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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2013, Vol. 07 ›› Issue (02) : 91 -96. doi: 10.3877/cma. j. issn.1674-0807.2013.02.004

论著

Ki67、增殖细胞核抗原在不同分子分型乳腺癌组织中的表达及意义
董欢1, 林燕苹1, 应学翔1, 何萍青1,†()   
  1. 1.200233 上海,上海交通大学附属第六人民医院普外科
  • 收稿日期:2012-10-29 出版日期:2013-04-01
  • 通信作者: 何萍青

Expression of Ki67 and proliferating cell nuclear antigen in different subtypes of breast cancer and their clinical significance

Huan DONG1, Yan-ping LIN1, Xue-xiang YING1, Ping-qing HE1,†()   

  1. 1.Department of General Surgery, Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai 200233, China
  • Received:2012-10-29 Published:2013-04-01
  • Corresponding author: Ping-qing HE
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董欢, 林燕苹, 应学翔, 何萍青. Ki67、增殖细胞核抗原在不同分子分型乳腺癌组织中的表达及意义[J/OL]. 中华乳腺病杂志(电子版), 2013, 07(02): 91-96.

Huan DONG, Yan-ping LIN, Xue-xiang YING, Ping-qing HE. Expression of Ki67 and proliferating cell nuclear antigen in different subtypes of breast cancer and their clinical significance[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2013, 07(02): 91-96.

目的

探讨Ki67、增殖细胞核抗原(PCNA)在不同分子类型乳腺癌组织中的表达及临床意义。

方法

采用免疫组化法检测251 例乳腺癌组织中Ki67、PCNA 的表达情况,采用kruskal-wallis 秩和检验分析Ki67、PCNA 在不同分子类型乳腺癌组织中的表达差异;采用Spearman 相关分析法,分析不同分子类型中Ki67 与PCNA 表达的相关性及其分别与原发肿瘤直径、腋窝淋巴结转移及病理组织学分级的相关性;采用生存分析法,分析Ki67、PCNA 对乳腺癌预后的意义。

结果

Luminal 型、HER-2 型及三阴性乳腺癌组织中Ki67、PCNA 表达强度差异均无统计学意义(χ2 =3.722,P=0.155;χ2 =5.135,P=0.077)。 Ki67 与PCNA 总体呈正相关(rs=0.348,P=0.000),在Luminal 型中呈正相关(rs=0.467, P=0.000),而在HER-2 型、三阴性乳腺癌中无相关性(P＞0.05)。 Ki67 表达强度与原发肿瘤直径、腋窝淋巴结转移及组织学分级在Luminal 型乳腺癌呈正相关性(rs=0.180,P=0.017; rs=0.236,P=0.002; rs=0.156,P=0.039),而在HER-2 型及三阴性乳腺癌中无相关性(P＞0.05)。 PCNA 表达强度与Luminal 型乳腺癌的腋窝淋巴结转移呈正相关性(rs=0.166,P=0.028),与HER-2 型乳腺癌的原发肿瘤直径呈负相关性(rs=-0.342,P=0.020),与其他病理因素均无相关性(P＞0.05)。 单因素生存分析显示腋窝淋巴结转移、组织学分级对乳腺癌患者无瘤生存有影响(HR=4.431,95%CI:1.787 ～10.984; HR=2.492,95%CI:1.032 ～6.018),亚组分析显示腋窝淋巴结、PCNA 对Luminal 型乳腺癌患者无瘤生存有影响(HR=3.930,95%CI:1.343 ～11.501;HR=2.401,95%CI:1.044 ～5.524)。 多因素COX 回归分析显示腋窝淋巴结转移是总体和Luminal 型乳腺癌患者预后的独立影响因素(HR=3.780, 95%CI:1.461 ～9.775;HR=3.403,95%CI:1.150 ～10.075)。

结论

Ki67 和PCNA 对评估Luminal 型乳腺癌预后有一定指导意义,而对HER-2 型和三阴性乳腺癌预后无明显影响。

关键词: 乳腺肿瘤, 免疫组织化学, Ki67, 增殖细胞核抗原

Objective

To investigate the expression of Ki67 and proliferating cell nuclear antigen(PCNA) in three different subtypes of breast cancer and their clinical significance.

Methods

Immunohistochemistry was used to detect the expression of Ki67 and PCNA in tissue samples from 251 breast cancer patients. kruskal-wallis rank sum test was used to analyze the expression difference of Ki67 and PCNA in different subtypes, Spearman rank test for the correlation of their expressions, and the correlation with primary tumor diameter, axillary lymph node metastasis and pathological classification, respectively. Meanwhile, the survival analysis was conducted to display the prognostic value of Ki67 and PCNA expression.

Results

The expressions of Ki67 and PCNA were not significantly different among the three subtypes of breast cancer(luminal,HER-2 and triple negative) (χ2 =3.722,P=0.155;χ2 =5.135,P=0.077). There was a positive correlation between Ki67 and PCNA expressions in general(rs=0.348,P＜0.001)and in luminal subtype(rs=0.467, P＜0.001), but no correlation was observed in other subtypes(P＞0.05). In luminal subtype, the expression of Ki67 was positively correlated with primary tumor diameter, axillary lymph node status and histological grade (rs=0.180,P=0.017;rs=0.236,P=0.002;rs=0.156,P=0.039, respectively), and no correlation was showed in HER-2 and triple-negative subtypes(P ＞0.05). We also observed the positive correlation between PCNA expression and axillary lymph node status in luminal subtype, a negative correlation with primary tumor diameter in HER-2 subtype (rs = -0.342, P=0.020), but no correlations with other pathological factors were found (P ＞0.05). Univariate analysis showed axillary lymph node metastasis and nuclear grade had influence on tumor-free survival of breast cancer patients (HR=4.431, 95%CI: 1.787 to 10.984; HR= 2.492, 95% CI: 1.032 to 6.018). The subgroup analysis displayed axillary lymph node metastasis and PCNA had effects on tumor-free survival in luminal subtype (HR=3.930, 95%CI: 1.343 to 11.501; HR=2.401, 95% CI: 1.044 to 5.524). Multivariate COX analysis showed axillary lymph node metastasis was an independent prognostic factor in general and luminal subtype breast cancer patients (HR=3.780,95%CI:1.461 to 9.775; HR=3.403,95%CI:1.150 to 10.075).

Conclusion

Ki67 and PCNA can indicate the poor prognosis of luminal subtype breast cancer patients to a certain extent, but have no influence on HER-2 and triple negative subtypes.

Key words: breast neoplasms, immunohistochemistry, Ki67, proliferating cell nuclear antigen
表1 251 例乳腺癌患者的临床及病理资料
变量 例数(%)
年龄
≤50岁 85(34)
＞50岁 166(66)
组织学分级
Ⅰ、Ⅱ 143(57)
Ⅲ 108(43)
肿瘤直径
≤2cm 127(51)
＞2cm 124(49)
腋窝淋巴结
阴性 167(67)
阳性 84(33)
Ki67
+ 120(48)
++ 87(35)
+++ 44(17)
PCNA
+ 63(25)
++ 156(62)
+++ 32(13)
分子分型
Luminal型 175(70)
HER-2型 46(18)
三阴性乳腺癌 30(12)
表2 Ki67、PCNA 表达与Luminal 型乳腺癌临床病理因素的关系
病理因素 Ki67表达(例) rs值 P值 PCNA表达(例) rs值 P值
+ ++ +++ + ++ +++
PTD
≤2cm 56 25 12 0.180 0.017 24 57 12 0.095 0.213
＞2cm 35 29 18 16 51 15
ALN
- 67 34 12 0.236 0.002 30 70 13 0.166 0.028
+ 24 20 18 10 38 14
组织学分级
Ⅰ、Ⅱ 57 32 11 0.156 0.039 28 56 16 0.090 0.235
Ⅲ 34 22 19 12 52 11
图1 乳腺癌患者的无瘤生存曲线
表3 单因素生存分析结果
影响因素 回归系数 统计量(Z值) P值 HR(95%CI)
总体
年龄(≤50岁/＞50岁) 0.567 1.11 0.269 1.763(0.646～4.815)
肿瘤直径(＞2cm/≤2cm) 0.806 1.74 0.082 2.238(0.903～5.548)
腋窝淋巴结(+/-) 1.489 3.21 0.001 4.431(1.787～10.984)
组织学分级(Ⅲ/Ⅰ、Ⅱ) 0.913 2.03 0.042 2.492(1.032～6.018)
Ki67(+++/+、++) 0.023 0.08 0.938 1.023(0.569～1.841)
PCNA(+++/+、++) 0.526 1.48 0.140 1.691(0.842～3.397)
Luminal型(亚组)
年龄(≤50岁/＞50岁) 0.440 0.75 0.452 1.552(0.494～4.876)
肿瘤直径(＞2cm/≤2cm) 0.634 1.20 0.229 1.886(0.670～5.303)
腋窝淋巴结(+/-) 1.369 2.50 0.012 3.930(1.343～11.501)
组织学分级(Ⅲ/Ⅰ、Ⅱ) 0.841 1.59 0.111 2.320(0.824～6.526)
Ki67(+++/++/+) 0.262 0.79 0.430 1.299(0.679～2.487)
PCNA(+++/++/+) 0.876 2.06 0.039 2.401(1.044～5.524)
表4 多因素生存分析结果
影响因素 回归系数 统计量(Z值) P值 HR(95%CI)
总体
腋窝淋巴结(+/-) 1.330 2.74 0.006 3.780(1.461～9.775)
组织学分级(Ⅲ/Ⅰ、Ⅱ) 0.513 1.09 0.276 1.670(0.664～4.202)
Luminal型(亚组)
腋窝淋巴结(+/-) 1.225 2.21 0.027 3.403(1.150～10.075)
PCNA(+++/++/+) 0.729 1.68 0.092 2.073(0.887～4.842)
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