Abstract
背景与目的
骨是非小细胞肺癌最常见转移部位之一，可引起疼痛病理性骨折等，严重影响患者生活质量。本研究探讨非小细胞肺癌骨转移的临床特点及预后因素。
方法
回顾性分析我科近5年收治的600例非小细胞肺癌患者，单光子计算机断层扫描（emission computed tomography, ECT）作为筛查方法，计算机断层扫描（computed tomography, CT）/磁共振成像（magnetic resonance imaging, MRI）/X线或病理学诊断作为骨转移的确诊方法。
结果
肺腺癌发生骨转移的比率最高，脊柱、骨盆、股骨等为骨转移高发部位。ECT显示3个浓聚灶及以上者，行CT/MRI/X线可以证实骨转移，确诊骨转移的几率远远高于ECT显示1个-2个浓聚灶的患者[80.6%（203/252）vs 50.79%（32/63）, P < 0.001]。出现骨转移后未发生骨相关事件（skeletal related events, SRE）的患者生存期长于发生SRE者，1年生存率和中位生存期分别为44.75%、14.74个月 vs 36.17%、12.25个月（P=0.022）。经Cox多因素分析，病理组织学诊断为非腺癌、骨转移病灶数少于3个，单纯骨转移为有益于生存期的预后因素。
结论
ECT异常浓聚灶的数目与骨转移影像学的确诊有关。病理组织学非腺癌、骨转移病灶数少于3个、单纯骨转移是非小细胞肺癌骨转移的独立预后因素。
Keywords: 肺肿瘤, 骨转移, ECT, CT, MRI, X线
Abstract
Background and objective
Bone metastases are the most common metastases of the non-small cell lung cancer (NSCLC). It can lead to bone ache and pathology fracture, deteriorate the quality of life.
Methods
We retrospectively investigated the characteristics, diagnosis and prognosis factors of bone metastases in NSCLC. All of the 600 patients are from department of thoracic oncology in recently 5 years. Emission computed tomography (ECT) was used to screen the bone metastases and the diagnosis of bone metastases was confrmed by computed tomography (CT)/magnetic resonance imaging (MRI)/X-ray or pathology.
Results
Among the total 322 bone metastases patients, subtype of adenocarcinoma had the most opportunity to occur bone metastases, and we found that vertebrae, pelvis and femora et al were the most frequently involved metastases sites. Patients who had more than 3 high 18F-FDG uptake sites of ECT, could be confrmed bone metastases by CT/MRI/X-ray than those with 1-2 high 18F-FDG uptake sites [80.6% (203/252) vs 50.79% (32/63), P < 0.001]. The patients with bone metastases who had non-SRE had longer survival than that of SRE [1-yr survival 44.75% (non-SRE) vs 36.17% (SRE); median survival 14.74 mo (non-SRE) vs 12.25 mo (SRE)]. Multivariables analysis showed the pathology were non-adnocarcinoma, bone metastases less than 3 sites and bone metastases without other organs metastases would have good prognosis.
Conclusion
Tere were relations between the numbers of abnormal dense sites of ECT and the diagnosis of skeletal metastases, non-adnocarcinoma bone metastases less than 3 sites and bone metastases without other organs metastases were the independent prognosis factors..
Keywords: Lung neoplasms, Bone metastases, ECT, CT, MRI, X-ray
肺癌是我国发病率和死亡率最高的恶性肿瘤，2012年中国肿瘤登记年报显示：肺癌发病率及死亡率分别为53.57/10万和45.57/10万[1]，且发病隐秘，不易早期诊断，确诊时50%为晚期，骨是非小细胞肺癌(nonsmall cell lung cancer, NSCLC)主要的血循转移部位之一。骨转移后的骨相关事件(skeletal related events, SRE)严重影响患者生活质量和生存期[2, 3]。骨转移早期诊断对于预防和治疗SRE具有重要的意义。骨发射单光子计算机断层扫描(emission computed tomography, ECT)是最常用的筛查骨转移的方法，但是其假阳性率较高。X线特异性高、操作简单、能基本显示骨质密度变化且费用低廉，可对其他影像检查发现的骨质异常进行进一步确认，但其敏感性低。计算机断层扫描(computed tomography, CT)可以显示骨骼的细微结构，为ECT阳性患者的确诊性检查，以明确是否有骨破坏、并了解破坏程度。磁共振成像(magnetic resonance imaging, MRI)诊断骨转移的敏感性和特异性均高，显示骨髓和软组织解剖清晰，诊断脊柱神经压迫症状时有优势。本研究回顾性分析了我科连续收治的600例NSCLC患者，总结肺癌骨转移的规律及诊断治疗经验。
1. 材料及方法
1.1. 研究对象
以北京大学临床肿瘤学院胸部肿瘤内科2006年1月-2011年12月连续收治的600例NSCLC患者为研究对象。入选标准：①病理或细胞学检查确诊为NSCLC；②肿瘤-淋巴结-转移(tumor-node-metastasis, TNM)分期为Ⅳ期；③美国东部肿瘤协作组(Eastern Cooperative Oncology Group, ECOG) ≤2；④完成全面分期检查(胸部CT、ECT、腹部B超、脑核磁或CT等)。排除标准：①双重癌或多重癌；②ECOG≥3；③无病理诊断；④未完成分期检查。患者的一般特征见表 1。
1.
600例NSCLC患者临床特点
Clinical characteristic of 600 patients with NSCLC
| n (No. of bone metastases percent) | X2 value | P value | ||
| NSCLC: non-small cell lung cancer; ADC: adenocarcinoma; LCC: large cell carcinoma; SQC: squamous cell carcinoma; BAC: bronchioloalveolar carcinoma. | ||||
| Gender | 0.640 | 0.461 | ||
| Male | 310 (162, 52.26%) | |||
| Female | 290 (160, 55.17%) | |||
| Age (yr) | 0.060 | 0.835 | ||
| ≥70 | 113 (55, 48.67%) | |||
| ﹤70 | 487 (267, 54.83%) | |||
| Histology | 1.616 | 0.806 | ||
| ADC | 310 (168, 54.19%) | |||
| SQC | 197 (104, 52.79%) | |||
| BAC | 20 (11, 55.00%) | |||
| LCC | 8 (6, 75.00%) | |||
| Others | 65 (33, 50.77%) | |||
| Cell differentiation | 3.043 | 0.109 | ||
| Poor-moderate | 548 (301, 54.93%) | |||
| Well | 52(21, 40.38%) | |||
1.2. 方法
600例患者均在治疗前行ECT，对显示浓聚部位进行CT/MRI/X线检查，部分患者行局部组织穿刺活检获得病理诊断。骨转移的确诊标准为[4]：①临床或病理诊断肺癌，骨病变活检符合肺癌转移；②肺癌病理诊断明确，具有典型的骨转移影像学表现。排除标准：CT或MRI未见骨质破坏且随访6个月仍未见骨质破坏。确诊骨转移的患者定期行实验室监测血钙等，监测SRE的发生时间(包括高钙血症、严重骨痛需要放疗、压迫脊髓、病理性骨折等)，予双磷酸盐治疗(帕米磷酸二钠或唑来磷酸)，同时对症止痛治疗。全身治疗以含铂双药化疗为主。疗效评价以实体瘤疗效评价标准(Response Evaluation Criteria in Solid Tumors, RECIST)为准，生存期以治疗首日至死亡日期为准，以月计。
1.3. 统计学方法
数据采用SPSS 16.0统计软件包进行处理，定性数据以百分比表示，计数资料采用χ2检验，Kaplan-Merier法绘制生存曲线，Log-rank法进行差异分析，P < 0.05为差异具有统计学意义。
2. 结果
2.1. ECT与CT/MRI/X线结果的比较
2.1.1. ECT的敏感性与特异性
600例患者中有442例ECT阳性，确诊骨转移322例，其中315例为ECT阳性同时CT/MRI/X线发现明确骨质破坏而确诊，7例ECT阴性患者因CT/MRI/X线发现骨质破坏而确诊，127例ECT阳性患者随访6个月仍未发现骨质破坏及转移症状而除外骨转移。ECT敏感性为97.83%，特异性为54.32%，准确性为77.66%，漏诊率为22.33%，假阳性率为28.73%，假阴性率为4.43%。见表 2。
2.
ECT的敏感性及特异性
Sensitivity and specificity of ECT
| ECT positive | ECT negative | Total | |
| Sensitivity: 315/(315+7)=97.83%; Specificity: 151/(127+151)=54.32%; ECT: emission computed tomograph. | |||
| Bone metastasis | 315 | 7 | 322 |
| Not bone metastasis | 127 | 151 | 278 |
| Total | 442 | 158 | 600 |
2.1.2. ECT浓聚灶数目与与影像学诊断关系
ECT显示1个-2个浓聚灶和3个以上病例数分别是63例和252例，通过影像学证实率分别是50.79%(32/63)和80.56% (203/252)(χ2=23.562, P < 0.001)，两组有统计学差异。见表 3。
3.
ECT阳性浓聚灶数与不同诊断方法对骨转移确诊的比较
The relationship of positive sites of ECT and bone metastases diagnosis with different methods
| Numbers of positive sites | n | Bone damage | No bone damage | CT (+) | MRI (+) | X-ray (+) | Confirm (percent) |
| *χ2=23.562, P < 0.001; CT: computed tomography; MRI: magnetic resonance imaging. | |||||||
| 1-2 positive sites* | 63 | 32 | 31 | 20 | 12 | 0 | 50.79% (32/63) |
| ≥3 positive sites* | 252 | 203 | 49 | 104 | 87 | 12 | 80.56% (203/252) |
| Total | 315 | 235 | 80 | 124 | 99 | 12 | |
2.2. NSCLC骨转移的临床特点
2例骨转移患者中症状的有无，是否多脏器转移的例数统计学无明显差异。骨转移部位(承重骨转移、扁骨转移)，骨转移的类型(溶骨性骨转移、成骨性骨转移、混合型转移)例数上有统计学差异。脊柱为NSCLC骨转移最常见的部位，其次为骨盆、股骨、肋骨、胸骨。见表 4。
4.
NSCLC骨转移的特点
The characteristic of bone metastases in NSCLC
| Item | Percent & Number | U value | P value | |
| Syndrome of bone metastases | > 0.05 | |||
| With syndrome | 60.56% (195/322) | 0.53 | ||
| Non syndrome | 39.44% (127/322) | |||
| Sites of bone metastases | 13.56 | ﹤0.01 | ||
| Bearing bone metastasis | 65.53% (211/322) | |||
| Flat bone metastasis | 34.47% (111/322) | |||
| Multi-organs metastases | 1.34 | > 0.05 | ||
| Bone metastases only | 34.16% (110/322) | |||
| Bone metastases with other organs | 65.84% (212/322) | |||
| Type of bone damage | 6.67 | ﹤0.05 | ||
| Osteolysis metastases | 87.58% (282/322) | |||
| Osteogenesis metastases | 2.48% (8/322) | |||
| Mixing type metastases | 7.76% (25/322) | |||
| Others | 2.17% (7/322) | |||
| Sites of bone metastases | 2.34 | > 0.05 | ||
| Spinal column | 54.35% (175/322) | |||
| Pelvis | 34.78% (112/322) | |||
| Femora | 25.16% (81/322) | |||
| Rib | 13.35% (43/322) | |||
| Sternum | 12.42% (40/322) | |||
| Others | 17.70% (57/322) |
2.3. SRE的发生率
208例患者出现了SRE，严重骨痛而放疗(188例，90.38%)为最常见的SRE，高钙血症发生率最低(4例，1.92%)。见表 5。(骨痛需要放疗的SRE定义：①非承重骨的骨转移，伴骨痛(VAS≥4分)，经中度止痛药无效而接受放疗属于SRE；②承重骨骨转移，伴疼痛(VAS≥4分)，接受放疗属于SRE。
5.
NSCLC骨转移SRE发生情况表
SRE in NSCLC with bone metastases
| Type of SRE | Percent & Number |
| SRE: skeletal related events. | |
| Pathologic fractures | 2.40% (5/208) |
| Radiotherapy in bone metastases | 90.38% (188/208) |
| Hypercalcemia of malignancy | 1.92% (4/208) |
| Spinal cord and nerve root compression | 5.29% (11/208) |
2.4. 骨转移的治疗情况
骨转移的治疗是在全身治疗的基础上辅以双磷酸盐、局部放疗、对症止痛治疗及针对病理性骨折和脊髓压迫的姑息手术治疗。详见表 6。
6.
NSCLC骨转移的治疗
Therapy of bone metastases in NSCLC
| Percent & Number | Response rate | |
| Paregoric | 36.96% (119/322) | 73.11% (87/119) |
| Bisphosphonate | 52.80% (170/322) | 47.06% (80/170) |
| Radiotherapy | 58.39% (188/322) | 77.13% (145/188) |
| Surgery | 2.80% (9/322) | 77.78% (7/9) |
| Chemotherapy | 89.13% (287/322) | 46.34% (133/287) |
2.5. 生存情况
2.5.1. 生存情况
322例患者中，6例失访，失访率为1.86%，至末次随访日176例患者死亡，140例生存。发生骨转移后的1年生存率为40.99%，中位生存期为12.90个月。骨转移后无或SRE者的1年生存率分别44.75% vs 36.17%，中位生存期为14.74个月 vs 12.25个月(χ2=5.268, P=0.022)，二者有统计学差异。见图 1。
1.
SRE与生存期的关系
Relationship of SRE and survival time
2.5.2. 单因素分析结果
病理类型、骨转移数量、是否合并其它部位转移、是否出现SRE、双磷酸盐治疗、局部姑息放射治疗、无症状骨转移、承重骨有无转移与预后相关。
2.5.3. Cox多因素回归分析
患者病理诊断非腺癌(RR = 1.123, P = 0.018)，骨转移病灶数少于3个(RR = 1.366, P = 0.046)，单纯骨转移(RR = 1.497, P=0.008)为有益于生存期的预后因素(P < 0.05)。见表 7。
7.
Cox回归变量表
Cox proportional hazards regression model multivariable analysis
| B | SE | Wald | df | Sig. | Exp(B) | 95%CI Exp(B) | ||
| Lower | Upper | |||||||
| Pathology | 0.116 | 0.049 | 5.609 | 1 | 0.018 | 1.123 | 1.020 | 1.236 |
| Radiotherapy | 0.072 | 0.158 | 0.207 | 1 | 0.649 | 1.075 | 0.788 | 1.465 |
| Bisphosphonate | -0.018 | 0.144 | 0.015 | 1 | 0.902 | 0.982 | 0.741 | 1.303 |
| SRE | 0.407 | 0.256 | 2.528 | 1 | 0.112 | 1.502 | 0.910 | 2.481 |
| Syndrome | -0.007 | 0.092 | 0.006 | 1 | 0.937 | 0.993 | 0.830 | 1.188 |
| Mono bone metastases | 0.403 | 0.152 | 7.052 | 1 | 0.008 | 1.497 | 1.111 | 2.015 |
| Bearing bone | 0.211 | 0.143 | 2.169 | 1 | 0.141 | 1.235 | 0.933 | 1.634 |
| Numbers of bone metastases | 0.312 | 0.156 | 3.988 | 1 | 0.046 | 1.366 | 1.006 | 1.854 |
3. 讨论
骨转移的发生率与原发癌的病理类型有关。本组观察到骨转移患者中病理类型是腺癌的最多，为52.17% (168/322)，其次是鳞癌32.30%(104/322)。肺癌易发生骨转移的原因是：肺循环的血流丰富，脱落的肿瘤细胞易随血流进入肺循环和体循环到达全身骨骼系统；椎体、骨盆及肋骨等富含具有造血功能的红色骨髓，血流丰富，且毛细血管丰富，癌细胞易于定植而发生转移。肺腺癌多发生于肺边缘的杯状细胞或黏液细胞，向管外生长，易发生早期转移及侵犯血管淋巴管，继而发生全身转移；同时肺腺癌易出现局部侵犯累及肋骨及胸椎，是本组患者腺癌发生骨转移多的主要原因[3]。根据骨转移发生率高低排序，骨转移好发部位如下：脊柱、骨盆、股骨、肋骨、胸骨，与文献[4-7]报道相似。
《肺癌骨转移诊疗专家共识(2014版)》 [4]将ECT作为初筛手段。因其为非特异性的骨骼显像方法，灵敏度高，但特异性低，尤其是孤立性病灶，需排除骨代谢疾病及陈旧性骨病。本组ECT示1个-2个浓聚灶者和大于或等于3个浓聚灶者，经CT/MRI证实率分别为：50.79%(32/63)和80.56%(203/252)。经Pearson卡方检验，两组有统计学差异(χ2=23.562, P < 0.001)。通过本组数据分析显示ECT敏感性为97.82%，特异性为54.32%，准确性为77.66%，漏诊率为22.33%，假阳性率为28.73%，假阴性率为4.43%。与高等[8]报道的结果一致。提示在ECT显示大于或等于3个以上浓聚灶者确诊骨转移的几率远远高于ECT显示2个以下浓聚灶的患者。因此对于ECT显示为1个-2个病灶者，进一步行CT/MRI等检查，并结合临床做出骨转移诊断尤为重要，以减少假阳性。本组7例ECT阴性患者，因有临床症状而行影像学检查证实骨转移，提示ECT作为骨转移的初筛手段，虽有较高的灵敏性，但亦有假阴性可能。此时骨转移病灶可能为溶骨性破坏，故不能通过反映骨盐代谢程度的ECT检测得到阳性诊断。因此临床上对具有固定疼痛部位的患者，尽管ECT阴性，亦应考虑对相应部位进行CT/MRI/X线，甚至PET-CT检查，以减少ECT的假阴性发生率。
NSCLC骨转移患者发生SRE将极大的降低生活质量，缩短生存期。Tsuya等[7]报道：SRE明显缩短肺癌骨转移患者生存时间。本回顾性研究显示无SRE的患者生存期长于发生SRE者[1年生存率分别为44.75%(nonSRE) vs 36.17%(SRE)；中位生存期分别为14.74个月 vs 12.25个月(P=0.022)]，双磷酸盐治疗可以改善生活质量，减少SRE发生，延长生存期[6, 9]。Cox回归分析显示：病理组织学非腺癌、骨转移病灶数少于3个、单纯骨转移是NSCLC骨转移的独立预后因素。无SRE发生者，Exp(B)=1.502，P=0.112。因统计设计中P < 0.05为入选标准，因此未成为独立预后因素。已呈现成为独立预后因素的趋势，尚需增加病例资料，进一步证实。
近年来，通过对骨标志物的研究发现，多种实体瘤骨转移治疗前骨标志物的升高，与SRE发生率升高，生存期降低有关，可以作为预测疗效的标志之一；根据骨标志物的水平进行个体化治疗的临床实验正在进行中。这些骨标志物包括：尿NTX、血清BALP、LDH和OPN(Osteopontin)等[10, 11]。NTX升高与SRE发生的风险呈正相关，NTX升高者骨转移进展和死亡风险是正常者的2倍，而且使用唑来磷酸可以降低35%的危险度[9]。81%的NTX升高的乳腺癌患者，使用唑来磷酸后降为正常；血清LDH的升高亦是乳腺癌骨转移进展和生存的重要预后指标，基线血清ALP小于正常值高限及经唑来磷酸治疗后ALP降至正常值高限以下者预后较好[12, 13]。大部分骨转移患者化疗及双磷酸盐治疗前后，LDH和ALP发生改变，提示此两项标志物可能反映骨转移治疗疗效，值得进一步探讨。本组患者未行相关检测。双磷酸盐治疗可以有效抑制破骨细胞活性，控制溶骨性骨破坏从而达到止痛，减少SRE的发生的作用[14-16]。
综上所述，本研究通过大样本回顾性分析显示肺腺癌骨转移发生率高，常见转移部位为脊柱、骨盆。ECT异常浓聚灶数目与转移确诊有关，出现SRE的患者生存期短于未发生SRE者。Cox回归分析显示：病理组织学非腺癌、骨转移病灶数少于3个、单纯骨转移是NSCLC骨转移的独立预后因素。
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