2024, Vol. 31
2. 复旦大学附属中山医院厦门医院血液科, 厦门 361015
2. Department of Hematology, Zhongshan Hospital(Xiamen Branch), Fudan University, Xiamen 361015, Fujian, China
黏膜相关淋巴组织（mucosa-associated lymphoidtissue, MALT）淋巴瘤是边缘区淋巴瘤（marginal zone lymphoma，MZL）的最常见亚型[1]，其中胃是最常见的受累部位[2]。胃MALT淋巴瘤在原发胃淋巴瘤中约占38%，仅次于胃弥漫大B细胞淋巴瘤[3]。慢性炎症刺激和自身免疫疾病是MALT淋巴瘤发病的两大重要因素[4]。而幽门螺旋杆菌（Helicobacter pylori，H. pylori）感染是胃MALT淋巴瘤的重要致病因素[5]。
基于营养状况和（或）炎症反应的多种评分体系，如中性粒细胞/淋巴细胞比值、淋巴细胞/单核细胞比值、血小板/淋巴细胞比值、Glasgow预后评分已用于多种肿瘤患者的预后评估[6-8]。C反应蛋白（C-creative protein, CRP）/白蛋白（albumin, ALB）比值（CAR）能同时反映肿瘤患者的炎症及营养状况[9-10]。已有研究发现高CAR值与鼻咽癌[11]、胃癌[12]等多种实体瘤患者不良预后相关。目前，CAR与淋巴瘤关系的研究较少。本研究旨在探讨CAR应用于胃MALT淋巴瘤患者预后评估的价值。
1 资料与方法 1.1 一般资料纳入2004年1月至2020年6月在复旦大学附属中山医院初诊的胃MALT淋巴瘤患者。纳入标准：年龄≥18岁；经胃镜活检或手术后病理检查证实为胃MALT淋巴瘤。胃MALT淋巴瘤诊断参照2016年WHO造血和淋巴组织肿瘤分类（第4版）标准。排除标准：病理发生组织学转化（如向弥漫大B细胞淋巴瘤转化）；初诊时合并其他恶性肿瘤；合并可能影响CRP水平的其他疾病，如急慢性炎症、风湿性疾病等。共纳入93例患者，男性60例、女性33例，年龄23~83岁，平均年龄（58.9±12.3）岁。
1.2 治疗方法根据B细胞淋巴瘤NCCN指南推荐，对患者进行抗H. pylori治疗、局部治疗、系统性治疗。3例患者无治疗指征，定期随访。38例患者仅接受抗H. pylori治疗。39例患者接受靶向治疗和（或）全身化疗，其中部分患者接受抗H. pylori治疗。6例患者外科手术或内镜黏膜下剥离术（endoscopic submucosal dissection，ESD）后达完全缓解（CR），持续观察随访直至末次随访。7例患者接受局部放疗。
1.3 基线指标及分组收集入组患者初诊入院后基线资料，包括性别、年龄、症状、结外受累部位，血红蛋白、血小板、白细胞、淋巴细胞、中性粒细胞、CRP、ALB、乳酸脱氢酶（LDH）、免疫球蛋白、β2微球蛋白（β2-microglobulin, β2-MG）、血清铁蛋白（serum ferritin, SF）等实验室检查结果，影像学检查结果（全身增强CT或PET-CT），病理检查结果。临床分期采用胃肠道淋巴瘤Lugano分期系统，分为Ⅰ期、Ⅱ期、ⅡE期和Ⅳ期[13]。预后评分采用MALT国际预后指数（MALT international prognostic index, MALT-IPI）。计算患者CAR，用X-tile软件获得CAR的最佳临界值。根据该临界值将患者分为高CAR组与低CAR组。
1.4 结局指标分别于初诊后1年、3年、5年随访患者生存情况，随访截止时间为患者死亡或末次随访的时间，末次随访时间为2022年6月30日。总生存期（overall survival, OS）指从疾病确诊至患者死亡或观察截止的时间。无进展生存期（progression-free survival, PFS）指从疾病确诊至发生进展或因任何原因死亡的时间。最终疗效指疾病首次进展前的疗效，若无进展，则根据最后1次随访时的状态来评估。患者治疗后达到CR或部分缓解（partial remission, PR），为疗效良好，否则为疗效不佳。
1.5 统计学处理采用SPSS 23.0软件进行统计学分析。计量资料符合正态分布时用x±s表示，两组间比较采用t检验；不符合正态分布时用M(P25, P75) 表示，组间比较采用非参数检验。计数资料以n(%)表示，组间比较采用χ2检验。采用Kaplan-Meier法绘制生存曲线。采用Cox风险模型分析生存影响因素。检验水准（α）为0.05。
2 结果 2.1 低CAR组与高CAR组间基线指标比较CAR最佳临界值为0.05，CAR≥0.05者27例（高CAR组）、CAR＜0.05者66例（低CAR组）。结果（表 1）显示：与低CAR组患者相比，高CAR组≥70岁、贫血患者更多，国际预后指数（IPI）评分更高，β2-MG水平更高（P＜0.05）。
| Indicator | Low-CAR group (n＝66) | High-CAR group (n＝27) | χ2/t/U value | P value |
| Age n(%) | 4.763 | 0.029 | ||
| ≥70 years | 9(13.64) | 9(33.33) | ||
| ＜70 years | 57(86.36) | 18(66.67) | ||
| Sex n(%) | 2.923 | 0.087 | ||
| Male | 39(59.09) | 21(77.78) | ||
| Female | 27(40.91) | 6(22.22) | ||
| Hb/(g·L﹣1) | 130.42±18.83 | 123.70±23.52 | ﹣1.450 | 0.150 |
| WBC/(×109·L﹣1) | 5.41±1.46 | 5.64±1.86 | 0.643 | 0.522 |
| N/(×109·L﹣1) | 3.40±1.14 | 3.55±1.42 | 0.542 | 0.589 |
| L/(×109·L﹣1) | 1.48±0.63 | 1.55±0.56 | 0.477 | 0.635 |
| PLT/(×109·L﹣1) | 216.18±70.75 | 206.26±60.51 | ﹣0.639 | 0.525 |
| ALB/(g·L﹣1) | 43.64±4.10 | 39.22±4.07 | ﹣4.722 | ＜0.001 |
| GLB/(g·L﹣1) | 25.86±4.04 | 26.67±4.85 | 0.819 | 0.415 |
| LDH/(U·L﹣1) | 175.05±29.08 | 181.44±37.19 | 0.886 | 0.378 |
| IgG/(g·L﹣1) | 11.85(10.26, 13.70) | 11.04(10.05, 12.84) | 0.849 | 0.396 |
| β2-MG/(mg·L﹣1) | 1.94(1.63, 2.33) | 2.83(2.25, 3.49) | 3.575 | ＜0.001 |
| CRP/(mg·L﹣1) | 0.60(0.40, 1) | 5.40(2.70, 11.50) | 7.499 | ＜0.001 |
| SF/(ng·mL﹣1) | 116.95(33.57, 241.35) | 77.50(24.30, 188.45) | 0.678 | 0.498 |
| Symptom B n(%) | 10(15.15) | 5(18.51) | 0.008 | 0.928 |
| Anemia n(%) | 8(12.12) | 9(33.33) | 4.439 | 0.035 |
| Lymph nodes involvement n(%) | 33(50.00) | 18(66.67) | 2.149 | 0.143 |
| Ki-67* n(%) | 0.105 | 0.746 | ||
| ≥30% | 11(18.33) | 3(12.50) | ||
| ＜30% | 49(81.67) | 21(87.50) | ||
| Lugano stage n(%) | ﹣1.378 | 0.168 | ||
| StageⅠ | 27(40.91) | 8(29.63) | ||
| StageⅡ+ⅡE | 24(36.36) | 9(33.33) | ||
| Stage Ⅳ | 15(22.73) | 10(37.04) | ||
| MALT-IPI score n(%) | ﹣2.289 | 0.022 | ||
| 0 | 39(59.09) | 10(37.04) | ||
| 1 | 27(40.91) | 14(51.85) | ||
| 2 | 0 | 3(11.11) | ||
| Final efficacy n(%) | 0.043 | 0.836 | ||
| CR+PR | 45(68.18) | 19(70.37) | ||
| PD+SD | 21(31.82) | 8(29.63) | ||
| CAR: C-reactive protein/albumin ratio; Hb: hemoglobin; WBC: leukocyte; N: neutrophil; L: lymphocyte; PLT: platelet; ALB: albumin; GLB: globulin; LDH: lactate dehydrogenase; IgG: immunoglobulin G; β2-MG: β2 microglobulin; CRP: C-reative protein; SF: serum ferritin; CR: complete remission; PR: partial remission; PD: progressive disease; SD: stable disease. *84 patients underwent detection of Ki-67. | ||||
单因素Cox生存分析结果（表 2）显示：最终疗效、ALB水平、IgG水平、CAR与胃MALT淋巴瘤患者预后相关。多因素Cox生存分析结果显示，IgG为胃MALT淋巴瘤患者预后独立预测因素（HR＝0.528, 95%CI 0.304~0.915, P＝0.023）。
| Variable | HR (95% CI) | P value |
| Age (≥70 years vs＜70 years) | 0.970 (0.111-8.462) | 0.978 |
| Sex (Male vs Female) | 0.282 (0.033-2.431) | 0.250 |
| Ki-67 (≥30% vs＜30%) | 2.560 (0.258-25.429) | 0.422 |
| Anemia | 2.709 (0.484-15.169) | 0.257 |
| Symptom B | 2.743 (0.491-15.334) | 0.250 |
| Lugano stage (Stage Ⅰ vs [Ⅱ+ⅡE]) | 0.386 (0.078-1.920) | 0.245 |
| MALT-IPI score (≥1 vs＜1) | 1.873 (0.479-7.321) | 0.367 |
| MALT-IPI score (2 vs＜2) | 1.873 (0.479-7.321) | 0.367 |
| Final efficacy ([CR+PR] vs [PD+SD]) | 0.027 (0.003-0.266) | 0.002 |
| CAR(≥0.05 vs＜0.05) | 0.118 (0.014-1.013) | 0.049 |
| Hb | 0.984 (0.950-1.020) | 0.386 |
| WBC | 1.268 (0.758-2.123) | 0.366 |
| N | 1.664 (0.915-3.027) | 0.095 |
| L | 0.836 (0.239-2.921) | 0.779 |
| PLT | 0.997 (0.985-1.008) | 0.560 |
| ALB | 0.676 (0.494-0.924) | 0.014 |
| GLB | 0.936 (0.782-1.119) | 0.468 |
| LDH | 0.991 (0.963-1.021) | 0.557 |
| IgG | 0.634 (0.427-0.944) | 0.025 |
| β2-MG | 1.427 (0.677-3.006) | 0.350 |
| CRP | 0.988 (0.889-1.085) | 0.799 |
| SF | 1.000 (0.994-1.006) | 0.905 |
| CR: complete remission; PR: partial remission; PD: progressive disease; SD: stable disease; CAR: C-reactive protein/albumin ratio; Hb: hemoglobin; WBC: leukocyte; N: neutrophil; L: lymphocyte; PLT: platelet; ALB: albumin; GLB: globulin; LDH: lactate dehydrogenase; IgG: immunoglobulin G; β2-MG: β2-microglobulin; CRP: C-reative protein; SF: serum ferritin. | ||
高CAR组中位OS 112.7个月、中位PFS 96.5个月；低CAR组中位OS 172.8个月，中位PFS 152.8个月。截至随访终点，低CAR组除3例（4.5%）失访外均存活，高CAR组中有6例（22.2%）死亡。结果（图 1、表 3）显示：低CAR组患者OS高于高CAR组（P＝0.020），两组间PFS差异无统计学意义（P＝0.446）；随着随访时间延长，两组生存差异更明显。
|
| 图 1 Kaplan-Meier曲线分析低CAR组和高CAR组患者生存 Fig 1 Kaplan-Meier survival analysis of patients in high and low CAR groups CAR: C-reactive protein/albumin ratio. |
| % | |||||||||||||||||||||||||||||
| Group | OS rate | PFS rate | |||||||||||||||||||||||||||
| 1 year | 3 years | 5 years | 1 year | 3 years | 5 years | ||||||||||||||||||||||||
| High CAR | 100.0 | 96.2 | 89.7 | 88.0 | 84.0 | 77.5 | |||||||||||||||||||||||
| Low CAR | 100.0 | 100.0 | 100.0 | 92.0 | 83.6 | 83.6 | |||||||||||||||||||||||
| CAR: C-reactive protein/albumin ratio; OS: overall survival; PFS: progression-free survival. | |||||||||||||||||||||||||||||
不同MALT-IPI评分组患者OS差异无统计学意义（P＝0.358，图 2A）。将高CAR记为1分，低CAR记为0分，并与MALT-IPI评分相加，得出CAR联合MALT-IPI评分，结果（图 2B）显示，联合评分2分组预后明显差于0分组（P＝0.021）和1分组（P＝0.049）。
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| 图 2 Kaplan-Meier曲线分析不同CAR联合MALT-IPI评分组患者生存 Fig 2 Kaplan Meier survival analysis of patients in different CAR combined with MALT-IPI scoring groups A: MALT-IPI only; B: CAR combined with MALT-IPI. High CAR as 1 point, low CAR as 0 point. |
炎症与肿瘤发生、预后的关系已获得广泛关注，如乙肝病毒感染与肝细胞癌，H. pylori感染与胃腺癌、胃MALT淋巴瘤，慢性食管炎、食管腺上皮化生和食管癌[13-14]等。对于分期局限的胃MALT患者，如存在H. pylori感染，约75%在控制感染后获得持续的疾病缓解[15]。CRP是临床上常用的炎症指标[16]，可用于评估多种实体肿瘤患者的预后[17-18]。国内有学者发现，基线血清CRP水平在评估结外NK/T细胞淋巴瘤（鼻型）患者预后方面有重要意义[19]。Troppan等[20]发现，初诊时血清CRP水平高是弥漫性大B细胞淋巴瘤患者预后的独立危险因素，同时可提高修订后的国际预后指数（R-IPI）的预测水平。Adams等[21]发现，治疗前CRP水平升高与弥漫性大B细胞淋巴瘤患者的无进展生存率和总生存率降低显著相关。
ALB主要在肝脏合成，占血浆总蛋白的50%，为临床评估患者营养状况的常用指标。血清ALB降低与多种肿瘤患者的总生存时间缩短有关[22-23]。肿瘤患者因炎症状态及慢性消耗可发生血清ALB水平降低。在血液系统恶性肿瘤中，ALB已被纳入多个预后评分系统，如晚期霍奇金淋巴瘤国际预后评分（IPS）[24]、多发性骨髓瘤国际分期系统（ISS）[25]。
在鼻咽癌[11]、胃肠道恶性肿瘤[12]、肺癌[26]、和生殖系统肿瘤[27]等实体肿瘤中，CAR为很好的预后预测指标。目前CAR在血液系统肿瘤中的预后预测价值尚不明确。国内外研究[11-12, 26-28]显示，CAR对实体肿瘤患者预后的预测价值的截断值波动于0.03~0.68。本研究应用X-tile软件分析得出的CAR的最佳截断值为0.05。本研究发现，低CAR组与高CAR组之间年龄、贫血患者比例、CRP、ALB水平、β2-MG水平差异均有统计学意义，且高CAR组OS明显短于低CAR组（P＝0.020），与实体肿瘤研究[17, 26]结果一致。两组患者间OS率、PFS率在随访1年时相近，这与胃MALT淋巴瘤属于惰性淋巴瘤，患者总体生存时间均较长有关；随着随访时间延长，高CAR组OS率、PFS率下降更明显。
IPI评分为评估非霍奇金淋巴瘤患者预后最常用的指标，并不适用于惰性的MALT淋巴瘤[29]。对于MALT淋巴瘤患者，临床常使用基于临床分期、年龄、LDH的MALT-IPI评分评估预后[30]，但临床分期需要依据实验室检查、骨髓穿刺及活检、全身影像学检查等判断。本研究将MALT-IPI评分与CAR相联合，结果显示联合评分为2分患者的OS更短，且评估效果优于单独MALT-IPI评分。
综上所述，胃MALT淋巴瘤患者中，CAR≥0.05组OS更短，CAR联合MALT-IPI评分可提高MALT-IPI单独应用的预后评估效果，且CAR值计算方便，有代替MALT-IPI用于该类患者的预后评估的潜在价值。但是，由于本研究多因素Cox分析未发现CAR对患者预后的影响，同时本研究为单中心研究、纳入病例数有限，因此结论有待扩大样本量的多中心研究证实。
伦理声明 本研究经医院伦理委员会审批（B2017-033R），患者知情并签署知情同意书。
利益冲突 所有作者声明不存在利益冲突。
作者贡献 施淼颉：收集、分析数据，撰写论文；魏征：核对数据，修改论文；刘澎：研究设计。
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