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恶性黑色素瘤(malignant melanoma,MM)是一种少见的、恶性程度极高的肿瘤,其发病率仅占皮肤恶性肿瘤的3%,但病死率却高达65%[1]。MM在西方人群中发病率较高,在中国、韩国、日本等亚洲国家较少见,但近40年来,亚洲人的发病率也呈稳定增长趋势[2]。约1/3的患者会出现局部复发或转移的风险[3],美国癌症联合委员会(AJCC)黑色素瘤分期数据库的统计结果显示,Ⅳ期患者的5年生存率仅为15%~20%[4]。因此,早期预测疾病的转归并采取积极有效的治疗迫在眉睫。
全身18F-FDG PET/CT是评估肿瘤葡萄糖代谢和增殖最常用的功能成像方法。转移性MM可能累及身体任何远离原发病变的器官,因此局部成像不能对疾病进行全方位地评估。已有研究结果证实,18F-FDG PET/CT在检测黑色素瘤局部复发和隐匿性远处转移、预后和对治疗的影响等方面的诊断准确率均优于CT [5-7]。
SUV已成为评估患者葡萄糖代谢水平的常用指标。大多数肿瘤的18F-FDG PET/CT研究都使用SUVmax单一指标评估肿瘤的代谢情况[8-9]。然而,SUVmax仅代表肿瘤最活跃的部分,不能反映肿瘤的整体代谢情况。Biehl等[10]和Larson等[11]已提出采用肿瘤代谢体积(metabolic tumour volume,MTV)和病灶糖酵解总量(total lesion glycolysis,TLG)克服SUVmax的局限性。目前,全身MTV和全身TLG对转移性MM患者预后的研究报道较少。本研究旨在评估基线18F-FDG PET/CT的代谢参数在预测转移性MM患者预后中的价值。
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47例MM患者中,13例(27.7%)的血清LDH水平≥245 U/L(正常范围109~245 U/L);39例(83.0%)的肿瘤原发部位为四肢,7例(14.9%)的肿瘤原发部位非四肢,1例(2.1%)的肿瘤原发部位不明;40例(85.1%)伴有淋巴结转移。M分期结果:M0期20例(42.6%)、M1期27例(57.4%)(M1a期12例、M1c期13例、M1d期2例)。TNM分期结果:Ⅲ期20例(42.6%)、Ⅳ期27例(57.4%)。随访结果:22例(46.8%)病情进展、17例(36.2%)病死。
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ROC曲线分析结果:SUVmax、全身MTV和全身TLG的最佳临界值分别为10.86、8.12 cm3和91.45(图1)。高于临界值的SUVmax、全身MTV和全身TLG的患者疾病进展率和病死率均上升,分别为92%、90%、94%和69%、47%、56%。7例病死患者的SUVmax、全身MTV和全身TLG均高于临界值。
图 1 预测转移性恶性黑色素瘤PET/CT参数最佳临界值的ROC曲线
Figure 1. Receiver operating characteristic curve analysis showed the PET parameters optimal threshold of metastatic malignant melanoma
根据ROC曲线获得的PET参数的最佳临界值将患者重新分组,分别生成Kaplan-Meier生存曲线。由图2可见,通过Log-rank检验,全身MTV和全身TLG以最佳临界值为界的2组患者PFS的差异均有统计学意义(χ2=5.04、5.02,均P<0.05);SUVmax和全身TLG以最佳临界值为界的2组患者MSS的差异均有统计学意义(χ2=10.22、4.38,均P<0.05)。由表1可知,SUVmax>10.86、全身MTV>8.12 cm3、全身TLG>91.45组患者的中位生存时间、1年和2年生存率均低于SUVmax≤10.86、全身MTV≤8.12 cm3、全身TLG≤91.45组。
项目 SUVmax 全身MTV 全身TLG ≤10.86 >10.86 ≤8.12 cm3 >8.12 cm3 ≤91.45 >91.45 中位生存时间(个月) 39.0 11.0 15.0 7.3 36.0 12.2 1年生存率(%) 55.9 38.5 58.8 47.6 54.8 29.2 2年生存率(%) 29.4 15.4 41.2 20.0 32.3 8.3 注:表中,FDG:氟脱氧葡萄糖;PET:正电子发射断层显像术;CT:计算机体层摄影术;SUVmax:最大标准化摄取值;MTV:肿瘤代谢体积;TLG:病灶糖酵解总量 表 1 18F-FDG PET/CT参数临界值评估47例转移性恶性黑色素瘤患者的生存时间和生存率
Table 1. Survival time and survival rate evaluated by 18F-FDG PET/CT parameter threshold in 47 patients with metastatic malignant melanoma
图 2 47例转移性恶性黑色素瘤患者PFS、MSS的Kaplan-Meier生存曲线
Figure 2. Kaplan-Meier survival curves of progression-free survival and melanoma-specific survival in 47 patients with metastatic malignant melanoma
应用临床变量(性别、年龄、LDH水平、原发灶部位、转移灶部位、淋巴结转移、M分期、TNM分期、治疗方式)和PET参数对PFS和MSS进行单因素分析,由表2可知,MSS的预后危险因素包括LDH≥245 U/L、淋巴结转移、SUVmax>10.86和全身TLG>91.45;PFS的预后危险因素包括M1期、全身MTV>8.12 cm3和全身TLG>91.45。
变量 例数 黑色素瘤特异性生存期 无进展生存期 危险比 95%CI P值 危险比 95%CI P值 性别 男 20 0.46 0.17~1.27 0.140 0.59 0.31~1.15 0.120 女 27 年龄(岁) ≤60 27 0.82 0.28~2.45 0.720 0.97 0.50~1.86 0.920 >60 20 LDH(U/L) <245 34 2.84 0.96~8.34 0.048 1.47 0.71~3.05 0.300 ≥245 13 原发灶部位 四肢/非四肢 46 0.81 0.20~3.23 0.770 1.40 0.73~2.69 0.300 原发灶不明 1 转移灶部位 单纯淋巴结/脏器转移 21 1.12 0.35~6.88 0.560 1.32 0.92~1.89 0.130 多发转移 26 淋巴结转移 否 7 1.56 0.97~9.85 0.045 1.78 0.68~4.63 0.240 是 40 M分期 0期 20 1.32 0.93~1.87 0.120 1.27 1.01~1.59 0.042 1期 27 TNM分期 Ⅲ期 20 1.38 0.50~3.77 0.530 1.60 0.83~3.01 0.160 Ⅳ期 27 治疗方式 化疗、靶向治疗 16 0.77 0.52~1.13 0.180 1.24 0.94~1.62 0.120 免疫治疗、联合治疗 31 SUVmax ≤10.86 34 4.22 1.62~11.05 0.001 1.51 0.76~3.00 0.239 >10.86 13 全身MTV(cm3) ≤8.12 17 3.08 0.87~10.80 0.064 2.17 1.08~4.35 0.025 >8.12 30 全身TLG ≤91.45 31 2.69 1.02~7.07 0.036 2.11 1.08~4.12 0.025 >91.45 16 注:表中,CI:可变区间;LDH:乳酸脱氢酶;TNM:肿瘤、淋巴结、转移;SUVmax:最大标准化摄取值;MTV:肿瘤代谢体积;TLG:病灶糖酵解总量 表 2 47例转移性恶性黑色素瘤患者预后危险因素的单因素分析
Table 2. Univariate analysis of prognostic risk factors in 47 patients with metastatic malignant melanoma
将单因素分析有意义的变量进行多因素Cox比例风险模型分析,评估转移性MM的独立预后危险因素,由表3可知,MSS的独立预后危险因素是SUVmax>10.86(危险比 4.11,95%CI:1.40~11.78,P=0.008)。
变量 例数 黑色素瘤特异性生存期 无进展生存期 危险比 95%CI P值 危险比 95%CI P值 SUVmax ≤10.86 34 4.11 1.40~11.78 0.008 − − − >10.86 13 全身MTV(cm3) ≤8.12 17 − − − 1.80 0.80~3.00 0.145 >8.12 30 全身TLG ≤91.45 31 2.14 0.75~6.15 0.157 1.79 0.80~3.69 0.116 >91.45 16 注:表中,CI:可变区间;SUVmax:最大标准化摄取值;MTV:肿瘤代谢体积;TLG:病灶糖酵解总量;−:无此项数据 表 3 47例转移性恶性黑色素瘤患者预后危险因素的多因素分析
Table 3. Multivariate analysis of prognostic risk factors in 47 patients with metastatic malignant melanoma
基线18F-FDG PET/CT在转移性恶性黑色素瘤患者预后评估中的价值
Prognostic value of pretreatment 18F-FDG PET/CT in patients with metastatic malignant melanoma
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摘要:
目的 探讨治疗前18F-氟脱氧葡萄糖(FDG)PET/CT代谢参数在转移性恶性黑色素瘤(MM)患者预后评估中的价值。 方法 回顾性分析2011年8月至2018年12月在南京大学医学院附属鼓楼医院确诊为转移性MM的47例患者的临床资料,其中男性20例、女性27例,中位年龄59(23~86)岁。对所有患者行化疗、免疫或靶向治疗。随访时间为0.5~53.6个月。黑色素瘤特异性生存期(MSS)和无进展生存期(PFS)分别定义为从18F-FDG PET成像到患者病死的时间和疾病进展或病死的时间。所有患者在治疗前均行18F-FDG PET/CT检查,测量最大标准化摄取值(SUVmax),并以SUV>40% SUVmax的体素边界作为临界值,分别测量并计算全身肿瘤代谢体积(MTV)和全身病灶糖酵解总量(TLG)。采用受试者工作特征(ROC)曲线分析得出PET参数的最佳临界值,并以SUVmax、全身MTV和全身TLG临界值为界分别将患者分为2组,共6组。采用Kaplan-Meier法及Log-rank检验预测2组间MSS和PFS的差异。采用单因素分析法评估PET参数和临床变量的预后意义。采用Cox比例风险模型多因素分析PET参数是否为MSS和PFS的独立预后危险因素。 结果 SUVmax、全身MTV和全身TLG的最佳临界值分别为10.86、8.12 cm3和91.45。全身MTV和全身TLG以临界值为界的2组患者PFS的差异均有统计学意义(χ2=5.04、5.02,均P<0.05);SUVmax和全身TLG以临界值为界的2组患者MSS的差异均有统计学意义(χ2=10.22、4.38,均P<0.05)。单因素分析结果表明,血清乳酸脱氢酶水平≥245 U/L、淋巴结转移、SUVmax>10.86和全身TLG>91.45是MSS的预后危险因素;M1期、全身MTV>8.12 cm3和全身TLG>91.45是PFS的预后危险因素。多因素分析结果表明,SUVmax>10.86是MSS的独立预后危险因素。 结论 18F-FDG PET/CT代谢参数SUVmax是转移性MM患者病死的最佳预测因素,而全身MTV和全身TLG对转移性MM患者的预后具有一定的预测价值。 -
关键词:
- 黑色素瘤 /
- 氟脱氧葡萄糖F18 /
- 正电子发射断层显像术 /
- 体层摄影术,X线计算机 /
- 肿瘤代谢体积 /
- 病灶糖酵解总量
Abstract:Objective To demonstrate whether 18F-FDG PET/CT metabolic parameters could predict prognosis in patients with metastatic maligant melanoma (MM). Methods A retrospective analysis was conducted on a dataset composed of 47 patients who were newly diagnosed with metastatic MM and currently undergoing pretreatment 18F-FDG PET/CT in the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital from August 2011 to December 2018. Of 47 patients, 20 were male, 27 were female and median age 59 (23−86) years. All patients were treated with chemotherapy, immunotherapy or targeted therapy and follow-up time was 0.5 to 53.6 months. Melanoma-specific survival (MSS) and progression-free survival (PFS) were defined as the time from 18F-FDG PET/CT imaging to the patient's death and the patient's death or progression of the disease, separately. All patients underwent 18F-FDG PET/CT imaging before treatment.The maximum standardized uptake value (SUVmax) was measured. Whole-body metabolic tumor volume (MTV) and whole-body total lesion glycolysis (TLG) were measured automatically and SUV>40% SUVmax voxel boundary was used as threshold. The optimal thresholds of PET parameters were obtained using the receiver operating characteristic (ROC) curve, and the patients were divided into two groups separately according to the optimal thresholds of SUVmax, whole-body MTV and whole-body TLG and six groups were obtained. The difference of MSS and PFS between the two groups were predicted by Kaplan-Meier method and Log-rank test. Univariate analysis was conducted to evaluate the prognostic value of PET parameters and clinical variables. The Cox proportional risk model multivariate analysis was used to determine whether the PET parameters can act as independent prognostic risk factors for MSS and PFS. Results The cut-off values for SUVmax, whole-body MTV, and whole-body TLG were 10.86, 8.12 cm3, and 91.45, respectively, as shown in the ROC curve analysis. The PFS was significantly different in two groups divided by optimal thresholds of whole-body MTV or whole-body TLG, separately (χ2=5.04, 5.02; both P<0.05). Similarly, the MSS was significantly different in two groups divided by optimal thresholds of SUVmax or whole-body TLG, separately (χ2=10.22, 4.38; both P<0.05). The univariate analysis results were as follows: the serum lactate dehydrogenase level≥245 U/L, lymphatic metastasis, SUVmax>10.86 and whole-body TLG>91.45, which were associated with predictors of MSS. M l stage, whole-body MTV>8.12 cm3 and whole-body TLG>91.45, which were associated with PFS. The multivariate analysis results showed that SUVmax>10.86, proving its potential as an independent prognostic risk factor for MSS. Conclusion The 18F-FDG PET/CT metabolic parameter SUVmax was the best predictive marker in metastatic MM patients, whole-body MTV and whole-body TLG helped for the prognosis of metastatic MM patients. -
表 1 18F-FDG PET/CT参数临界值评估47例转移性恶性黑色素瘤患者的生存时间和生存率
Table 1. Survival time and survival rate evaluated by 18F-FDG PET/CT parameter threshold in 47 patients with metastatic malignant melanoma
项目 SUVmax 全身MTV 全身TLG ≤10.86 >10.86 ≤8.12 cm3 >8.12 cm3 ≤91.45 >91.45 中位生存时间(个月) 39.0 11.0 15.0 7.3 36.0 12.2 1年生存率(%) 55.9 38.5 58.8 47.6 54.8 29.2 2年生存率(%) 29.4 15.4 41.2 20.0 32.3 8.3 注:表中,FDG:氟脱氧葡萄糖;PET:正电子发射断层显像术;CT:计算机体层摄影术;SUVmax:最大标准化摄取值;MTV:肿瘤代谢体积;TLG:病灶糖酵解总量 表 2 47例转移性恶性黑色素瘤患者预后危险因素的单因素分析
Table 2. Univariate analysis of prognostic risk factors in 47 patients with metastatic malignant melanoma
变量 例数 黑色素瘤特异性生存期 无进展生存期 危险比 95%CI P值 危险比 95%CI P值 性别 男 20 0.46 0.17~1.27 0.140 0.59 0.31~1.15 0.120 女 27 年龄(岁) ≤60 27 0.82 0.28~2.45 0.720 0.97 0.50~1.86 0.920 >60 20 LDH(U/L) <245 34 2.84 0.96~8.34 0.048 1.47 0.71~3.05 0.300 ≥245 13 原发灶部位 四肢/非四肢 46 0.81 0.20~3.23 0.770 1.40 0.73~2.69 0.300 原发灶不明 1 转移灶部位 单纯淋巴结/脏器转移 21 1.12 0.35~6.88 0.560 1.32 0.92~1.89 0.130 多发转移 26 淋巴结转移 否 7 1.56 0.97~9.85 0.045 1.78 0.68~4.63 0.240 是 40 M分期 0期 20 1.32 0.93~1.87 0.120 1.27 1.01~1.59 0.042 1期 27 TNM分期 Ⅲ期 20 1.38 0.50~3.77 0.530 1.60 0.83~3.01 0.160 Ⅳ期 27 治疗方式 化疗、靶向治疗 16 0.77 0.52~1.13 0.180 1.24 0.94~1.62 0.120 免疫治疗、联合治疗 31 SUVmax ≤10.86 34 4.22 1.62~11.05 0.001 1.51 0.76~3.00 0.239 >10.86 13 全身MTV(cm3) ≤8.12 17 3.08 0.87~10.80 0.064 2.17 1.08~4.35 0.025 >8.12 30 全身TLG ≤91.45 31 2.69 1.02~7.07 0.036 2.11 1.08~4.12 0.025 >91.45 16 注:表中,CI:可变区间;LDH:乳酸脱氢酶;TNM:肿瘤、淋巴结、转移;SUVmax:最大标准化摄取值;MTV:肿瘤代谢体积;TLG:病灶糖酵解总量 表 3 47例转移性恶性黑色素瘤患者预后危险因素的多因素分析
Table 3. Multivariate analysis of prognostic risk factors in 47 patients with metastatic malignant melanoma
变量 例数 黑色素瘤特异性生存期 无进展生存期 危险比 95%CI P值 危险比 95%CI P值 SUVmax ≤10.86 34 4.11 1.40~11.78 0.008 − − − >10.86 13 全身MTV(cm3) ≤8.12 17 − − − 1.80 0.80~3.00 0.145 >8.12 30 全身TLG ≤91.45 31 2.14 0.75~6.15 0.157 1.79 0.80~3.69 0.116 >91.45 16 注:表中,CI:可变区间;SUVmax:最大标准化摄取值;MTV:肿瘤代谢体积;TLG:病灶糖酵解总量;−:无此项数据 -
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