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Article(id=1203057883039621186, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203057879566737430, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2023.02.0204, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1649952000000, receivedDateStr=2022-04-15, revisedDate=null, revisedDateStr=null, acceptedDate=1660579200000, acceptedDateStr=2022-08-16, onlineDate=1764760951051, onlineDateStr=2025-12-03, pubDate=1677513600000, pubDateStr=2023-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764760951051, onlineIssueDateStr=2025-12-03, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764760951051, creator=13701087609, updateTime=1764760951051, updator=13701087609, issue=Issue{id=1203057879566737430, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='2', pageStart='123', pageEnd='244', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764760950222, creator=13701087609, updateTime=1764762101198, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1203062707223241334, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203057879566737430, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1203062707223241335, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203057879566737430, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=204, endPage=210, ext={EN=ArticleExt(id=1203057883354193998, articleId=1203057883039621186, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Analysis of the efficacy of rituximab combined with CHOP for treating patients with primary breast lymphoma, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To analyze the clinical and pathological features of primary breast lymphoma (PBL) and explore the value of appling rituximab for the prognosis of patients with PBL. Methods The clinicopathological characteristics and therapeutic effect of rituximab were retrospectively analyzed of 65 patients with PBL admitted in the Cancer Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences from January 1, 2000 to January 31, 2020. According to different treatment methods,they were divided into CHOP group [n=41, using CHOP regimen (cyclophosphamide + epirubicin + vincristine + prednisone)] and RCHOP group (n=24, using rituximab combined CHOP regimen treatment). Patients received telephone follow-up or outpatient review until January 31, 2022 or mortality. Univariate regression analysis and multivariate regression analysis were used to analyze the factors influencing the prognosis of patients with PBL. Results All the 65 patients were female, aged 57(23, 86) years old.The tumor size was 2.8(0.4, 5.3) cm, and the follow-up time was 4.3(0.7, 21.8) years. There was a statistically significant difference in Ki-67 expression between the two groups (P=0.043), and there was no significant difference in other clinicopathological features and treatment plans (P>0.05). The 5- and 10-year overall survival rate of the 65 PBL patients were 93.4% and 87.9%,and the 5- and 10-year progression-free survival rate were 88.2% and 79.6%, the central nervous system recurrence rate was 4.6%.The 5-year overall survival rate in CHOP group was 93.8% and in RCHOP group was 92.9% (P=0.733), and 5-year progression-free survival rate was 89.9% in CHOP group, and in RCHOP group was 92.9% (P=0.897). Multivariate logistic regression analysis showed the international prognostic index (IPI) score and the level of β2 microglobulin were the independent risk factors of overall survival (P<0.05). Conclusions There is no special clinical manifestation of PBL. The definite diagnosis mainly depends on histopathological examination and immunophenotype. Radical surgical resection can not improve the prognosis of patients, and comprehensive treatment based on full-term chemotherapy should be adopted; whether patients with PBL received rituximab was not associated with the survival benefits.

, correspAuthors=Xin Wang, Xiang Wang, authorNote=null, correspAuthorsNote=
* Wang Xin, E-mail:
Wang Xiang, E-mail:
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目的 分析原发性乳腺淋巴瘤（PBL）的临床病理学特征并探讨利妥昔单抗对其预后的影响。方法 回顾性分析2000年1月1日-2020年1月31日中国医学科学院北京协和医学院肿瘤医院收治的65例PBL患者的临床病理特征及利妥昔单抗的治疗效果，根据治疗方法的不同分为CHOP组[n=41，采用CHOP方案（环磷酰胺+表阿霉素+长春新碱+泼尼松）]与RCHOP组[n=24，采用利妥昔单抗联合CHOP方案]。采用门诊复查、电话方式随访，随访至患者死亡或截至2022年1月31日，通过单因素和多因素logistic回归分析PBL患者的预后影响因素。结果 共纳入65例PBL患者，均为女性，发病年龄57（23，86）岁，肿瘤大小为2.8（0.4，5.3）cm，随访时间为4.3（0.7，21.8）年。两组Ki-67表达情况差异有统计学意义（P=0.043），其他临床病理特征及治疗方案无明显差异（P>0.05）。65例PBL患者5年、10年总生存率分别为93.4%、87.9%，无进展生存率分别为88.2%、79.6%；中枢神经系统复发率为4.6%。Kaplan-Meier生存分析显示，CHOP组和RCHOP组5年总生存率分别为93.8%、92.9%（P=0.733），5年无进展生存率分别为89.9%、92.9%（P=0.897）。多因素logistic回归分析显示，国际预后指数（IPI）评分和β2微球蛋白水平是影响总生存的独立危险因素（P<0.05）。结论 PBL无特殊临床表现，确诊主要依靠组织病理学检查和免疫表型，根治性手术切除并不能改善患者的预后，其治疗应采用以足疗程化疗为主的综合治疗；PBL患者是否接受利妥昔单抗治疗与生存获益无关。

, correspAuthors=王昕, 王翔, authorNote=null, correspAuthorsNote=
王昕，E-mail：
王翔，E-mail：
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冯轲昕，博士研究生，主要从事乳腺肿瘤的外科治疗研究

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冯轲昕，博士研究生，主要从事乳腺肿瘤的外科治疗研究

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冯轲昕，博士研究生，主要从事乳腺肿瘤的外科治疗研究

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J Clin Oncol, 2017, 35(22): 2515-2526., articleTitle=Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the german high-grade non-Hodgkin's lymphoma study group, refAbstract=null), Reference(id=1203057895698031228, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, doi=null, pmid=null, pmcid=null, year=2019, volume=53, issue=4, pageStart=473, pageEnd=479, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=Rajasooriyar C, Tey J, Wong LC, journalName=Radiol Oncol, refType=null, unstructuredReference=Rajasooriyar C, Tey J, Wong LC, et al. A multi-institutional analysis of diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiotherapy and the impact of cell-of-origin on outcomes[J]. Radiol Oncol, 2019, 53(4): 473-479., articleTitle=A multi-institutional analysis of diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiotherapy and the impact of cell-of-origin on outcomes, refAbstract=null), Reference(id=1203057895828054657, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, doi=null, pmid=null, pmcid=null, year=2012, volume=35, issue=2, pageStart=126, pageEnd=129, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=Aviles A, Neri N, Nambo MJ, journalName=Am J Clin Oncol, refType=null, unstructuredReference=Aviles A, Neri N, Nambo MJ. The role of genotype in 104 cases of diffuse large B-cell lymphoma primary of breast[J]. Am J Clin Oncol, 2012, 35(2): 126-129., articleTitle=The role of genotype in 104 cases of diffuse large B-cell lymphoma primary of breast, refAbstract=null), Reference(id=1203057895924523651, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, doi=null, pmid=null, pmcid=null, year=2021, volume=53, issue=3, pageStart=847, pageEnd=856, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=Kim HD, Cho H, Kim S, journalName=Cancer Res Treat, refType=null, unstructuredReference=Kim HD, Cho H, Kim S, et al. Prognostic stratification of patients with burkitt lymphoma using serum β2-microglobulin levels[J]. Cancer Res Treat, 2021, 53(3): 847-856., articleTitle=Prognostic stratification of patients with burkitt lymphoma using serum β2-microglobulin levels, refAbstract=null)], funds=[Fund(id=1203057891923157524, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, awardId=2019YFE0110000, language=EN, fundingSource=National Key Research and Development Program of China(2019YFE0110000), fundOrder=null, country=null), Fund(id=1203057892002849304, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, awardId=2019YFE0110000, language=CN, fundingSource=国家重点研发计划(2019YFE0110000), fundOrder=null, country=null), Fund(id=1203057892111901213, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, awardId=82072097, language=EN, fundingSource=National Natural Science Foundation of China(82072097), fundOrder=null, country=null), Fund(id=1203057892187398689, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, awardId=82072097, language=CN, fundingSource=国家自然科学基金(82072097), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1203057886290206944, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, xref=1, ext=[AuthorCompanyExt(id=1203057886298595551, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, companyId=1203057886290206944, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100021, China), AuthorCompanyExt(id=1203057886306984160, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, companyId=1203057886290206944, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院乳腺外科，北京 100021)]), AuthorCompany(id=1203057886449590505, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, xref=2, ext=[AuthorCompanyExt(id=1203057886457979115, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, companyId=1203057886449590505, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Breast Surgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100070, China), AuthorCompanyExt(id=1203057886474756334, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, companyId=1203057886449590505, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2首都医科大学附属北京天坛医院乳腺科，北京 100070)])], figs=[ArticleFig(id=1203057891025576415, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=EN, label=Fig. 1, caption=Kaplan-Meier survival curves of patients with primary breast lymphoma (PBL), figureFileSmall=1XewbPmdeXbIpJNyM0rUrA==, figureFileBig=8sQ6asDBFueCvmIJfb0k6Q==, tableContent=null), ArticleFig(id=1203057891109462501, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=CN, label=图1, caption=PBL患者的Kaplan-Meier生存曲线

PBL. 原发性乳腺淋巴瘤

, figureFileSmall=1XewbPmdeXbIpJNyM0rUrA==, figureFileBig=8sQ6asDBFueCvmIJfb0k6Q==, tableContent=null), ArticleFig(id=1203057891327566323, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=EN, label=Fig. 2, caption=Kaplan-Meier survival curves of patients with primary breast lymphoma (PBL) in the two groups, figureFileSmall=CjtpOT9Tw0EfavrD8uuxNQ==, figureFileBig=NY8JfSBmTQFUSce1O2/Ndw==, tableContent=null), ArticleFig(id=1203057891428229623, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=CN, label=图2, caption=两组PBL患者的Kaplan-Meier生存曲线

PBL. 原发性乳腺淋巴瘤

, figureFileSmall=CjtpOT9Tw0EfavrD8uuxNQ==, figureFileBig=NY8JfSBmTQFUSce1O2/Ndw==, tableContent=null), ArticleFig(id=1203057891499532796, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=EN, label=Tab. 1, caption=

Clinicopathological characteristics of 65 PBL patients[n(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
临床病理特征CHOP组(n=41)RCHOP组(n=24)χ2P
年龄(岁)  0.5910.782
 <6025(61.0)13(51.2)
 ≥6016(39.0)11(45.8)
病理类型  2.7950.488
 非GCB型18(43.9)10(41.7)
 GCB型10(24.4)10(41.7)
 数据缺失13(31.7)4(16.7)
Ann-Arbor临床分期  4.4500.108
 ⅠE期24(58.5)13(54.2)
 ⅡE期16(39.0)7(29.2)
 ⅣE期1(2.4)4(16.7)
乳腺超声肿物大小(cm)  1.7260.369
 <535(85.4)23(95.8)
 ≥56(14.6)1(4.2)
B症状  ––
 有00
 无41(100.0)24(100.0)
IPI评分(分)  0.1170.949
 0～129(70.7)16(66.7)
 2～512(29.3)8(33.3)
LDH水平  0.5270.807
 正常24(58.5)13(54.2)
 升高14(34.1)10(41.7)
 数据缺失3(7.3)1(4.2)
Ki-67  5.4450.043
 <50%8(19.5)0
 ≥50%31(75.6)23(95.8)
 数据缺失2(4.9)1(4.2)
白细胞计数  0.6700.707
 正常37(90.2)20(83.3)
 升高1(2.4)1(4.2)
 数据缺失3(7.3)3(12.5)
中性粒细胞计数  3.6600.191
 正常18(43.9)16(66.7)
 升高17(41.5)7(29.2)
 数据缺失6(14.6)1(4.1)
淋巴细胞计数  1.0640.588
 正常23(56.0)11(45.8)
 升高9(22.0)5(20.8)
 数据缺失9(22.0)8(33.3)
β2微球蛋白  0.3080.857
 正常21(51.2)14(58.3)
 升高10(24.4)5(20.8)
 数据缺失10(24.4)5(20.8)
c-Myc表达  0.4790.787
 阴性14(34.1)7(29.2)
 阳性15(36.6)8(33.3)
 数据缺失12(29.3)9(37.5)
BCL2表达  1.1780.589
 阴性12(29.3)8(33.3)
 阳性24(58.5)15(62.5)
 数据缺失5(12.2)1(4.2)
BCL6表达  2.1000.354
 阴性5(12.2)4(16.7)
 阳性23(56.1)9(37.5)
 数据缺失13(31.7)11(45.8)
p53表达  1.5630.458
 阴性11(26.8)10(41.7)
 阳性16(39.0)7(29.2)
 数据缺失14(34.1)7(29.2)
CD5表达  0.9830.612
 阴性17(41.5)13(54.2)
 阳性13(31.7)6(25.0)
 数据缺失11(26.8)5(20.8)
CD30  1.0010.606
 阴性17(41.5)7(29.2)
 阳性8(19.5)6(25.0)
 数据缺失16(39.0)11(45.8)
放疗  3.0140.262
 是8(19.5)1(1.5)
 否8(19.5)6(25.0)
 数据缺失25(61.0)17(70.8)
手术治疗  2.9130.149
 是22(53.7)18(75.0)
 否19(46.3)6(25.0)  
), ArticleFig(id=1203057891591807491, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=CN, label=表1, caption=

65例PBL患者的临床病理特征[例(%)]

, figureFileSmall=null, figureFileBig=null, tableContent=
临床病理特征CHOP组(n=41)RCHOP组(n=24)χ2P
年龄(岁)  0.5910.782
 <6025(61.0)13(51.2)
 ≥6016(39.0)11(45.8)
病理类型  2.7950.488
 非GCB型18(43.9)10(41.7)
 GCB型10(24.4)10(41.7)
 数据缺失13(31.7)4(16.7)
Ann-Arbor临床分期  4.4500.108
 ⅠE期24(58.5)13(54.2)
 ⅡE期16(39.0)7(29.2)
 ⅣE期1(2.4)4(16.7)
乳腺超声肿物大小(cm)  1.7260.369
 <535(85.4)23(95.8)
 ≥56(14.6)1(4.2)
B症状  ––
 有00
 无41(100.0)24(100.0)
IPI评分(分)  0.1170.949
 0～129(70.7)16(66.7)
 2～512(29.3)8(33.3)
LDH水平  0.5270.807
 正常24(58.5)13(54.2)
 升高14(34.1)10(41.7)
 数据缺失3(7.3)1(4.2)
Ki-67  5.4450.043
 <50%8(19.5)0
 ≥50%31(75.6)23(95.8)
 数据缺失2(4.9)1(4.2)
白细胞计数  0.6700.707
 正常37(90.2)20(83.3)
 升高1(2.4)1(4.2)
 数据缺失3(7.3)3(12.5)
中性粒细胞计数  3.6600.191
 正常18(43.9)16(66.7)
 升高17(41.5)7(29.2)
 数据缺失6(14.6)1(4.1)
淋巴细胞计数  1.0640.588
 正常23(56.0)11(45.8)
 升高9(22.0)5(20.8)
 数据缺失9(22.0)8(33.3)
β2微球蛋白  0.3080.857
 正常21(51.2)14(58.3)
 升高10(24.4)5(20.8)
 数据缺失10(24.4)5(20.8)
c-Myc表达  0.4790.787
 阴性14(34.1)7(29.2)
 阳性15(36.6)8(33.3)
 数据缺失12(29.3)9(37.5)
BCL2表达  1.1780.589
 阴性12(29.3)8(33.3)
 阳性24(58.5)15(62.5)
 数据缺失5(12.2)1(4.2)
BCL6表达  2.1000.354
 阴性5(12.2)4(16.7)
 阳性23(56.1)9(37.5)
 数据缺失13(31.7)11(45.8)
p53表达  1.5630.458
 阴性11(26.8)10(41.7)
 阳性16(39.0)7(29.2)
 数据缺失14(34.1)7(29.2)
CD5表达  0.9830.612
 阴性17(41.5)13(54.2)
 阳性13(31.7)6(25.0)
 数据缺失11(26.8)5(20.8)
CD30  1.0010.606
 阴性17(41.5)7(29.2)
 阳性8(19.5)6(25.0)
 数据缺失16(39.0)11(45.8)
放疗  3.0140.262
 是8(19.5)1(1.5)
 否8(19.5)6(25.0)
 数据缺失25(61.0)17(70.8)
手术治疗  2.9130.149
 是22(53.7)18(75.0)
 否19(46.3)6(25.0)  
), ArticleFig(id=1203057891679887881, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=EN, label=Tab. 2, caption=

Univariate and multivariate analysis of affecting the prognosis of patients with PBL

, figureFileSmall=null, figureFileBig=null, tableContent=
临床病理特征无进展生存总生存
单因素分析多因素分析单因素分析多因素分析
OR(95%CI)PHR(95% CI)POR(95%CI)PHR(95% CI)P
利妥昔单抗1.440(0.347～5.981)0.897  1.152(0.178～7.432)0.733
年龄(岁)1.932(0.467～7.992)0.126  2.250(0.349～14.486)0.173
病理分型0.316(0.033～3.064)0.639  0.893(0.785～1.015)0.796
Ann-Arbor临床分期–0.257  –0.584
IPI评分2.000(0.475～8.416)0.0313.815(0.360～40.372)0.2661.556(0.239～10.118)0.0296.474(1.021～41.145)0.046
LDH3.158(0.680～14.664)0.120  2.500(0.386～16.208)0.199
Ki-671.174(1.050～1.312)0.201  1.102(1.012～1.200)0.780
白细胞计数0.860(0.774～0.955)0.907  0.912(0.842～0.989)0.515
中性粒细胞计数1.974(0.470～8.288)0.870  2.286(0.352～14.859)0.936
淋巴细胞计数0.446(0.047～4.210)0.818  0.882(0.780～0.998)0.491
β2微球蛋白0.744(0.132～4.190)0.365  2.200(0.282～17.137)0.0305.753(1.184～27.953)0.030
c-Myc表达0.900(0.161～5.038)0.260  0.571(0.086～3.808)0.562
BCL2表达0.588(0.139～2.490)0.0582.791(0.175～44.573)0.4681.333(0.204～8.708)0.562
BCL6表达1.185(1.021～1.376)0.188  1.103(0.987～1.234)0.100
p53表达0.405(0.066～2.4830.938  0.273(0.026～2.852)0.505
CD5表达0.588(0.102～3.391)0.0200.288(0.079～1.055)0.0600.778(0.066～9.217)0.167
CD301.769(0.102～30.709)0.749  1.071(0.936～1.227)0.615
手术治疗6.000(0.702～51.261)0.502  1.143(1.017～1.285)0.933
放疗0.474(0.075～3.002)0.798  0.615(0.057～6.700)0.763  
), ArticleFig(id=1203057891797328398, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203057883039621186, language=CN, label=表2, caption=

影响PBL患者预后的单因素和多因素分析

, figureFileSmall=null, figureFileBig=null, tableContent=
临床病理特征无进展生存总生存
单因素分析多因素分析单因素分析多因素分析
OR(95%CI)PHR(95% CI)POR(95%CI)PHR(95% CI)P
利妥昔单抗1.440(0.347～5.981)0.897  1.152(0.178～7.432)0.733
年龄(岁)1.932(0.467～7.992)0.126  2.250(0.349～14.486)0.173
病理分型0.316(0.033～3.064)0.639  0.893(0.785～1.015)0.796
Ann-Arbor临床分期–0.257  –0.584
IPI评分2.000(0.475～8.416)0.0313.815(0.360～40.372)0.2661.556(0.239～10.118)0.0296.474(1.021～41.145)0.046
LDH3.158(0.680～14.664)0.120  2.500(0.386～16.208)0.199
Ki-671.174(1.050～1.312)0.201  1.102(1.012～1.200)0.780
白细胞计数0.860(0.774～0.955)0.907  0.912(0.842～0.989)0.515
中性粒细胞计数1.974(0.470～8.288)0.870  2.286(0.352～14.859)0.936
淋巴细胞计数0.446(0.047～4.210)0.818  0.882(0.780～0.998)0.491
β2微球蛋白0.744(0.132～4.190)0.365  2.200(0.282～17.137)0.0305.753(1.184～27.953)0.030
c-Myc表达0.900(0.161～5.038)0.260  0.571(0.086～3.808)0.562
BCL2表达0.588(0.139～2.490)0.0582.791(0.175～44.573)0.4681.333(0.204～8.708)0.562
BCL6表达1.185(1.021～1.376)0.188  1.103(0.987～1.234)0.100
p53表达0.405(0.066～2.4830.938  0.273(0.026～2.852)0.505
CD5表达0.588(0.102～3.391)0.0200.288(0.079～1.055)0.0600.778(0.066～9.217)0.167
CD301.769(0.102～30.709)0.749  1.071(0.936～1.227)0.615
手术治疗6.000(0.702～51.261)0.502  1.143(1.017～1.285)0.933
放疗0.474(0.075～3.002)0.798  0.615(0.057～6.700)0.763  
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利妥昔单抗联合CHOP方案治疗原发性乳腺淋巴瘤的疗效分析
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冯轲昕 1 , 王文彦 2 , 刘佳祥 1 , 商庆尧 1 , 杨琛轩 1 , 任斐 1 , 王昕 1, * , 王翔 1, *
解放军医学杂志 | 临床研究 2023,48(2): 204-210
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解放军医学杂志 | 临床研究 2023, 48(2): 204-210
利妥昔单抗联合CHOP方案治疗原发性乳腺淋巴瘤的疗效分析
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冯轲昕1, 王文彦2, 刘佳祥1, 商庆尧1, 杨琛轩1, 任斐1, 王昕1, * , 王翔1, *
作者信息
  • 1国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院乳腺外科，北京 100021
  • 2首都医科大学附属北京天坛医院乳腺科，北京 100070

    • 冯轲昕，博士研究生，主要从事乳腺肿瘤的外科治疗研究

通讯作者:

王昕，E-mail：
王翔，E-mail：
Analysis of the efficacy of rituximab combined with CHOP for treating patients with primary breast lymphoma
Ke-Xin Feng1, Wen-Yan Wang2, Jia-Xiang Liu1, Qing-Yao Shang1, Chen-Xuan Yang1, Fei Ren1, Xin Wang1, * , Xiang Wang1, *
Affiliations
  • 1Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical School, Beijing 100021, China
  • 2Department of Breast Surgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100070, China
出版时间: 2023-02-28 doi: 10.11855/j.issn.0577-7402.2023.02.0204
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摘要
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目的 分析原发性乳腺淋巴瘤（PBL）的临床病理学特征并探讨利妥昔单抗对其预后的影响。方法 回顾性分析2000年1月1日-2020年1月31日中国医学科学院北京协和医学院肿瘤医院收治的65例PBL患者的临床病理特征及利妥昔单抗的治疗效果，根据治疗方法的不同分为CHOP组[n=41，采用CHOP方案（环磷酰胺+表阿霉素+长春新碱+泼尼松）]与RCHOP组[n=24，采用利妥昔单抗联合CHOP方案]。采用门诊复查、电话方式随访，随访至患者死亡或截至2022年1月31日，通过单因素和多因素logistic回归分析PBL患者的预后影响因素。结果 共纳入65例PBL患者，均为女性，发病年龄57（23，86）岁，肿瘤大小为2.8（0.4，5.3）cm，随访时间为4.3（0.7，21.8）年。两组Ki-67表达情况差异有统计学意义（P=0.043），其他临床病理特征及治疗方案无明显差异（P>0.05）。65例PBL患者5年、10年总生存率分别为93.4%、87.9%，无进展生存率分别为88.2%、79.6%；中枢神经系统复发率为4.6%。Kaplan-Meier生存分析显示，CHOP组和RCHOP组5年总生存率分别为93.8%、92.9%（P=0.733），5年无进展生存率分别为89.9%、92.9%（P=0.897）。多因素logistic回归分析显示，国际预后指数（IPI）评分和β2微球蛋白水平是影响总生存的独立危险因素（P<0.05）。结论 PBL无特殊临床表现，确诊主要依靠组织病理学检查和免疫表型，根治性手术切除并不能改善患者的预后，其治疗应采用以足疗程化疗为主的综合治疗；PBL患者是否接受利妥昔单抗治疗与生存获益无关。

原发性乳腺淋巴瘤  /  利妥昔单抗  /  靶向治疗

Objective To analyze the clinical and pathological features of primary breast lymphoma (PBL) and explore the value of appling rituximab for the prognosis of patients with PBL. Methods The clinicopathological characteristics and therapeutic effect of rituximab were retrospectively analyzed of 65 patients with PBL admitted in the Cancer Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences from January 1, 2000 to January 31, 2020. According to different treatment methods,they were divided into CHOP group [n=41, using CHOP regimen (cyclophosphamide + epirubicin + vincristine + prednisone)] and RCHOP group (n=24, using rituximab combined CHOP regimen treatment). Patients received telephone follow-up or outpatient review until January 31, 2022 or mortality. Univariate regression analysis and multivariate regression analysis were used to analyze the factors influencing the prognosis of patients with PBL. Results All the 65 patients were female, aged 57(23, 86) years old.The tumor size was 2.8(0.4, 5.3) cm, and the follow-up time was 4.3(0.7, 21.8) years. There was a statistically significant difference in Ki-67 expression between the two groups (P=0.043), and there was no significant difference in other clinicopathological features and treatment plans (P>0.05). The 5- and 10-year overall survival rate of the 65 PBL patients were 93.4% and 87.9%,and the 5- and 10-year progression-free survival rate were 88.2% and 79.6%, the central nervous system recurrence rate was 4.6%.The 5-year overall survival rate in CHOP group was 93.8% and in RCHOP group was 92.9% (P=0.733), and 5-year progression-free survival rate was 89.9% in CHOP group, and in RCHOP group was 92.9% (P=0.897). Multivariate logistic regression analysis showed the international prognostic index (IPI) score and the level of β2 microglobulin were the independent risk factors of overall survival (P<0.05). Conclusions There is no special clinical manifestation of PBL. The definite diagnosis mainly depends on histopathological examination and immunophenotype. Radical surgical resection can not improve the prognosis of patients, and comprehensive treatment based on full-term chemotherapy should be adopted; whether patients with PBL received rituximab was not associated with the survival benefits.

primary breast lymphoma  /  rituximab  /  targeted therapy
冯轲昕, 王文彦, 刘佳祥, 商庆尧, 杨琛轩, 任斐, 王昕, 王翔. 利妥昔单抗联合CHOP方案治疗原发性乳腺淋巴瘤的疗效分析. 解放军医学杂志, 2023 , 48 (2) : 204 -210 . DOI: 10.11855/j.issn.0577-7402.2023.02.0204
Ke-Xin Feng, Wen-Yan Wang, Jia-Xiang Liu, Qing-Yao Shang, Chen-Xuan Yang, Fei Ren, Xin Wang, Xiang Wang. Analysis of the efficacy of rituximab combined with CHOP for treating patients with primary breast lymphoma[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (2) : 204 -210 . DOI: 10.11855/j.issn.0577-7402.2023.02.0204
正文
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原发性乳腺淋巴瘤(primary breast lymphoma，PBL)是一种非常罕见的结外淋巴瘤，约占所有乳腺原发性恶性肿瘤的0.5%，所有非霍奇金淋巴瘤的1.0%[1]。与其他部位的结外非霍奇金淋巴瘤相比，PBL更具侵袭性，预后更差，目前尚无明确的治疗指南。超过80%的PBL为B细胞淋巴瘤，绝大多数表达CD20，弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphoma，DLBCL)是PBL最常见的组织学亚型。近年来，抗CD20单克隆抗体利妥昔单抗被广泛用于治疗PBL，但其预后价值仍存在争议。如Hu等[2]的多中心研究显示，利妥昔单抗可显著降低PBL患者进展或复发的总体累积风险；而一项来自美国8个医疗中心和韩国16个医疗机构的多中心研究发现，利妥昔单抗的使用与生存获益无关[3]。本研究回顾性分析65例PBL患者的临床病理资料，总结其发病特点、诊断及利妥昔单抗治疗后的预后情况，以期为制定规范化和个体化的临床诊疗方案提供参考。
1 资料与方法
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1.1 研究对象
回顾性分析2000年1月1日-2020年1月31日中国医学科学院北京协和医学院肿瘤医院收治的65例PBL患者的临床病理资料。纳入标准：(1)取得足够的病理标本且经病理学证实为恶性淋巴瘤；(2)乳腺为首发部位，可同时伴有或继发同侧腋窝淋巴结肿大；(3)无其他部位淋巴瘤病史；(4)无同期全身播散的证据。排除标准：确诊PBL前已被诊断为血液恶性肿瘤或伴有播散性/全身性证据，或确诊后未经任何治疗。根据治疗方法不同分为CHOP组[n=41，采用CHOP方案(环磷酰胺+表阿霉素+长春新碱+泼尼松)治疗]与RCHOP组(n=24，采用利妥昔单抗联合CHOP方案治疗)。本研究经中国医学科学院肿瘤医院伦理委员会批准(20/468-2664)。
1.2 方法
1.2.1 标本获取
所有患者均行术前细针穿刺，其中40例接受手术治疗。
1.2.2 资料收集
收集患者入院时的临床资料，包括年龄、病理分型、乳腺超声检查结果、是否有B症状、Ann-Arbor临床分期、国际预后指数(international prognostic index，IPI)评分、血清乳酸脱氢酶(lactate dehydrogenase，LDH)水平、Ki-67表达水平、白细胞计数、淋巴细胞计数、中性粒细胞计数、β2微球蛋白水平，c-Myc、BCL2、BCL6、p53、CD5、CD30表达情况，以及是否使用利妥昔单抗、是否手术治疗和是否放疗等。
根据Lugano标准[3]，中期和治疗完全结束后使用PET-CT评估疗效，疗效评价标准包括完全缓解(complete regression，CR)、部分缓解(partial response，PR)、疾病稳定(stable disease，SD)和疾病进展(progressive disease，PD)，评价依据为PET 5分法(Deauville标准)。CR：完全代谢缓解，评分1~3分，伴或不伴残余病灶，未累及骨髓；PR：评分4~5分，摄取值较治疗前减低；SD：评分4~5分，摄取值较治疗前无明显变化，骨髓摄取值与治疗前基线一致；PD：评分4~5分，摄取值较治疗前增加，或出现新出现或复发的骨髓受累。
1.2.3 随访
采用门诊复查、电话方式随访，随访至患者死亡或截至2022年1月31日。总生存时间定义为确诊之日至末次随访或死亡时间，无进展生存时间定义为疾病获得完全缓解至疾病复发、进展或末次随访时间。
1.2.4 预后影响因素分析
采用单因素logistic回归分析进行单因素分析，以P<0.1为标准筛选出相关影响因素后进行多因素二元logistic回归分析。
1.3 统计学处理
采用R 3.6.3软件进行统计分析。计量资料以M(Q1，Q3)表示，两组间比较采用独立样本t检验；计数资料以例(%)表示，两组间比较采用χ2检验或Fisher检验。采用Kaplan-Meier法绘制生存曲线，log-rank检验分析两组间生存的差异。P<0.05为差异有统计学意义。
2 结果
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2.1 两组临床资料比较
共纳入PBL患者65例，均为女性，发病年龄57(23，86)岁，其中41例接受CHOP方案治疗，24例接受利妥昔单抗联合CHOP方案治疗，化疗剂量根据标准化疗剂量选择(环磷酰胺600 mg/m2，表阿霉素60 mg/m2，长春新碱1.4 mg/m2，泼尼松40 mg/m2，利妥昔单抗375 mg/m2)。其中51例(78.5%)出现无痛可触及的乳房肿块，5例(7.7%)出现双侧乳房受累。所有患者均未出现任何临床B症状(发热、体重减轻和盗汗)。乳腺超声检查结果显示肿瘤大小为2.8(0.4，5.3) cm，其中7例(10.8%)肿瘤超过5 cm。根据Ann-Arbor临床分期标准，65例患者中，ⅠE期37例(56.9%)，ⅡE期23例(35.4%)，ⅣE期5例(7.7%，双侧乳房肿块)。根据IPI评分进行风险分层调查，45例(69.2%)IPI评分为0~1分，20例(30.8%)IPI评分为2~5分。25例(38.5%)细胞学穿刺结果可以明确诊断，25例(38.5%)通过乳房肿物切除活检术明确诊断，15例(23.1%)通过粗针穿刺明确诊断。24例(36.9%) LDH升高；2例(3.1%)白细胞数高于正常值范围上限，24例(36.9%)中性粒细胞数高于正常值范围上限，14例(21.5%)淋巴细胞数高于正常值范围上限。15例(23.1%)β2微球蛋白升高；54例(83.1%)Ki-67≥50%，8例(12.3%)Ki-67<50%。两组患者的临床病理特征及治疗情况如表1所示，除Ki-67表达情况(P=0.043)外，其他临床病理特征及治疗方案均未见明显差异(P>0.05)。
2.2 随访结果
随访时间为4.3(0.7，21.8)年。其中18例(27.7%)在首个疗程治疗后评效为CR，10例(15.4%)为PR，14例(21.5%)为SD，11例(16.9%)在一线治疗后出现PD，其余患者首个疗程治疗后的缓解情况评估记录缺失。全部治疗完成至随访结束，共9例出现复发或进展，其中6例首次复发部位为同侧乳腺；有5例侵犯同侧腋窝淋巴结，3例侵犯中枢神经系统，1例侵犯腰椎；共5例死亡。5年、10年总生存率分别为93.4%、87.9%，无进展生存率分别为88.2%、79.6%(图1)。中枢神经系统复发率为4.6%。
2.3 预后情况
Kaplan-Meier生存分析显示，CHOP组5年、10年总生存率分别为93.8%、78.1%，无进展生存率分别为89.9%、70.3%；RCHOP组5年、10年总生存率分别为92.9%、79.6%，无进展生存率分别为92.9%、72.4%。两组总生存率、无进展生存率比较，差异均无统计学意义(P=0.733、P=0.897，图2)。
2.4 PBL患者预后影响因素分析
分别以总生存和无进展生存为因变量，以年龄、病理分型、Ann-Arbor临床分期、IPI评分、LDH水平、Ki-67表达水平、白细胞计数、淋巴细胞计数、中性粒细胞计数、β2微球蛋白水平，c-Myc、BCL2、BCL6、p53、CD5、CD30表达情况，以及是否使用利妥昔单抗、是否手术治疗和是否放疗为自变量进行单因素分析，结果显示，IPI评分、CD5表达与PBL患者的无进展生存有关(P<0.05)，IPI评分和β2微球蛋白水平与PBL患者的总生存有关(P<0.05)。
以表2中P<0.1的IPI评分、BCL2表达、CD5表达为自变量进行无进展生存的多因素回归分析，以IPI评分和β2微球蛋白水平为自变量进行总生存的多因素回归分析，结果显示，IPI评分和β2微球蛋白水平是影响总生存的独立危险因素(P<0.05，表2)。
3 讨论
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西方国家PBL发病年龄通常为60~64岁[4]，东亚国家的发病年龄较低，为40~60岁[5]。本研究中，PBL患者发病年龄为57(23，86)岁，与既往研究一致[4]。乳腺淋巴瘤缺乏特异性的影像学表现，难以与乳腺癌区分。PBL的诊断主要依靠穿刺或术后病理检查，具体分类最终需通过免疫组织化学确认。但由于细胞学检查敏感性较低，许多患者需要手术活检获得组织病理学以确认PBL的诊断。本研究中仅25例(38.5%)术前细胞学穿刺可以确诊，15例进一步通过粗针穿刺明确诊断，而其余25例通过手术切除活检确诊。由于PBL预后差，早期明确诊断及早期预测复发风险并选择合适的治疗策略对于患者至关重要[6]。
PBL的治疗方案尚未达成共识，多数医师主张应采取手术、化疗、放疗等综合治疗方案，而手术仅限于获取足够标本用于病理组织学诊断。根治性切除术并不能提高PBL患者的生存获益，反而可能增加患者的死亡风险[7]。本研究单因素和多因素回归分析结果也显示手术与PBL患者的生存预后无关(P>0.05)。对于初治PBL患者，化疗多采用CHOP方案(环磷酰胺+阿霉素+长春新碱+泼尼松)治疗。在系统性B细胞非霍奇金淋巴瘤的治疗中，CHOP方案为标准治疗方案，而联用利妥昔单抗可明显提高疗效，因此，化疗联合免疫治疗已成为系统性B细胞非霍奇金淋巴瘤的治疗标准，但利妥昔单抗在乳腺淋巴瘤中的应用价值仍存在争议。检索2000-2021年PubMed和Web of Science数据库显示，共12篇文献分析了使用/不使用利妥昔单抗治疗PBL的生存情况，其中9项研究发现使用利妥昔单抗治疗后，虽然5年无进展生存率或5年总生存率有所提高，但与未使用利妥昔单抗组比较，差异并无统计学意义(P>0.05)[1,8-15]；另外3项回顾性研究报道了RCHOP治疗PBL患者的5年无进展生存期或总生存期明显优于单独使用CHOP治疗的患者[2,16-17]。本研究结果显示，RCHOP治疗可提高患者的5年总生存率和无进展生存率，但与未使用利妥昔单抗组比较，差异也无统计学意义(P>0.05)。
目前利妥昔单抗对中枢神经系统复发的预防作用也存在争议。有研究发现，利妥昔单抗可降低中枢神经系统复发的风险[18-19]。Shen等[17]的研究也发现，利妥昔单抗治疗后中枢神经系统复发时间明显延长(P=0.003)。但Hu等[2]的研究发现，虽然利妥昔单抗可以明显降低PBL患者的复发和进展风险，但不能降低中枢神经系统复发率(P=0.72)。Hosein等[9]的多中心研究对影响中枢神经系统复发的因素进行了单因素和多因素回归分析，结果显示，是否使用利妥昔单抗与中枢神经系统复发无关(P>0.05)。本研究中，由于时间跨度较大(2000年1月1日-2020年1月31日)，患者入院时未行骨髓穿刺评估中枢神经受累风险，且发生中枢神经系统复发的患者均未接受利妥昔单抗治疗，无法评估利妥昔单抗对预防中枢神经系统复发的作用。
既往研究中PBL的预后影响因素包括IPI评分[5]、病理类型[20]，以及是否使用利妥昔单抗[17]和放疗[21]等。IPI评分主要包括年龄、体力指数、乳酸脱氢酶、涉及结外部位数量、分期等5个预后指标，其中IPI评分0~1分为低危、2分为低中危、3分为中高危、4~5分为高危，IPI评分越高，患者预后越差[17]。本研究对临床病理特征进行单因素和多因素回归分析，发现IPI评分是影响总生存的独立危险因素(P<0.05)。PBL根据细胞起源可分为生发中心B细胞(GCB)、活化B细胞(ABC)和未分类(基因表达谱分类)三型，或分为GCB型和非GCB型(Hans免疫组织化学分类)。关于PBL病理类型对预后的影响，有研究显示，在PBL中，非GCB型更常见，但GCB与非GCB患者的预后没有显著差异[22]。本研究结果显示病理类型中非GCB型较多(43.9%)，且单因素和多因素回归分析发现GCB与非GCB患者的预后没有明显差异(表2)，表明病理类型对PBL的预后价值有限，与Aviles等[22]的研究一致。在利妥昔单抗广泛使用前，放疗对PBL患者的预后价值已经得到验证[21]，但是随着利妥昔单抗的广泛使用，放疗对预后的意义出现争议。本研究单因素和多因素回归分析结果显示，放疗不是PBL患者总生存和无进展生存的危险因素(P>0.05)。β2微球蛋白是一种存在于所有有核细胞(包括淋巴细胞)细胞膜上的低分子量(11.8 kD)蛋白。血清β2微球蛋白水平升高已被证实与各种类型淋巴瘤的不良预后相关[23]，提示其在淋巴瘤疾病的发生和进展中具有潜在的生物学作用，升高的原因可能是肿瘤细胞合成β2微球蛋白的速度加快。因此，测定血清β2微球蛋白可用于评估淋巴瘤的活动程度。本研究通过多因素回归分析也证实β2微球蛋白是影响PBL患者总生存的独立危险因素(P<0.05)。
综上所述，PBL无特殊临床表现，确诊主要依赖组织病理学检查和免疫表型，根治性手术切除并不能改善患者的预后，其治疗应采用以足疗程化疗为主的综合治疗。本研究中PBL患者是否接受利妥昔单抗治疗与生存获益无关，但由于纳入病例的时间跨度较大、临床资料缺失较多，利妥昔单抗和放疗对PBL患者的预后价值仍需通过大样本的前瞻性研究进一步证实。
基金
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  • 国家重点研发计划(2019YFE0110000)
  • 国家自然科学基金(82072097)
文献
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2023年第48卷第2期
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doi: 10.11855/j.issn.0577-7402.2023.02.0204
  • 接收时间：2022-04-15
  • 首发时间：2025-12-03
  • 出版时间：2023-02-28
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  • 收稿日期：2022-04-15
  • 录用日期：2022-08-16
基金
National Key Research and Development Program of China(2019YFE0110000)
国家重点研发计划(2019YFE0110000)
National Natural Science Foundation of China(82072097)
国家自然科学基金(82072097)
作者信息
    1国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院乳腺外科，北京 100021
    2首都医科大学附属北京天坛医院乳腺科，北京 100070

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
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