1、3630124(6):717 726.14 SUSNERWALA SS,SHANKS JH,BANERJEE SS,et al.Extr-amedullary plasmacytoma of the head and neck region:clinico-pathological correlation in 25 cases J.Br J Cancer,1997,75(6):921 927.15WIRK B,WINGARD JR,MOREB JS,et al.Extramedullary dis-ease in plasma cell myeloma:the iceberg phenome
2、non J.Bone黄相艳,等低级别子宫内膜样腺癌预后影响因素及其与MELF浸润的关系Marrow Trans-plant,2013,48(1):10-18.16 LONIAL S,ANDERSON KC.Association of response endpointswith survival outcomes in multiple myeloma J.Leukemia,2014,28(2):258-268.17 MOHAMMAD JH,SABINA K,MUKTA P,et al.Extramedullaryplasmacytoma of the thyroid:report of a
3、 rare case J.Blood Res,2014(49):275 285.（编校：巩森淼）低级别子宫内膜样腺癌预后影响因素及其与MELF浸润的关系黄相艳,王富强,段情,王苗苗,李秀芳!1安阳市肿瘤医院妇瘤科；病理中心,河南安阳4550 0 0【摘要】目的：探讨病理分级1-2 级子宫内膜样腺癌预后影响因素及与微囊性/伸长/碎片状（microcys-tic,elongated,and fragmented,MELF)浸润的关系，为临床治疗方案制定及预后评估提供更多证据。方法：回顾性纳人2 0 10 年0 1月至2 0 17 年0 6 月于我院诊治病理分级12 级子宫内膜样腺癌患者共2 6 6
4、 例，由高年资病理医生重新阅片，根据是否存在MELF浸润分为MELF组（40 例）和非MELF组（2 2 6 例），比较两组临床病理特征资料及随访生存资料，采用多因素法评估盆腔淋巴结转移风险和5年无进展生存独立影响因素,并进一步评估MELF浸润对患者临床预后的影响及预测价值。结果：MELF组CA125水平、子宫颈间质侵犯比例、子宫肌层侵犯达1/2 以上比例、盆腔淋巴结转移比例及脉管癌栓比例均显著高于非MELF组（P 0.0 5）。整体人群MELF组5年无进展生存率显著低于非MELF组（P0.05）;FI G O I 期和FIGOI期患者中非MELF组5年无进展生存率高于MELF组（P0.05）
5、。Lo g i s t i c 回归模型多因素分析结果显示,MELF浸润是盆腔淋巴结转移独立危险因素（P0.05）;C o x 比例风险回归模型多因素分析结果显示,MELF浸润与脉管癌栓均是无进展生存独立危险因素（P0.05）；RO C曲线分析结果显示，MELF浸润用于盆腔淋巴结转移及疾病进展风险预测具有良好效能，AUC分别为0.8 2(95%CI:0.700.90）、0.8 4（95%C I:0.7 40.96）。结论：MELF浸润与CA125水平、子宫颈间质侵犯、子宫肌层侵犯程度、盆腔淋巴结转移及脉管癌栓有一定相关性;MELF浸润的子宫内膜样腺癌患者存在更高盆腔淋巴结转移及疾病进展风险。【
6、关键词】子宫内膜样腺癌；预后；微囊性/伸长/碎片状浸润；淋巴结转移；无进展生存【中图分类号】R737.33【文章编号】16 7 2-49 9 2-（2 0 2 3)19-36 30-0 5Prognostic factors and relationship with MELF invasion in endometrioid adenocarcinomapatients with low gradeHUANG Xiangyan,WANG Fuqiang,DUAN Qing,WANG Miaomiao,LI XiufangDepartment of Gynecological Oncology
7、;Pathology Center,Anyang Cancer Hospital,Henan Anyang 455000,China.Abstract Objective:To investigate the prognostic factors and relationship with microcystic,elongated,and frag-mented(MELF)invasion in endometrioid adenocarcinoma patients with grade 1-2,to provide more evidence for clin-ical treatmen
8、t planning and prognostic evaluation.Methods:266 endometrioid adenocarcinoma patients with grade 1-2 were retrospectively chosen in the period from January 2010 to June 2017.All patients were grouped according topresence or absence of MELF infiltration and included MELF group(40 cases)and non-MELF g
9、roup(226 cases).The clinicopathological characteristics and follow-up survival data were compared between 2 groups.The risk of pel-vic lymph node metastasis and independent influencing factors of 5-year progression-free survival were evaluatedby multivariate analysis method,and the influence and pre
10、dictive value of MELF infiltration on clinical prognosis were【收稿日期】2023 04-25【作者简介】黄相艳（198 5），女，河南安阳人，副主任医师，主要从事妇科肿瘤工作。Ema i l：h u a n g x i a n g y a n g 8 5 12 6.c o m【通信作者】李秀芳（197 5一），女，河南安阳人，主任医师，主要从事妇科肿瘤工作。Ema i l:mu h e c a o 2 0 0 6 16 3.c o m【文献标识码】A【修回日期】2 0 2 3-0 6-2 5D0I:10.3969/j.issn.16
11、72-4992.2023.19.018现代肿瘤医学2 0 2 3年10 月第31卷第19 期further evaluated.Results:The level of CA125,the proportion of cervical interstitial invasion,the proportion of myometri-uminvasion more than half,the proportion of pelvic lymph node metastasis and the proportion of vascular tumorthrombus in MELF group w
12、ere significantly higher than non-MELF group(P0.05).The 5-year progression-freesurvival of MELF group was significantly lower than non-MELF group in overall population(P0.05).The 5-yearprogression-free survival of non-MELF group was significantly higher than MELF group in FIGO stage I and IIpopulati
13、on(P0.05).Multivariate analysis of Logistic regression modelshowed that MELF infiltration was the independent risk factor of pelvic lymph node metastasis(P0.05).Multivari-ate analysis of Cox proportional hazards regression model showed that MELF infiltration and vascular tumor thrombuswere the indep
14、endent risk factors of progression-free survival(P0.05).ROC curve analysis showed that MELF in-filtration had satisfactory efficacy in predicting the risk of pelvic lymph node metastasis and disease progression withAUC of 0.82(95%CI:0.70 0.90)and 0.84(95%CI:0.74 0.96),respectively.Conclusion:MELF in
15、filtrationwas correlated with CA125 level,cervical interstitial invasion,uterine muscle invasion,pelvic lymph node metastasisand vascular cancer thrombus.Patients with MELF-infiltrated endometrioid adenocarcinoma are at higher risk forpelvic lymph node metastasis and disease progression.Key wordsend
16、ometrioid adenocarcinoma,prognosis,microcystic/elongating/fragmented invasion,lymph node me-tastasis,progression-free survivalModern Oncology 2023,31(19):3630-3634子宫内膜样腺癌约占子宫内膜癌患者总数的7 5%1.3资料收集85%,影响该病患者临床预后主要因素包括FIGO分期和组登录医院电子病历系统，收集入组患者人口学资料、实织学分级,其中FIGO分期I期及病理组织学分级低级验室检查指标、临床分期及病理组织学检查资料。因本研究别(1级
17、和2 级）患者往往预后良好，但仍有部分低级别子宫为回顾性研究,为避免既往认识不足导致的诊断不充分,所内膜样腺癌患者出现复发并预后不良1-3。微囊性/伸长/有病理组织学检查均由2 位中级及以上职称高年资病理诊碎片状（microcystic,elongated,and fragmented,MELF）浸润好断医师重新阅片完成，评估是否存在MELF浸润、有无子宫发于低级别子宫内膜样腺癌，属于子宫内膜癌特殊肌层浸润颈间质侵犯、子宫肌层侵犯深度、有无盆腔淋巴结转移及脉形式4。有报道提示MELF浸润可能增加子宫内膜癌患者管癌栓等指标，协商一致后发出报告。盆腔淋巴结转移风险，但亦有反对观点认为两者间并无直接
18、1.4随访情况关系5。因低级别子宫内膜样腺癌远期复发转移及死亡率采用电话、门诊或住院复查方式完成随访，随访截止时间为2 0 2 2 年0 6 月；随访终点事件包括为肿瘤复发、转移或均较低,导致临床在分析MELF浸润与患者临床预后间相关死亡。无进展生存时间（progressionf r e e s u r v i v a l,PFS）指从性方面难度较大，同时不同研究间结论亦存在差异，而且对治疗开始至复发、转移、死亡、随访截止或失访时间；入选患于存在MELF浸润的早期患者,临床是否应在术后给予辅助放化疗存在争议6-7 。故本研究通过回顾性分析子宫内膜样腺癌预后影响因素及其与MELF浸润的关系,研究
19、子宫内膜癌MELF浸润模式的临床及病理特点,探讨其对早期内膜癌预后的影响价值，旨在为临床治疗方案制定及预后评估提供更多证据。1资料与方法1.1研究对象纳入标准：经病理组织学检查确诊子宫内膜样腺癌；病理组织学分级1-2 级；完成全子宫+双附件切除淋巴结清扫手术；临床病理及随访资料完整。排除标准：其他子宫内膜癌亚型；合并其他类型恶性肿瘤；合并严重脏器功能障碍；术前接受新辅助治疗或其他药物治疗；随访数据不完整或失访。本研究最终纳入2 0 10 年0 1月至2 0 17 年0 6 月于我院诊治的病理分级12 级子宫内膜样腺癌患者共2 6 6 例。1.2分组人选患者根据是否存在MELF浸润分为MELF组
20、（40例）和非MELF组（2 2 6 例）。MELF浸润病理组织学判定标准：低倍光镜下可见浸润肿瘤细胞位于肿瘤浸润最前端；浸润肿瘤细胞呈微囊状、拉长裂隙样及碎片状表现；腺腔内衬细胞质嗜酸或类内皮样改变；间质可见黏液水肿样纤维改变及以中性粒细胞为主的炎症细胞浸润 8 。MODERN ONCOLOGY,Oct.2023,VOL.31,No.19者中位随访时间56（13 110）个月，失访33例，失访率为12.41%。1.5统计学处理选择SPSS20.0软件分析数据；正态性评估采用Kolmog-orov-Smirnov检验,其中符合正态分布计量资料比较采用t检验,以(xs)表示;计数资料比较采用检验
21、或Fisher确切概率法,以%表示；盆腔淋巴结转移影响因素的多因素分析采用Logistic 回归模型；无进展生存影响因素的多因素分析采用Cox比例风险回归模型;P0.05为差异有统计学意义。2结果2.1两组临床病理特征比较MELF组CA125水平、子宫颈间质侵犯比例、子宫肌层侵犯达1/2 以上比例、盆腔淋巴结转移比例及脉管癌栓比例均显著高于非MELF组（P0.05）,见表1。2.2两组随访生存资料比较266例患者随访过程中发生肿瘤复发4例，远处转移3例,死亡2 例。整体人群MELF组5年无进展生存率显著低于非MELF组（P0.05）;FI G O I 期和FIGOI期患者中非MELF组5年无进
22、展生存率高于MELF组（P0.05）,见表2。3631:3632Tab.1Comparison of clinicopathologic characteristics between 22Tab.3Multivariate analysis of influencing factors of pelvic lymph nodegroupsnIndexNon-MELFgroup(n=226)Age(years)5050Maximum focaldiameter(x s,cm)CA125(x s,U/mL)FIGO stage1IHistopathological grade12Uterine
23、interstitial invasionNoYesDepth of myometriuminvasion1/21/2Lymph node metastasisNoYesUncleanedVascular cancer thrombusNoYesTab.2Comparison of follow-up survival data between 2 groups%(n)MELF groupIndex(n=40)PFS rate87.50(35/40)FIGO I stage93.55(29/31)FIGO II stage60.00(3/5)FIGO II stage75.00(3/4)注：*
24、Fisher确切概率法。Note:*Fisher exact probability method.2.3金盆腔淋巴结转移影响因素的多因素分析Logistic回归模型多因素分析结果显示,MELF浸润是盆腔淋巴结转移独立危险因素（P0.05）,见表3。2.4无进展生存影响因素的多因素分析Cox比例风险回归模型多因素分析结果显示,MELF浸润与脉管癌栓均是无进展生存独立危险因素(P0.05）,见表4。2.5MELF浸润用于盆腔淋巴结转移及疾病进展风险预测临床效能分析ROC曲线分析结果显示，MELF浸润用于盆腔淋巴结转移及疾病进展风险预测具有良好效能,AUC分别为0.8 2(95%CI:0.70 0
25、.90),0.84(95%CI:0.74 0.96),见图 1-2 。黄相艳，等表1两组临床病理特征资料比较nMELF groupStatistical(n=40)value0.1947011156293.32 0.753.40 0.8116.79 3.4434.15 6.842003121554110221161820535215203202320201305420621632108表2 两组随访生存资料比较%（n）Non-MELF groupStatiticalvalue(n=226)98.23(22/226)99.00(198/200)100.00(21/21)60.00(3/5)低级别
26、子宫内膜样腺癌预后影响因素及其与MELF浸润的关系表3盆腔淋巴结转移影响因素的多因素分析metastasisIndexPMELF invasion0.660CA125Cervical interstitial invasionIntrusions of myometriumreached more than 1/20.5820.56115.6870.0010.0070.9310.5440.4614.0950.04339.7690.0015.7780.01610.7150.001P15.3900.0014.6880.0300.048*一0.4051.970.837.570.026.861.22
27、19.481.640.754.950.374.700.86 9.03-0.81 1.690.310.750.540.30 1.251.550.731.290.303.090.67 9.61Vascular cancer thrombus0.24 1.500.540.60表4无进展生存影响因素的多因素分析Tab.4Multivariate analysis of the factors influencing progression-freesurvivalIndexMELF invasionLymph node metastasisCervical interstitial invasionI
28、ntrusions of myometriumreached more than 1/2Vascular cancer thrombus(%)AIAUIsUS图1MELF浸润用于盆腔淋巴结转移风险预测ROC曲线Fig.1 ROC curve of MELF infiltration for risk prediction of pelvic lymphnode metastasis10080(%)KuAmIsues604020图2 MELF浸润用于疾病进展风险预测ROC曲线Fig.21ROC curve of MELF infiltration for predicting the risk
29、of diseaseprogression3讨论3.1MELF浸润模式与临床病理特征的关系本研究纳人2 6 6 例患者，存在MELF浸润40 例，占比为15.04%，低于文献报道的42.2%的发生率9】，考虑与既往对MELF认识不足导致部分患者取材不充分有关。对其临床病理特征进行分析显示，MELF浸润与CA125水平、子宫颈间质侵犯、子宫肌层侵犯程度、盆腔淋巴结转移及脉管癌栓有一定相关性（P0.05）。这一结论与之前的部分报道结果相符10-m)。目前认为MELF 浸润以肌层最深处最为多见,因WaldPOR95%CI0.740.22 1.83BWaldRR95%CI-1.61 1.457.930
30、.430.21 0.75-0.38 1.132.090.690.47 1.180.830.890.951.750.91 2.380.701.100.672.510.75 4.032.631.245.619.9831.10 23.400.0410080604020P0.030.250.470.71204060 80100100-specificity(%)20406080100100-specificity(%)现代肿瘤医学2 0 2 3年10 月第31卷第19 期子宫肌壁深层淋巴血管相对丰富,故这一浸润模式下肿瘤细胞多呈散在、簇状或碎片拉伸状改变,且多存在上皮型钙黏蛋白或波形蛋白表达异常，据此
31、推测MELF浸润可能与上皮间叶转化有关，理论上能更易导致脉管浸润及淋巴结转移12-14O盆腔淋巴结转移是子宫内膜样腺癌转移常见形式之一，亦与预后不良关系密切15-1；多项研究提示盆腔淋巴结转移与MELF浸润模式相关，MELF浸润的子宫内膜癌患者存在更高发生率的淋巴结转移,并认为MELF浸润可能对盆腔淋巴结转移有提示作用17-18 。在本研究中,临床病理特征分析提示MELF浸润与盆腔淋巴结转移有一定相关性。进一步行盆腔淋巴结转移影响因素的多因素分析结果证实MELF浸润与子宫内膜样腺癌患者盆腔淋巴结转移间的独立关系，存在MELF浸润的子宫内膜样腺癌患者发生淋巴结转移的风险更高。且基于本研究数据进行
32、的MELF浸润对于盆腔淋巴结转移风险预测ROC曲线结果AUC为0.8 2(9 5%CI:0.700.90），具有良好的预测价值。鉴于这一结果,笔者建议对部分内膜腺癌患者的后续治疗提出重新思考,对于存在MELF浸润而未清扫淋巴结的早期患者,是否建议补充淋巴结清扫术，或积极补充治疗以防遗漏潜在的淋巴结转移，从而降低子宫内膜癌的复发转移风险及提高整体生存质量。3.2MLEF浸润模式与预后价值的关系有报道认为,MELF浸润与子宫内膜样腺癌患者预后不良直接相关19-2 0 。但亦有观点认为，MELF浸润对于子宫内膜样腺癌患者进展复发的影响仍有待证实2 1。本次研究266例患者随访过程中发生肿瘤复发4例,
33、远处转移3例,死亡2 例，考虑到早期低级别子宫内膜样腺癌死亡等不良事件发生数较少，故在生存资料比较中采用5年无进展生存率这一指标进行评价。本研究多因素模型显示，MELF浸润及脉管癌栓均是低级别子宫内膜样腺癌无进展生存独立危险因素,且基于本研究数据进行的MELF浸润对于疾病进展风险预测R0C曲线结果AUC为0.8 4（95%CI:0.740.96），提示在早期低级别子宫内膜样腺癌中MELF浸润相较于无MELF浸润者生物学行为侵袭性更强，可能加快肿瘤进展，从而可能影响临床预后。本次研究整体人群MELF组5年无进展生存率显著低于非MELF组（P0.05）;FI G O I 期和FIGO期患者中非ME
34、LF组5年无进展生存率高于MELF组（P0.05），笔者认为这可能提示MELF浸润是肿瘤进展过程中的存在状态而非肿瘤进展的启动或决定因素，单纯MELF浸润尚无法有效预测低级别子宫内膜癌患者的生存预后。亦有可能与期占比较少且期患者多采用手术+放疗+化疗的综合治疗有关，提示我们系统的综合治疗有可能拮抗MELF浸润的侵袭性并降低疾病进展风险,存在MELF浸润的患者尽早积极进行综合治疗可能是受益的。研究不足：本研究属于单中心回顾性研究，且并未将IV期患者纳人其中,是因IV期患者混杂有姑息性手术导致的病理结果不全及术前放化疗导致的病理结果偏差因素，故以I期患者为主。尽管通过多因素分析校正混杂因素影响，但
35、仍可能无法完全避免选择偏倚，且早期低级别子宫内膜样腺癌患者预后较好，随访不良事件较少，后续仍有待多MODERN ONCOLOGY,Oct.2023,VOL.31,No.19中心前瞻性研究进一步明确其在低级别子宫内膜癌中的发生机制及作用地位，以期为临床治疗方案制定及预后评估提供更多证据。综上所述，MELF浸润是子宫内膜癌的一种特殊肌层浸润形式，本研究提示其与CA125水平、子宫颈间质侵犯、子宫肌层侵犯程度、盆腔淋巴结转移及脉管癌栓有一定相关性，同时MELF浸润的子宫内膜样腺癌患者存在更高盆腔淋巴结转移及疾病进展风险，但其不是预测低级别子宫内膜癌生存预后的有效指标。1王伟，于水,宋波,等.52 例
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