Abstract
目的
探究结直肠间质瘤预后相关因素,并通过列线图预测该肿瘤生存概率,为指导临床评估预后提供依据.
方法
通过监测流行病学和最终结果(surveillance, epidemiology, and end results, SEER)数据库获取1992年1月至2015年12月结直肠间质瘤临床病理及预后相关资料,对入组患者进行生存分析,将分析得到的独立预后因素绘制成列线图,之后采用校准曲线评估列线图预测生存准确性.
结果
546例结直肠间质瘤患者被纳入研究.中位发病年龄64岁,区域淋巴结转移率9.4%.546例患者多因素生存分析显示发病年龄 > 64岁,未婚/离婚,结肠间质瘤(与直肠间质瘤相比),非手术治疗,组织分化级别高,区域淋巴结转移及远处转移具有更差的肿瘤特异性生存和总生存(P均<0.05), 美国东部地区诊治患者比西部地区患者具有更长的总生存时间(P = 0.027),以上独立预后因素预测肿瘤特异性生存率和总生存率的C指数分别为0.76(95%CI: 0.72-0.80)和0.75(95%CI: 0.72-0.78).在174例组织分化级别和肿瘤部位明确的患者中,影响肿瘤特异性生存和总生存的独立预后因素为年龄,组织分化级别和是否行手术治疗(P均<0.05),而肿瘤部位仅与肿瘤特异性生存显著相关(P = 0.041),未证实与总生存显著相关(P = 0.057),采用这4个预后影响因素预测546例患者肿瘤特异性生存率和总生存率的C指数分别是0.71(95%CI: 0.66-0.75)和0.73(95%CI: 0.70-0.77), 能较准确预测结直肠间质瘤患者总生存率.
结论
结直肠间质瘤预后受多个临床病理因素影响,列线图能为预测结直肠间质瘤患者生存率提供依据.
Keywords: 结直肠间质瘤, 临床病理特征, 预后, 列线图
Abstract
Objective
The incidence of colorectal stromal tumor is low among digestive tract tumors, therefore the literatures about clinicopathological features and prognosis of colorectal stromal tumor are few at home and abroad. In this study, we performed survival analyses for colorectal stromal tumor. The nomogram made by prognostic factors provided basis for evaluation of prognosis.
Methods
The clinico-pathological and prognostic data of colorectal stromal tumor between January 1992 and December 2015 were collected from the surveillance, epidemiology, and end results (SEER) database. The survival analyses were made by SPSS 24.0 software. The nomogram and calibration curve were made by RMS package in R 3.5.2 software.
Results
In the study, 546 patients with colorectal stromal tumor were included. The median age of onset was 64 years. The regional lymph node metastasis (LNM) rate was 9.4%. The multivariate Cox regression analyses of the 546 cases showed that the older age of onset (>64 years), single or divorce, colon tumor (compared with rectal tumor), non-surgery, high histological grade, LNM and distant metastasis were associated with worse cancer specific survival (CSS) and overall survival (OS), P < 0.05 for all. The treatment district was independent prognostic factor of OS (P = 0.027). The C-index of independent prognostic factors predicting CSS and OS probability were 0.76 (95%CI: 0.72-0.80) and 0.75 (95%CI: 0.72-0.78), respectively. Multivariate analyses were further carried out in the 174 patients with definite histological grade and tumor location, which revealed that the age of onset, histological grade, surgery or not were independent prognostic factors of CSS and OS (P < 0.05 for all). Tumor location was associated with CSS (P = 0.041) but not OS (P = 0.057) among the 174 cases. Four independent prognostic factors influencing the 174 patients' prognosis were used to make nomogram for predicting survival probability of 546 cases. The C-index of four prognostic factors predicting probability of CSS and OS of the 546 cases were separately 0.71 (95%CI: 0.66-0.75) and 0.73 (95%CI: 0.70-0.77). The nomogram had more accuracy for predicting OS probability of colorectal stromal tumors.
Conclusion
The prognosis of colorectal stromal tumor was affected by multiple clinicopathological factors. The nomogram provided the basis for predicting the survival probability of patients with colorectal stromal tumor.
Keywords: Colorectal stromal tumor, Clinicopathological features, Prognosis, Nomogram
(本文编辑:刘淑萍)
胃肠间质瘤(gastrointestinal stromal tumors, GISTs)是消化道最常见的间叶来源肿瘤,但仅占胃肠肿瘤的1%~3%[1,2].既往研究发现GISTs来源于胃肠道肌间神经丛周围的Cajal间质细胞,绝大部分GISTs表达酪氨酸激酶受体(CD117)和骨髓干细胞抗原(CD34),可用于与其他胃肠间质来源肿瘤相鉴别诊断[2,3].GISTs主要发病部位为胃和小肠,其中胃间质瘤占所有GISTs的56%,小肠间质瘤占32%,而结直肠间质瘤相对罕见,仅占6%[4].与胃间质瘤相比,结直肠间质瘤预后要更差[2].GISTs对传统的化疗和放疗效果较差,手术切除仍然是最主要的治疗方式[5,6].酪氨酸激酶抑制剂的问世使GISTs的预后得到明显改善[6],但由于结直肠间质瘤生物学行为更为复杂,整体疗效上差于胃间质瘤[7].
目前而言,由于结直肠间质瘤罕见,国内外关于结直肠间质瘤的文献报道相对少见.监测流行病学和最终结果(surveillance, epidemiology, and end results, SEER)数据库覆盖美国近28%的人口,收集了来自美国不同地区的癌症数据.本文基于SEER大样本数据分析结直肠间质瘤临床病理特征及预后相关因素,为指导临床诊治及评估预后提供进一步依据.
1. 资料与方法
1.1. 研究对象
通过使用SEER*Stat 8.3.6软件中病例提取功能(case listing session)获取美国SEER数据库1992年1月至2015年12月结直肠间质瘤临床病理资料并整理分析.纳入标准:(1)发病部位(代码:ICD-O-3/WHO 2008):结直肠;(2)病理组织学确诊为GISTs(代码:ICD-O-3 Hist/behav 8935/0,8935/3,8936/2,8936/3).546例结直肠间质瘤患者满足入选标准.本研究已通过天津医科大学肿瘤医院伦理委员会审查批准.SEER数据库发布的肿瘤数据是允许公开报道的,且不需要知情同意.SEER数据库公布数据之前已去除任何可识别患者的信息.
1.2. 临床病理资料收集及分析
本研究收集SEER数据库结直肠间质瘤临床病理及预后相关资料,包括年龄,性别,婚姻状态,种族,肿瘤部位,是否手术治疗,组织分化级别,肿瘤大小,区域淋巴结切除,区域淋巴结转移,远处转移,生存情况等.中位发病年龄为64岁,年龄范围21~93岁.中位随访时间48个月.
1.3. 统计学方法
采用 SPSS 24.0 软件进行生存率计算,单因素生存分析采用 Kaplan-Meier 法,生存率之间的比较采用 Log-Rank 检验;多因素生存分析采用 Cox 回归,以 P < 0.05 为差异具有统计学意义.列线图采用R 3.5.2软件中rms和survival安装包进行绘制,survcomp安装包计算C指数(一致性指数)及其95%可信区间用来评价模型的预测能力.根据多因素Cox回归中独立预后影响因素分别绘制肿瘤特异性生存和总生存列线图,并通过计算列线图C指数和绘制校准曲线判断预测模型准确性.
2. 结果
2.1. 基本临床病理资料
共546例患者纳入本研究.结肠和直肠间质瘤病灶分别占 44.1%(241/546)和 51.3%(280/546), 4.6%(25/546)患者不能明确间质瘤病灶在结肠或直肠.接受手术治疗患者占78.4%(428/546),非手术治疗患者20.0%(109/546),1.6%(9/546)患者不能明确是否手术切除肿瘤.组织学分级Ⅰ(分化好),Ⅱ(分化中),Ⅲ(分化差),Ⅳ(未分化)级患者分别占6.4%(35/546),10.3%(56/546),6.2%(34/546)和9.9%(54/546), 组织学分级不明确患者占67.2%(367/546).根据美国国立综合癌症网络发布的《软组织肉瘤临床实践指南(2019年第1版)》,将胃肠间质瘤大小分为4组,即≤ 2 cm,> 2~5 cm,> 5~10 cm,> 10 cm 4组,分别占11.9%(65/546),16.3%(89/546),22.0%(120/546)和9.2%(50/546), 40.7%(222/546)患者肿瘤大小不详.区域淋巴结切除患者204例,未行区域淋巴结切除患者310例,其余32例不能明确是否行区域淋巴结切除.在204例区域淋巴结切除患者中,1例淋巴结转移情况不明,184例无淋巴结转移,19例有淋巴结转移,淋巴转移率9.4%(19/203),其他临床资料详见表1.
1.
546例结直肠间质瘤临床病理资料及随访资料
Clinicopathological characteristics and follow-up data of 546 patients with colorectal stromal tumor
| Variables | n (%) |
| *, tumor size was not collected in SEER database before 2004; SEER, surveillance, epidemiology, and end results; LNM, lymph node metastasis. | |
| Age/years | |
| ≤ 64 | 273 (50) |
| > 64 | 273 (50) |
| Gender | |
| Male | 302 (55.3) |
| Female | 244 (44.7) |
| Marital status | |
| Married | 321 (58.8) |
| Single/divorced | 192 (35.2) |
| Unknown | 33 (6.0) |
| Ethnicity | |
| Caucasian | 361 (66.1) |
| African-American | 93 (17.0) |
| Other | 91 (16.7) |
| Unknown | 1 (0.2) |
| Date range/year | |
| 1992-2007 | 276 (50.5) |
| 2008-2015 | 270 (49.5) |
| SEER registry in America | |
| Eastern | 238 (43.6) |
| Western | 308 (56.4) |
| Tumor location | |
| Colon | 241 (44.1) |
| Rectum | 280 (51.3) |
| Unknown | 25 (4.6) |
| Surgery or not | |
| Yes | 428 (78.4) |
| No | 109 (20.0) |
| Unknown | 9 (1.6) |
| Differentiation grade | |
| Ⅰ | 35 (6.4) |
| Ⅱ | 56 (10.3) |
| Ⅲ | 34 (6.2) |
| Ⅳ | 54 (9.9) |
| Unknown | 367 (67.2) |
| Tumor size/cm* | |
| ≤ 2 | 65 (11.9) |
| > 2-5 | 89 (16.3) |
| > 5-10 | 120 (22.0) |
| > 10 | 50 (9.2) |
| Unknown | 222 (40.7) |
| Lymphadenectomy | |
| No | 310 (56.8) |
| Yes | 204 (37.4) |
| Unknown | 32 (5.9) |
| LNM | |
| Negative | 184 (33.7) |
| Positive | 19 (3.5) |
| Unknown | 343 (62.8) |
| LNM rate | 19/203 (9.4) |
| Distant metastasis | |
| No | 292 (53.5) |
| Yes | 47 (8.6) |
| Unknown | 207 (37.9) |
| Cancer-specific death | |
| Yes | 123 (22.5) |
| No | 423 (77.5) |
| Overall survival status | |
| Dead | 239 (43.8) |
| Alive | 307 (56.2) |
2.2. 单因素预后分析
发病年龄>64岁的结直肠间质瘤患者比≤ 64岁的患者具有更差的肿瘤特异性生存(P<0.001)和总生存(P<0.001).与未婚/离婚患者相比,已婚患者具有更长的肿瘤特异性生存(P=0.027)和总生存(P=0.007).黑人与其他人种比白人具有更长的总生存时间(P=0.035).美国东部地区患者肿瘤特异性生存时间要长于西部地区(P=0.029).直肠间质瘤肿瘤特异性生存(P=0.002)和总生存时间(P<0.001)均优于结肠间质瘤患者.病理组织分化级别越高,肿瘤特异性生存(P<0.001)和总生存(P<0.001)时间越短.与非手术,有区域淋巴结转移,远处转移患者相比,手术,无区域淋巴结转移/淋巴结转移不明,无远处转移患者具有更好的肿瘤特异性生存(P均<0.001)和总生存(P均<0.001).此外,肿瘤直径越大,患者肿瘤特异性生存(P=0.001)和总生存(P<0.001)时间越差(表2).
2.
546例结直肠间质瘤单因素预后分析
Univariate survival analyses of 546 patients with colorectal stromal tumor
| Variables | n | CSS | P | OS | P | ||
| 5-year survival rate/% | 10-year survival rate/% | 5-year survival rate/% | 10-year survival rate/% | ||||
| *, tumor size was not collected in SEER database before 2004; SEER, surveillance, epidemiology, and end results; LNM, lymph node metastasis; CSS, cancer-specific survival; OS, overall survival. | |||||||
| Age/years | < 0.001 | < 0.001 | |||||
| ≤ 64 | 273 | 85.2 | 76.8 | 79.1 | 66.5 | ||
| > 64 | 273 | 71.4 | 56.3 | 49.4 | 25.0 | ||
| Gender | 0.792 | 0.934 | |||||
| Male | 302 | 78.7 | 67.5 | 64.8 | 46.1 | ||
| Female | 244 | 78.8 | 68.4 | 63.6 | 46.0 | ||
| Marital status | 0.027 | 0.007 | |||||
| Married | 321 | 80.6 | 70.6 | 67.8 | 50.1 | ||
| Single/Divorced | 192 | 73.8 | 61.2 | 56.8 | 38.5 | ||
| Unknown | 33 | 88.6 | 78.8 | 74.4 | 45.5 | ||
| Ethnicity | 0.154 | 0.035 | |||||
| Caucasian | 361 | 75.9 | 65.9 | 59.7 | 44.0 | ||
| African-American | 93 | 87.1 | 74.5 | 73.8 | 48.6 | ||
| Other/Unknown | 92 | 80.7 | 67.7 | 72.6 | 49.5 | ||
| Date range/year | 0.146 | 0.733 | |||||
| 1992-2007 | 276 | 76.0 | 66.7 | 62.5 | 46.5 | ||
| 2008-2015 | 270 | 82.6 | 70.0 | 66.1 | 43.7 | ||
| SEER registry in America | 0.029 | 0.063 | |||||
| Eastern | 238 | 81.8 | 76.9 | 68.7 | 52.7 | ||
| Western | 308 | 76.3 | 62.9 | 61.0 | 42.2 | ||
| Tumor location | 0.002 | < 0.001 | |||||
| Colon | 241 | 69.1 | 60.6 | 53.4 | 41.0 | ||
| Rectum | 280 | 86.6 | 74.2 | 73.9 | 53.5 | ||
| Unknown | 25 | 84.8 | 68.9 | 66.2 | 12.1 | ||
| Surgery or not | < 0.001 | < 0.001 | |||||
| No/Unknown | 118 | 61.3 | 31.7 | 38.9 | 20.1 | ||
| Surgery | 428 | 82.1 | 73.3 | 70.6 | 51.7 | ||
| Differentiation grade | < 0.001 | < 0.001 | |||||
| Ⅰ | 35 | 97.1 | 83.3 | 93.5 | 74.8 | ||
| Ⅱ | 56 | 90.1 | 84.1 | 82.9 | 71.0 | ||
| Ⅲ | 34 | 55.8 | 55.8 | 41.5 | 26.0 | ||
| Ⅳ | 54 | 67.8 | 40.5 | 48.5 | 22.2 | ||
| Unknown | 367 | 79.4 | 68.5 | 64.0 | 47.3 | ||
| Tumor size/cm* | 0.001 | < 0.001 | |||||
| ≤2 | 65 | 95.0 | 95.0 | 82.8 | 77.6 | ||
| >2-5 | 89 | 89.4 | 61.3 | 73.8 | 48.5 | ||
| >5-10 | 120 | 83.3 | 76.8 | 69.9 | 55.7 | ||
| >10 | 50 | 74.9 | 59.0 | 61.9 | 37.5 | ||
| Unknown | 222 | 69.7 | 61.6 | 54.7 | 38.8 | ||
| Lymphadenectomy | 0.325 | 0.652 | |||||
| No/Unknown | 342 | 82.2 | 69.7 | 65.4 | 47.5 | ||
| Yes | 204 | 75.0 | 66.9 | 62.4 | 45.1 | ||
| LNM | < 0.001 | < 0.001 | |||||
| Negative/Unknown | 527 | 79.7 | 70.6 | 65.2 | 48.4 | ||
| Positive | 19 | 41.9 | 20.9 | 38.3 | 6.4 | ||
| Distant metastasis | < 0.001 | < 0.001 | |||||
| No/Unknown | 499 | 81.9 | 71.3 | 67.5 | 48.6 | ||
| Yes | 47 | 32.6 | 32.6 | 23.6 | 23.6 | ||
2.3. 多因素预后分析
546例结直肠间质瘤多因素预后分析显示发病年龄(P<0.001),婚姻状态(已婚vs.未婚/离婚,P=0.010),肿瘤部位(结肠vs.直肠, P=0.012),手术与否(P=0.001),组织学分级(Ⅰ vs. Ⅲ,P=0.032;Ⅰ vs. Ⅳ,P=0.009),区域淋巴结转移(P=0.004),远处转移(P=0.001)是影响肿瘤特异性生存的独立预后因素;发病年龄(P<0.001),婚姻状态(已婚vs.未婚/离婚,P=0.006),诊治地区(P=0.027),肿瘤部位(结肠vs.直肠,P=0.010),手术与否(P<0.001),组织学分级(Ⅰ vs. Ⅲ,P=0.004;Ⅰ vs. Ⅳ,P<0.001),区域淋巴结转移(P=0.002),远处转移(P=0.003)是影响总生存的独立预后因素(表3).
3.
546例结直肠间质瘤多因素预后分析
Multivariate survival analyses of 546 patients with colorectal stromal tumor
| Variables | n | CSS | P | OS | P | ||
| HR | 95%CI | HR | 95%CI | ||||
| *, tumor size was not collected in SEER database before 2004; SEER, surveillance, epidemiology, and end results; LNM, lymph node metastasis; CSS, cancer-specific survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. | |||||||
| Age/years | |||||||
| ≤ 64 | 273 | 1 | 1 | ||||
| > 64 | 273 | 2.53 | 1.71-3.73 | < 0.001 | 3.82 | 2.83-5.14 | < 0.001 |
| Gender | |||||||
| Male | 302 | 1 | 1 | ||||
| Female | 244 | 0.81 | 0.55-1.19 | 0.284 | 0.83 | 0.62-1.09 | 0.182 |
| Marital status | |||||||
| Married | 321 | 1 | 1 | ||||
| Single/divorced | 192 | 1.71 | 1.14-2.57 | 0.010 | 1.51 | 1.12-2.03 | 0.006 |
| Unknown | 33 | 0.67 | 0.23-1.92 | 0.456 | 0.74 | 0.38-1.46 | 0.391 |
| Ethnicity | |||||||
| Caucasian | 361 | 1 | 1 | ||||
| African-American | 93 | 0.79 | 0.43-1.45 | 0.449 | 0.90 | 0.60-1.36 | 0.618 |
| Other/Unknown | 92 | 0.93 | 0.55-1.58 | 0.788 | 0.76 | 0.51-1.14 | 0.191 |
| Date range/year | |||||||
| 1992-2007 | 276 | 1 | 1 | ||||
| 2008-2015 | 270 | 0.95 | 0.56-1.59 | 0.834 | 1.22 | 0.84-1.76 | 0.295 |
| SEER registry in America | |||||||
| Eastern | 238 | 1 | 1 | ||||
| Western | 308 | 1.46 | 0.97-2.20 | 0.073 | 1.39 | 1.04-1.86 | 0.027 |
| Tumor location | |||||||
| Colon | 241 | 1 | 1 | ||||
| Rectum | 280 | 0.58 | 0.38-0.89 | 0.012 | 0.67 | 0.50-0.91 | 0.010 |
| Unknown | 25 | 0.50 | 0.20-1.23 | 0.129 | 0.70 | 0.39-1.24 | 0.219 |
| Surgery or not | |||||||
| No/Unknown | 118 | 1 | 1 | ||||
| Surgery | 428 | 0.40 | 0.24-0.70 | 0.001 | 0.46 | 0.32-0.68 | < 0.001 |
| Differentiation grade | |||||||
| Ⅰ | 35 | 1 | 1 | ||||
| Ⅱ | 56 | 2.07 | 0.40-10.71 | 0.385 | 1.74 | 0.64-4.73 | 0.274 |
| Ⅲ | 34 | 5.54 | 1.15-26.59 | 0.032 | 4.18 | 1.58-11.05 | 0.004 |
| Ⅳ | 54 | 7.75 | 1.67-35.94 | 0.009 | 6.22 | 2.45-15.82 | < 0.001 |
| Unknown | 367 | 3.90 | 0.88-17.20 | 0.072 | 3.09 | 1.28-7.47 | 0.012 |
| Tumor size/cm* | |||||||
| ≤ 2 | 65 | 1 | 1 | ||||
| > 2-5 | 89 | 1.72 | 0.45-6.54 | 0.423 | 1.23 | 0.57-2.68 | 0.603 |
| > 5-10 | 120 | 2.03 | 0.58-7.14 | 0.268 | 1.49 | 0.72-3.08 | 0.286 |
| > 10 | 50 | 3.11 | 0.85-11.30 | 0.085 | 1.87 | 0.86-4.06 | 0.115 |
| Unknown | 222 | 3.84 | 1.13-13.06 | 0.031 | 2.81 | 1.39-5.67 | 0.004 |
| Lymphadenectomy | |||||||
| No/Unknown | 342 | 1 | 1 | ||||
| Yes | 204 | 1.00 | 0.63-1.60 | 0.987 | 0.90 | 0.64-1.25 | 0.519 |
| LNM | |||||||
| Negative/Unknown | 527 | 1 | 1 | ||||
| Positive | 19 | 2.88 | 1.41-5.88 | 0.004 | 2.50 | 1.41-4.42 | 0.002 |
| Distant metastasis | |||||||
| No/Unknown | 499 | 1 | 1 | ||||
| Yes | 47 | 2.55 | 1.48-4.40 | 0.001 | 1.91 | 1.24-2.95 | 0.003 |
174例组织学分级和肿瘤部位明确的结直肠间质瘤被筛选出并进行多因素Cox回归分析.发病年龄>64岁患者比≤64岁患者具有更差的生存预后(肿瘤特异性生存,P=0.037;总生存,P<0.001),直肠间质瘤患者比结肠间质瘤患者具有更长的肿瘤特异性生存(P=0.041),接受手术治疗的结直肠间质瘤患者比非手术患者具有更好的预后(肿瘤特异性生存,P=0.006;总生存,P=0.018),组织分化Ⅰ级结直肠间质瘤患者预后优于Ⅲ,Ⅳ级患者(Ⅰ vs. Ⅲ:肿瘤特异性生存,P=0.016,总生存,P=0.010;Ⅰ vs. Ⅳ:肿瘤特异性生存,P=0.008,总生存,P<0.001;表4).
4.
174例组织学分级和肿瘤部位明确的结直肠间质瘤多因素预后分析
Multivariate survival analyses of 174 patients diagnosed as colorectal stromal tumor with histological grade and tumor location
| Variables | n | CSS | P | OS | P | ||
| HR | 95%CI | HR | 95%CI | ||||
| *, tumor size was not collected in SEER database before 2004; SEER, surveillance, epidemiology, and end results; LNM, lymph node metastasis; CSS, cancer-specific survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. | |||||||
| Age/years | |||||||
| ≤ 64 | 83 | 1 | 1 | ||||
| > 64 | 91 | 2.27 | 1.05-4.91 | 0.037 | 4.97 | 2.70-9.15 | < 0.001 |
| Gender | |||||||
| Male | 89 | 1 | 1 | ||||
| Female | 85 | 1.02 | 0.48-2.18 | 0.963 | 1.12 | 0.64-1.98 | 0.696 |
| Marital status | |||||||
| Married | 107 | 1 | 1 | ||||
| Other | 67 | 0.58 | 0.24-1.38 | 0.215 | 0.99 | 0.55-1.80 | 0.972 |
| Ethnicity | |||||||
| Caucasian | 121 | 1 | 1 | ||||
| African-American | 28 | 0.69 | 0.21-2.35 | 0.557 | 0.51 | 0.20-1.27 | 0.149 |
| Other/Unknown | 25 | 1.43 | 0.48-4.21 | 0.520 | 0.69 | 0.27-1.77 | 0.441 |
| Date range/year | |||||||
| 1992-2007 | 86 | 1 | 1 | ||||
| 2008-2015 | 88 | 0.36 | 0.10-1.31 | 0.120 | 0.76 | 0.28-2.08 | 0.589 |
| SEER registry in America | |||||||
| 1992-2007 | 74 | 1 | 1 | ||||
| 2008-2015 | 100 | 0.92 | 0.42-2.02 | 0.827 | 1.08 | 0.61-1.93 | 0.795 |
| Tumor location | |||||||
| Colon | 91 | 1 | 1 | ||||
| Rectum | 83 | 0.43 | 0.19-0.97 | 0.041 | 0.58 | 0.34-1.02 | 0.057 |
| Surgery or not | |||||||
| No/Unknown | 13 | 1 | 1 | ||||
| Surgery | 161 | 0.15 | 0.04-0.58 | 0.006 | 0.29 | 0.11-0.81 | 0.018 |
| Differentiation grade | |||||||
| Ⅰ | 34 | 1 | 1 | ||||
| Ⅱ | 54 | 2.93 | 0.54-15.96 | 0.213 | 2.35 | 0.77-7.18 | 0.133 |
| Ⅲ | 32 | 7.93 | 1.47-42.75 | 0.016 | 4.39 | 1.43-13.47 | 0.010 |
| Ⅳ | 54 | 8.59 | 1.73-42.57 | 0.008 | 7.02 | 2.38-20.70 | < 0.001 |
| Tumor size/cm* | |||||||
| ≤ 2 | 27 | 1 | 1 | ||||
| > 2-5 | 30 | 0.46 | 0.07-2.91 | 0.412 | 0.77 | 0.14-4.34 | 0.766 |
| > 5-10 | 33 | 0.41 | 0.06-2.93 | 0.378 | 1.56 | 0.28-8.59 | 0.610 |
| > 10 | 14 | 0.72 | 0.09-5.66 | 0.754 | 1.81 | 0.32-10.32 | 0.506 |
| Unknown | 70 | 0.29 | 0.03-2.49 | 0.258 | 1.23 | 0.19-7.88 | 0.826 |
| Lymphadenectomy | |||||||
| No/Unknown | 92 | 1 | 1 | ||||
| Yes | 82 | 2.14 | 0.91-5.04 | 0.083 | 1.25 | 0.66-2.36 | 0.491 |
| LNM | |||||||
| Negative/Unknown | 164 | 1 | 1 | ||||
| Positive | 10 | 1.30 | 0.45-3.72 | 0.631 | 1.57 | 0.64-3.85 | 0.322 |
| Distant metastasis | |||||||
| No/Unknown | 155 | 1 | 1 | ||||
| Yes | 19 | 2.19 | 0.94-5.11 | 0.070 | 1.64 | 0.82-3.25 | 0.159 |
2.4. 列线图生存评估和校准曲线一致性
将影响肿瘤特异性生存,总生存的独立预后因素分别进行整合并计算相应预测生存率准确性C指数.546例肿瘤特异性生存独立影响因素(发病年龄,婚姻状态,肿瘤部位,治疗方式,组织学分级,区域淋巴转移及远处转移)预测肿瘤特异性生存率C指数是0.76(95%CI: 0.72-0.80)和总生存独立影响因素(发病年龄,婚姻状态,诊治地区,肿瘤部位,治疗方式,组织学分级,区域淋巴转移及远处转移)预测总生存率C指数是 0.75(95%CI: 0.72-0.78).174例组织学分级和肿瘤部位明确肿瘤特异性生存独立影响因素(发病年龄,肿瘤部位,组织学分级以及是否行手术治疗)预测546例肿瘤特异性生存率C指数是0.71(95%CI: 0.66-0.75),尽管多因素预后分析未证实肿瘤部位是影响总生存的独立预后因素,但P = 0.057接近0.05,因此将肿瘤部位与年龄,组织学分级以及是否行手术治疗组成模型预测546例总生存率为0.73(95%CI: 0.70-0.77).
图1A和1B分别显示了发病年龄,肿瘤部位,组织学分级以及是否行手术治疗预测546例结直肠间质瘤患者肿瘤特异性生存率和总生存率列线图.将列线图上每个预后影响因素进行评分,并计算总分数,即可预测患者存活5或10年肿瘤特异性生存率或总生存率.图2A和2B校准曲线显示了列线图预测546例结直肠间质瘤患者5年和10年肿瘤特异性生存率与实际生存率一致性;同样,图2C和2D校准曲线显示了列线图预测546例结直肠间质瘤患者10年总生存率与实际生存率的一致性.
1.
结直肠间质瘤肿瘤特异性生存(A)和总生存(B)预测列线图
Nomogram-predicted probability of cancer-specific survival (A) and overall survival (B) for colorectal stromal tumor
2.
结直肠间质瘤5年肿瘤特异性生存(A),10年肿瘤特异性生存(B),5年总生存(C)和10年总生存(D)预测校准曲线
The calibration curve for predicting cancer-specific survival at 5 (A) and 10 (B) years and overall survival at 5 (C) and 10 (D) years
3. 讨论
本研究总结和分析了SEER数据库结直肠间质瘤临床及预后相关信息.一篇系统荟萃全球13 550例GISTs患者的文献报道GISTs中位发病年龄为64岁[4].Miettinen等[8] 研究中显示结直肠间质瘤患者发病年龄与其他部位间质瘤相似,主要是成年人,大部分发病年龄在50~70岁,男性GISTs发病率要略高于女性.本研究中结直肠间质瘤患者发病中位年龄为64岁,男性发病率(55.3%)高于女性(44.7%),与既往研究相类似.
Al-Thani等[9]分析48例接受手术治疗的GISTs患者,其中有6例失访,剩余42例患者中有33例患者术后长期无瘤生存.Cao等[10]回顾分析上海仁济医院收治的181例GISTs,研究证实手术切除是原发GISTs治疗的金标准.本研究发现手术切除肿瘤是影响GISTs预后的主要治疗手段.多项研究证实肿瘤直径越大,病理组织学分化越差,GISTs预后越差[1,11-13].在我们研究中,多因素分析组织学分化级别越高,结直肠间质瘤患者肿瘤特异性生存和总生存时间越短;尽管单因素预后分析结直肠间质瘤直径越大生存时间越短,但并未证实直径大小是影响结直肠间质瘤患者肿瘤特异性生存和总生存的一个独立预后因素.但本研究由于有近41%患者无肿瘤直径大小记录,是否这些缺失值对评估结直肠间质瘤预后有独立影响并无法求证.GISTs淋巴转移并不常见,主要以远处转移常见,以肝脏和腹腔为主.Gaitanidis等[14]报道GISTs区域淋巴结转移率为9.8%,发生区域淋巴转移的患者具有更差的预后.Tokunaga等[15]分析57例行根治手术治疗的GISTs患者中,有5例出现淋巴结转移,淋巴结转移率为8.8%,发生淋巴结转移的患者生存时间均未超过5年.我们的研究显示区域淋巴结转移率为9.4%.本研究发现与结肠间质瘤相比,直肠间质瘤具有更好的预后,与此同时,Zhu等[16]分析美国国家癌症数据库(The National Cancer Database, NCDB)中2006年至2013年GISTs数据,将11 302 例胃间质瘤分别与398 例结肠间质瘤和393例直肠间质瘤进行生存预后对比,发现预后最好的间质瘤部位是直肠,其次是胃,最差的是结肠.黄湘辉等[17]回顾分析了102例GISTs临床资料及预后,指出发病年龄是影响GISTs预后的独立危险因素.Ge等[18]基于SEER数据库分析了6 089例GISTs患者,证实年龄是影响GISTs的一个重要预后因素,但没有对结直肠间质瘤患者年龄与预后的关系做进一步分层分析.本研究显示发病年龄64岁以上的老年结直肠间质瘤患者具有更差的肿瘤特异性生存和总生存.此外,婚姻状态,诊断地区被证实与结直肠间质瘤患者预后也有一定相关性,已婚状态明显好于未婚/离婚,这间接提示婚姻状态也是影响身体健康的一个关键因素[19];美国东部地区患者总生存优于西部地区,这可能与东部地区经济明显好于西部地区,拥有更好的医疗条件有关.
《美国国立卫生研究院(National Institutes of Health, NIH)(2008改良版)》,《中国胃肠间质瘤诊断治疗共识(2017 年版)》,美国国立综合癌症网络发布的《软组织肉瘤临床实践指南(2019年第1版)》等均评估了原发GISTs切除术后复发风险[20],其中涉及与GISTs术后复发和预后相关的独立危险因素包括胃肠道肿瘤部位,肿瘤大小及核分裂计数.非胃原发灶,肿瘤直径越大或核分裂计数越多复发风险越高,预后越差.
肿瘤组织学分级主要根据镜下HE染色切片中肿瘤组织结构和细胞异型性的大小,核分裂像或增殖指数的多少等因素来确定.546例结直肠间质瘤患者中有174例患者组织学分级和肿瘤部位明确,对这174例结直肠间质瘤患者有预后独立影响的变量为年龄,组织学分级,是否行手术治疗和肿瘤部位,其中肿瘤部位仅与肿瘤特异性生存相关.我们将预测模型中4个主要独立预后危险因素分别进行评分,通过计算总分数预测5年和10年肿瘤特异性生存率和总生存率.以上4个主要独立预后因素预测肿瘤特异性生存率和总生存率C指数均大于0.7,总生存C指数 95%CI下限为0.70(≥ 0.70),预测总生存率准确性较好,但肿瘤特异性生存率预测C指数 95%CI下限为0.66(< 0.70), 提示预测肿瘤特异性生存率准确性一般.本研究列线图预测5年和10年肿瘤特异性生存率和总生存率曲线与实际生存率曲线基本在一条线上.
c-kit和血小板源性生长因子受体α多肽(platelet-derived growth factor receptor alpha,PDGFRA)基因突变与GISTs的发生发展密切相关[21].大部分胃肠道来源的间质瘤CD117蛋白和DOG1蛋白表达阳性.艾力等[22]采用免疫组织化学Envision法发现73例GIST中CD117,DOG1,CD34的阳性率分别为94.52%,91.78%和91.78%,黄湘辉等[17]对102例GISTs进行免疫组织化学检测,其中 CD117,DOG-1,CD34的阳 性 率 分 别 为 89.2%, 86.5%和90.4%.目前CD117,DOG1和CD34被主要用于GISTs的鉴别诊断.我们未查阅到有关结直肠间质瘤c-Kit和PDGFRA基因突变与预后相关性的文章,这与结直肠间质瘤发病率低有一定相关性.但李超亿等[23] 报道c-kit与PDGFRA基因突变的(经手术治疗但未行酪氨酸激酶抑制剂药物治疗)GISTs患者预后优于野生型,但多因素分析未证实基因突变是影响预后的独立因素.
本研究存在的缺陷:第一,由于这是一个非前瞻性研究,数据筛选过程中可能会出现数据偏倚;第二,在SEER数据库登记的结直肠间质瘤数据缺少病理会诊再次明确病理类型;第三,SEER数据库中一些重要临床病理资料(基因检测结果和具体核分裂计数)无法获取,部分主要预后评估因素缺失较多,如组织分级和肿瘤大小等;第四,缺少一个验证数据集来证实列线图预测生存准确性.
总之,本研究通过分析SEER数据库结直肠间质瘤数据得到多个与肿瘤特异性生存和总生存相关的临床病理因素,这些影响预后的危险因素通过绘制列线图可以较准确地用于评估结直肠间质瘤患者的5年和10年生存率,为临床医师在预测结肠间质瘤患者生存时间提供一判断依据,但仍需通过继续增加样本量及完善相关重要临床病理信息验证预测模型.
Funding Statement
国家自然科学基金（81101870）; 国家临床重点专科建设项目（2013-544）; 天津市卫生健康委员会重点项目（16kg127）
Supported by the National Natural Science Foundation of China(81101870); the National Key Clinical Specialty Construction Project(2013-544); the Key Project of Tianjin Health and Family Planning Commission(16kg127)
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