一旦诊断明确，所有患者均仅接受手术治疗，如果技术上可行，则进行完全切除，因为软骨肉瘤对化疗和放疗有抵抗力。不能切除的肿瘤采用粒子束放疗。当软骨肉瘤患者在计划外手术且手术切缘不充分时被转诊，在局部复发发生之前，应立即考虑进行额外的广泛切除。这一诊断和治疗策略在所有 JMOG 医院中都很常见，在研究期间没有改变。79%（33/42）的患者接受了原发性广泛切除术，12%（5/42）的患者在初始手术不充分后接受了额外的广泛切除术，5%（2/42）的患者接受了刮除和植骨术，5%（2/42）的患者接受了放疗。在 JMOG 医院接受手术的 40 名患者中，手术切缘无肿瘤残留的患者占 93%（37/42），显微镜下肿瘤残留的患者占 2%（1/42），肉眼可见肿瘤残留或刮除后肿瘤残留的患者占 5%（2/42）。我们感兴趣的肿瘤学终点包括 5 年和 10 年的总生存率、无病生存率、局部无复发生存率和无远处转移生存率，这些通过 Kaplan-Meier 法计算，并使用对数秩检验进行比较。使用 Cox 回归模型估计风险比及其各自的 95%置信区间（CIs）。在多重检验校正中使用了 Bonferroni 调整。
性别分布为男性 74%（31/42），女性 26%（11/42），平均年龄为 47±17 岁。81%（34/42）的肿瘤发生在长骨的末端，股骨近端是最常见的部位，占 60%（25/42）。原发性肿瘤的平均大小为 6.3±2.7cm。26%（10/42）的患者存在明确的病理性骨折，另有 26%（10/42）的患者有骨外累及。患者就诊时均无转移。股骨近端 24%（6/25）的肿瘤被误诊为良性病变，未经活检即进行了不适当的治疗。29%（10/35）的患者活检时存在初始误诊，且细针活检的组织学诊断准确性较差。研究患者的 5 年和 10 年总生存率分别为 89%（95%CI 74%至 96%）和 89%（95%CI 74%至 96%），5 年和 10 年无病生存率分别为 77%（95%CI 58%至 89%）和 57%（95%CI 36%至 75%），5 年和 10 年局部无复发生存率分别为 86%（95%CI 68%至 95%）和 71%（95%CI 49%至 86%），5 年和 10 年无远处转移生存率分别为 84%（95%CI 67%至 93%）和 74%（95%CI 53%至 88%）。值得注意的是，骨转移（17%，7/42）与肺转移（14%，6/42）一样常见；有 4 例患者同时发生骨转移和肺转移。10 年总生存率与 10 年无病生存率之间的差异表明，初始治疗后 5 年以上仍存在非常晚期的复发。在进行多重比较校正后，我们发现唯一与局部无复发生存率相关的因素是初始治疗（阳性切缘与原发性广泛切除术）（风险比 8.83[95%CI 1.47 至 53.1]；p=0.022，Bonferroni 调整后）。额外的广泛切除术降低了局部复发的风险。
透明细胞软骨肉瘤最常见于股骨头，误诊为常见的良性病变的风险较高，导致初始手术不充分，继而局部复发的风险较高。对于初始手术不充分的患者，应立即考虑进行额外的广泛切除术，以降低局部复发的风险。由于透明细胞软骨肉瘤在骨骼和肺部可能在长期内局部或远处复发，因此应告知患者存在非常晚期复发的风险，以及需要数十年的随访以监测局部复发和肺及骨转移的必要性。
IV 级，治疗研究。
