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Article(id=1322218897282028239, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322218730805904072, articleNumber=null, orderNo=null, doi=10.16016/j.2097-0927.202311128, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1732636800000, receivedDateStr=2024-11-27, revisedDate=1739376000000, revisedDateStr=2025-02-13, acceptedDate=null, acceptedDateStr=null, onlineDate=1793171150751, onlineDateStr=2026-10-28, pubDate=1751212800000, pubDateStr=2025-06-30, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793171150751, onlineIssueDateStr=2026-10-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793171150751, creator=13701087609, updateTime=1793171150751, updator=13701087609, issue=Issue{id=1322218730805904072, tenantId=1146029695717560320, journalId=1319373162502258839, year='2025', volume='47', issue='12', pageStart='1261', pageEnd='1400', issueExtLink='null', onlineDate='null', pubDate='1751212800000', pubDateStr='2025-06-30', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1793171111059, creator='13701087609', updateTime=1793325445066, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322866054611714261, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322218730805904072, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322866054611714262, tenantId=1146029695717560320, journalId=1319373162502258839, issueId=1322218730805904072, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1312, endPage=1318, ext={EN=ArticleExt(id=1322218897483354832, articleId=1322218897282028239, tenantId=1146029695717560320, journalId=1319373162502258839, language=EN, title=Role of immunohistochemical markers CK20, CD10, PHLDA1, CD34, AR, Ber-EP4 and Ki-67 in differential diagnosis of trichoblastoma and basal cell carcinoma, columnId=1320434418116837551, journalTitle=Journal of Army Medical University, columnName=Basic Medicine, runingTitle=null, highlight=null, articleAbstract=
Objective

To analyze the expression patterns of immunohistochemical markers CK20, CD10, PHLDA1, CD34, AR, Ber-EP4, and Ki-67 in cutaneous trichoblastoma (TB) and basal cell carcinoma (BCC), and validate their diagnostic value in differentiating TB from BCC.

Methods‍

Pathological specimens were harvested from 35 TB patients and 35 BCC patients diagnosed with histopathological biopsy in our department between January 2013 and December 2023. Their clinical data were collected, and the expression levels of CK20, CD10, PHLDA1, CD34, AR, Ber-EP4, and Ki-67 in TB and BCC tissues were detected with immunohistochemical staining. The staining patterns and proportions of positive cells in basaloid tumor nests and peritumoral stroma were analyzed. χ2 test was used to screen statistically significant variables, and then multivariate logistic regression analysis was utilized to evaluate the diagnostic efficacy of each marker. Based on the significance of the markers, stepwise combinations of immunohistochemical markers were analyzed to determine their collective diagnostic performance.

Results‍

Peripheral CD10 positivity in basaloid cell nests (P<0.001) and diffuse CD10 positivity in basaloid cells (P<0.001) strongly supported BCC diagnosis. In contrast, CK20 positivity in basaloid cells (P=0.028), CD10 positivity in stromal cells (P<0.001), and PHLDA1 positivity in basaloid cells (P<0.001) favored TB. Stromal CD34 positivity (P=0.247), AR positivity in basaloid cells (P=0.794), Ber-EP4 positivity in basaloid cells (P=0.156), Ki-67 proliferation index (P=0.280), and Ki-67 staining patterns (P=0.897) showed no significant differences between TB and BCC. Multivariate logistic regression analysis identified stromal CD10 positivity (P<0.001) and PHLDA1 positivity (P=0.042) as independent predictors of TB, showing negative correlations with BCC. CK20 positivity in basaloid cells (P=0.340) showed no statistically significant difference in expression between TB and BCC. The combination of stromal CD10, PHLDA1, and CK20 demonstrated the highest diagnostic performance (Youden index=0.74).

Conclusion

Stromal CD10 and basaloid PHLDA1 positivity serve as reliable markers for distinguishing TB from BCC.

, authors=Chenxi LIU, Zhuoma DANGZENG, Lin WANG, authorsList=Chenxi LIU, Zhuoma DANGZENG, Lin WANG, authorCompany=null, correspAuthors=Lin WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=© 2025 Journal of Army Medical University, copyrightOwner=Editorial Office of Journal of Army Medical University, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1322218899601478355, articleId=1322218897282028239, tenantId=1146029695717560320, journalId=1319373162502258839, language=CN, title=CK20、CD10、PHLDA1、CD34、AR、Ber-EP4和Ki-67在毛母细胞瘤和基底细胞癌鉴别诊断中的作用, columnId=1322185528879993170, journalTitle=陆军军医大学学报, columnName=基础医学, runingTitle=null, highlight=null, articleAbstract=
目的

分析免疫组织化学标记 CK20、CD10、PHLDA1 、CD34、AR、Ber-EP4和Ki-67在皮肤毛母细胞瘤（trichoblastoma，TB）与基底细胞癌（basal cell carcinoma，BCC）中的表达模式，验证其在TB和BCC鉴别诊断中的价值。

方法

纳入2013年1月至2023年12月于四川大学华西医院皮肤科经组织活检确诊的35例TB患者与35例BCC患者的病理标本，整理患者临床资料，通过免疫组织化学染色检测CK20、CD10、PHLDA1、CD34、AR、Ber-EP4和Ki-67在TB和BCC中的表达情况，包括基底样细胞癌巢及癌周间质中的染色模式与阳性细胞比例。采用χ2检验筛选有统计学意义的变量，并进一步通过多因素Logistic回归分析各指标在鉴别诊断中的效能，最后按照多因素Logistic回归的显著性排序逐步纳入免疫组化标记联合鉴别诊断TB和BCC，分析不同组合标记的检验效能。

结果

基底样细胞巢团周边CD10阳性模式（P<0.001）及基底样细胞CD10阳性（P<0.001）更支持BCC的诊断；而基底样细胞CK20阳性（P=0.028）、间质细胞CD10阳性（P<0.001）与基底样细胞PHLDA1阳性（P<0.001）则更支持TB诊断，而间质细胞CD34阳性（P=0.247）、基底样细胞AR阳性（P=0.794）、基底样细胞Ber-EP4阳性（P=0.156）、基底样细胞Ki-67阳性计数（P=0.280）以及阳性模式（P=0.897）在TB以及BCC表达差异均无统计学意义。进一步通过多因素Logistic回归分析发现，间质CD10阳性（P<0.001）以及PHLDA1阳性（P=0.042）是TB的独立预测因子，与BCC呈负相关，而基底样细胞CK20阳性（P=0.340）在TB和BCC中表达差异无统计学意义。间质CD10、肿瘤基底样细胞巢团PHLDA1、CK20中任意2个标记阳性的约登指数为0.74，具备最好的诊断性能。

结论

肿瘤间质细胞CD10与基底样细胞PHLDA1的阳性表达可作为TB与BCC的鉴别诊断标志物。

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王琳，E-mail：
WANG LIN，E-mail：
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Isr Med Assoc J，2014，16（4）：229-232., articleTitle=Ki67 as a biologic marker of basal cell carcinoma：a retrospective study, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1322218899836359380, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, xref=1, ext=[AuthorCompanyExt(id=1322218899848942293, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, companyId=1322218899836359380, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Dermatology，West China Hospital，Sichuan University，Chengdu，Sichuan，China), AuthorCompanyExt(id=1322218899857330902, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, companyId=1322218899836359380, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1四川大学华西医院皮肤科，四川 成都)])], figs=[ArticleFig(id=1322218901308560108, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=EN, label=null, caption=null, figureFileSmall=2pzmVLKy6m7MbdcErnHGeQ==, figureFileBig=7xNhp0uoi+Y5RgzkmNyfEQ==, tableContent=null), ArticleFig(id=1322218901388251885, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=CN, label=图1, caption=TB和BCC中CD10、CK20、CD34、PHLDA1、AR、Ber-EP4、Ki-67表达情况, figureFileSmall=2pzmVLKy6m7MbdcErnHGeQ==, figureFileBig=7xNhp0uoi+Y5RgzkmNyfEQ==, tableContent=null), ArticleFig(id=1322218901589578478, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
免疫表型TB例数（%）BCC例数（%）P
CD10间质<0.001a
阳性比例76%~100%6（17.14）0
阳性比例51%~75%5（14.29）0
阳性比例26%~50%9（25.71）0
阳性比例1%~25%11（31.43）10（28.57）
阴性4（11.43）25（71.43）
CD10<0.001a
阳性比例76%~100%0（0.00）2（5.71）
阳性比例51%~75%6（17.14）5（14.29）
阳性比例26%~50%4（11.43）2（5.71）
阳性比例1%~25%3（8.57）18（51.43）
阴性22（62.86）8（22.86）
CD10阳性模式<0.001a
周边3（23.08）22（81.48）
中心0（0.00）1（3.70）
弥漫10（76.92）4（14.81）
CK200.028a
阳性8（22.86）1（2.86）
阴性27（77.14）34（97.14）
CD34间质
阳性比例76%~100%0（0.00）3（8.57）0.247a
阳性比例51%~75%1（2.86）4（11.43）
阳性比例26%~50%9（25.71）6（17.14）
阳性比例1%~25%11（31.43）8（22.86）
阴性14（40.00）14（40.00）
BerEP40.156
阳性比例76%~100%10（28.57）17（48.57）
阳性比例51%~75%7（20.00）4（11.43）
阳性比例26%~50%5（14.29）6（17.14）
阳性比例1%~25%11（31.43）4（11.43）
阴性2（5.71）4（11.43）
AR0.794
阳性10（28.57）11（31.43）
阴性25（71.43）24（68.57）
PHLDA14<0.001a
阳性比例76%~100%4（11.43）0（0.00）
阳性比例51%~75%4（11.43）0（0.00）
阳性比例26%~50%3（8.57）0（0.00）
阳性比例1%~25%5（14.29）1（2.86）
阴性19（54.29）34（97.14）
Ki-6740.280 a
阳性比例76%~100%0（0.00）0（0.00）
阳性比例51%~75%0（0.00）0（0.00）
阳性比例26%~50%3（8.57）0（0.00）
阳性比例1%~25%30（85.71）32（91.43）
阴性2（5.71）3（8.57）
Ki-67阳性0.897
阳性周边16（48.48）15（46.88）
阳性散在17（51.52）17（53.13）
), ArticleFig(id=1322218901681853167, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=CN, label=表1, caption=

CK20、CD10、CD34、PHLDA1、AR、Ber-EP4和Ki-67表达情况

, figureFileSmall=null, figureFileBig=null, tableContent=
免疫表型TB例数（%）BCC例数（%）P
CD10间质<0.001a
阳性比例76%~100%6（17.14）0
阳性比例51%~75%5（14.29）0
阳性比例26%~50%9（25.71）0
阳性比例1%~25%11（31.43）10（28.57）
阴性4（11.43）25（71.43）
CD10<0.001a
阳性比例76%~100%0（0.00）2（5.71）
阳性比例51%~75%6（17.14）5（14.29）
阳性比例26%~50%4（11.43）2（5.71）
阳性比例1%~25%3（8.57）18（51.43）
阴性22（62.86）8（22.86）
CD10阳性模式<0.001a
周边3（23.08）22（81.48）
中心0（0.00）1（3.70）
弥漫10（76.92）4（14.81）
CK200.028a
阳性8（22.86）1（2.86）
阴性27（77.14）34（97.14）
CD34间质
阳性比例76%~100%0（0.00）3（8.57）0.247a
阳性比例51%~75%1（2.86）4（11.43）
阳性比例26%~50%9（25.71）6（17.14）
阳性比例1%~25%11（31.43）8（22.86）
阴性14（40.00）14（40.00）
BerEP40.156
阳性比例76%~100%10（28.57）17（48.57）
阳性比例51%~75%7（20.00）4（11.43）
阳性比例26%~50%5（14.29）6（17.14）
阳性比例1%~25%11（31.43）4（11.43）
阴性2（5.71）4（11.43）
AR0.794
阳性10（28.57）11（31.43）
阴性25（71.43）24（68.57）
PHLDA14<0.001a
阳性比例76%~100%4（11.43）0（0.00）
阳性比例51%~75%4（11.43）0（0.00）
阳性比例26%~50%3（8.57）0（0.00）
阳性比例1%~25%5（14.29）1（2.86）
阴性19（54.29）34（97.14）
Ki-6740.280 a
阳性比例76%~100%0（0.00）0（0.00）
阳性比例51%~75%0（0.00）0（0.00）
阳性比例26%~50%3（8.57）0（0.00）
阳性比例1%~25%30（85.71）32（91.43）
阴性2（5.71）3（8.57）
Ki-67阳性0.897
阳性周边16（48.48）15（46.88）
阳性散在17（51.52）17（53.13）
), ArticleFig(id=1322218901774127856, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
免疫组化标记B标准误差瓦尔德自由度显著性Exp（B）EXP（B）的95%CI伪r2
下限上限
CD10-2.7550.79811.91510.0010.0640.0130.3040.794
PHLDA1-2.4011.1794.14710.0420.0910.0090.914
CK20-1.6941.7740.91210.3400.1840.0065.947
), ArticleFig(id=1322218901862208241, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=CN, label=表2, caption=

CD10、PHLDA1、CK20的多因素Logistic回归分析

, figureFileSmall=null, figureFileBig=null, tableContent=
免疫组化标记B标准误差瓦尔德自由度显著性Exp（B）EXP（B）的95%CI伪r2
下限上限
CD10-2.7550.79811.91510.0010.0640.0130.3040.794
PHLDA1-2.4011.1794.14710.0420.0910.0090.914
CK20-1.6941.7740.91210.3400.1840.0065.947
), ArticleFig(id=1322218901929317106, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
免疫组化标记组合判定条件敏感度1-特异度约登指数
CD10\0.890.290.60
CD10/PHLDA1均阳性0.400.000.40
任意一个阳性0.970.290.69
均阴性0.940.310.63
CD10/PHLDA1/CK20均阳性0.140.000.14
任意两个阳性0.740.000.74
任意一个阳性0.490.660.14
均阴性0.660.940.60
), ArticleFig(id=1322218902013203187, tenantId=1146029695717560320, journalId=1319373162502258839, articleId=1322218897282028239, language=CN, label=表3, caption=

CD10、PHLDA1、CK20免疫组化标记组合以及不同判定条件对诊断效能的影响

, figureFileSmall=null, figureFileBig=null, tableContent=
免疫组化标记组合判定条件敏感度1-特异度约登指数
CD10\0.890.290.60
CD10/PHLDA1均阳性0.400.000.40
任意一个阳性0.970.290.69
均阴性0.940.310.63
CD10/PHLDA1/CK20均阳性0.140.000.14
任意两个阳性0.740.000.74
任意一个阳性0.490.660.14
均阴性0.660.940.60
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CK20、CD10、PHLDA1、CD34、AR、Ber-EP4和Ki-67在毛母细胞瘤和基底细胞癌鉴别诊断中的作用
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刘晨希 , 当增卓玛 , 王琳
陆军军医大学学报 | 基础医学 2025,47(12): 1312-1318
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陆军军医大学学报 |基础医学 2025 , 47 (12) : 1312 -1318
CK20、CD10、PHLDA1、CD34、AR、Ber-EP4和Ki-67在毛母细胞瘤和基底细胞癌鉴别诊断中的作用
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刘晨希, 当增卓玛, 王琳
作者信息
  • 1四川大学华西医院皮肤科，四川 成都
通讯作者:
王琳，E-mail：
WANG LIN，E-mail：
Role of immunohistochemical markers CK20, CD10, PHLDA1, CD34, AR, Ber-EP4 and Ki-67 in differential diagnosis of trichoblastoma and basal cell carcinoma
Chenxi LIU, Zhuoma DANGZENG, Lin WANG
Affiliations
  • 1Department of Dermatology，West China Hospital，Sichuan University，Chengdu，Sichuan，China
出版时间: 2025-06-30 doi: 10.16016/j.2097-0927.202311128
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摘要
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目的

分析免疫组织化学标记 CK20、CD10、PHLDA1 、CD34、AR、Ber-EP4和Ki-67在皮肤毛母细胞瘤（trichoblastoma，TB）与基底细胞癌（basal cell carcinoma，BCC）中的表达模式，验证其在TB和BCC鉴别诊断中的价值。

方法

纳入2013年1月至2023年12月于四川大学华西医院皮肤科经组织活检确诊的35例TB患者与35例BCC患者的病理标本，整理患者临床资料，通过免疫组织化学染色检测CK20、CD10、PHLDA1、CD34、AR、Ber-EP4和Ki-67在TB和BCC中的表达情况，包括基底样细胞癌巢及癌周间质中的染色模式与阳性细胞比例。采用χ2检验筛选有统计学意义的变量，并进一步通过多因素Logistic回归分析各指标在鉴别诊断中的效能，最后按照多因素Logistic回归的显著性排序逐步纳入免疫组化标记联合鉴别诊断TB和BCC，分析不同组合标记的检验效能。

结果

基底样细胞巢团周边CD10阳性模式（P<0.001）及基底样细胞CD10阳性（P<0.001）更支持BCC的诊断；而基底样细胞CK20阳性（P=0.028）、间质细胞CD10阳性（P<0.001）与基底样细胞PHLDA1阳性（P<0.001）则更支持TB诊断，而间质细胞CD34阳性（P=0.247）、基底样细胞AR阳性（P=0.794）、基底样细胞Ber-EP4阳性（P=0.156）、基底样细胞Ki-67阳性计数（P=0.280）以及阳性模式（P=0.897）在TB以及BCC表达差异均无统计学意义。进一步通过多因素Logistic回归分析发现，间质CD10阳性（P<0.001）以及PHLDA1阳性（P=0.042）是TB的独立预测因子，与BCC呈负相关，而基底样细胞CK20阳性（P=0.340）在TB和BCC中表达差异无统计学意义。间质CD10、肿瘤基底样细胞巢团PHLDA1、CK20中任意2个标记阳性的约登指数为0.74，具备最好的诊断性能。

结论

肿瘤间质细胞CD10与基底样细胞PHLDA1的阳性表达可作为TB与BCC的鉴别诊断标志物。

基底细胞癌  /  毛母细胞瘤  /  免疫组化标记
Objective

To analyze the expression patterns of immunohistochemical markers CK20, CD10, PHLDA1, CD34, AR, Ber-EP4, and Ki-67 in cutaneous trichoblastoma (TB) and basal cell carcinoma (BCC), and validate their diagnostic value in differentiating TB from BCC.

Methods‍

Pathological specimens were harvested from 35 TB patients and 35 BCC patients diagnosed with histopathological biopsy in our department between January 2013 and December 2023. Their clinical data were collected, and the expression levels of CK20, CD10, PHLDA1, CD34, AR, Ber-EP4, and Ki-67 in TB and BCC tissues were detected with immunohistochemical staining. The staining patterns and proportions of positive cells in basaloid tumor nests and peritumoral stroma were analyzed. χ2 test was used to screen statistically significant variables, and then multivariate logistic regression analysis was utilized to evaluate the diagnostic efficacy of each marker. Based on the significance of the markers, stepwise combinations of immunohistochemical markers were analyzed to determine their collective diagnostic performance.

Results‍

Peripheral CD10 positivity in basaloid cell nests (P<0.001) and diffuse CD10 positivity in basaloid cells (P<0.001) strongly supported BCC diagnosis. In contrast, CK20 positivity in basaloid cells (P=0.028), CD10 positivity in stromal cells (P<0.001), and PHLDA1 positivity in basaloid cells (P<0.001) favored TB. Stromal CD34 positivity (P=0.247), AR positivity in basaloid cells (P=0.794), Ber-EP4 positivity in basaloid cells (P=0.156), Ki-67 proliferation index (P=0.280), and Ki-67 staining patterns (P=0.897) showed no significant differences between TB and BCC. Multivariate logistic regression analysis identified stromal CD10 positivity (P<0.001) and PHLDA1 positivity (P=0.042) as independent predictors of TB, showing negative correlations with BCC. CK20 positivity in basaloid cells (P=0.340) showed no statistically significant difference in expression between TB and BCC. The combination of stromal CD10, PHLDA1, and CK20 demonstrated the highest diagnostic performance (Youden index=0.74).

Conclusion

Stromal CD10 and basaloid PHLDA1 positivity serve as reliable markers for distinguishing TB from BCC.

basal cell carcinoma  /  trichoblastoma  /  immunohistochemical labeling
刘晨希, 当增卓玛, 王琳. CK20、CD10、PHLDA1、CD34、AR、Ber-EP4和Ki-67在毛母细胞瘤和基底细胞癌鉴别诊断中的作用. 陆军军医大学学报, 2025 , 47 (12) : 1312 -1318 . DOI: 10.16016/j.2097-0927.202311128
Chenxi LIU, Zhuoma DANGZENG, Lin WANG. Role of immunohistochemical markers CK20, CD10, PHLDA1, CD34, AR, Ber-EP4 and Ki-67 in differential diagnosis of trichoblastoma and basal cell carcinoma[J]. Journal of Army Medical University, 2025 , 47 (12) : 1312 -1318 . DOI: 10.16016/j.2097-0927.202311128
正文
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基底细胞癌（basal cell carcinoma，BCC）是最常见的皮肤恶性肿瘤，好发于日光暴露部位，具有局部侵袭性，可导致深层组织破坏。毛母细胞瘤（trichoblastoma，TB）是一种少见的良性皮肤附属器肿瘤，好发于头面部。组织病理学中，BCC和TB存在部分重叠特征，均可表现为周边栅栏状排列的基底样细胞巢团，并伴有纤维基质成分，二者在病理诊断工作中常需鉴别［1-2］。
典型的BCC与TB可以通过组织学特征进行区分。相较于BCC，TB的基底样细胞巢团界限清楚，缺乏细胞异型性、核分裂象及肿瘤坏死等恶性征象。此外，TB与BCC的间质成分亦有差别。BCC的间质富含透明质酸，组织固定后常形成特征性收缩间隙；而TB则表现为双向分化结构，癌巢周围间质可形成类似不成熟毛囊的原始毛乳头结构［1-2］。然而，当TB浸润皮肌致肿瘤境界不清；基底样上皮成分存在一定程度不典型性、核分裂象增多等；毛源性间质成分较少，或活检标本较小等情况下，仅凭组织学形态进行BCC和TB的鉴别诊断存在困难［3］。
近年来，免疫组化标记的应用为BCC与TB的鉴别诊断提供了新策略。免疫组化标记可协助鉴定BCC和TB中基底样细胞以及间质的组织学来源，进而辅助二者的鉴别诊断。然而，现有研究多聚焦于单一标记物的诊断效能，缺乏多指标联合检测体系的临床研究。本研究通过分析35例BCC与35例TB中CD10、CK20、CD34、PHLDA1、AR、Ber-EP4和Ki-67 中的表达差异及分布特征，旨在评估免疫组织化学标记在二者鉴别诊断中的应用价值。
1　资料与方法
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1.1　研究对象
本研究为横断面研究，纳入2013年1月至2023年12月四川大学华西医院皮肤科经组织活检确诊的35例TB与35例BCC患者的病理标本。本研究通过了四川大学华西医院生物医学伦理审查委员会的审批。
1.2　组织学及免疫组织化学染色
标本经3.7%中性甲醛固定，常规脱水，石蜡包埋，苏木精－伊红染色，采用 Envision 二步法染色。光镜观察组织形态。
1.3　主要试剂与仪器
检测抗体包括CD10（英国Abcam公司）、CK20（美国Thermo Scientific公司）、CD34（英国Abcam公司）、PHLDA1（美国Santa Cruz Biotechnology公司）、AR（美国Santa Cruz Biotechnology公司）、Ber‑EP4（英国Abcam公司）和 Ki‑67（美国Thermo Scientific公司）。检测仪器为光学显微镜（德国 Zeiss 公司）。
1.4　免疫组化标记定位与半定量分析
CD10表达定位于细胞膜或细胞质；CK20表达定位于细胞质和/或核旁点状； CD34表达定位于细胞膜或细胞质；PHLDA1表达定位于细胞质，瘤巢中散在分布的黑素细胞以及溃疡附近的阳性细胞应视作阴性；AR阳性定位于细胞核；Ber‑Ep4表达定位于细胞质；阳性细胞的比例分别为1%~25%、26%~50%、51%~75%、76%~100%。当阳性细胞比例低于1%时，则判断为阴性。TB或BCC基底样细胞巢团中仅周边栅栏状排列细胞染色阳性定义为周边阳性模式；仅中央区域的细胞染色阳性定义为中央阳性模式；周边栅栏状排列细胞及中央区域均染色阳性定义为弥漫阳性模式。
1.5　统计学分析
采用SPSS 26.0 统计软件进行统计分析。计数资料以例（%）表示，计量资料以x¯±s表示。组间率的比较采用Pearson χ2检验，若理论频数<5时，改用Fisher确切概率法，检验标准为α=0.05，显著性检验采用双尾检验。采用多因素Logistic回归法计算各因素的优势比Exp（B）及其95%置信区间。基于多因素Logistic回归中显著性水平P值由小到大逐一将免疫组化标记加入诊断组合，计算每个组合不同判定条件的灵敏度、1-特异度和约登指数。
2　结果
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2.1　临床特征
本研究纳入的35例TB患者中，男性13例（37.1%），女性22例（62.9%）。患者年龄10~86岁，平均年龄（53.8±19.6）岁。共30例（85.7%）TB发生在头颈部；4例（11.4%）TB发生在四肢； 1例（2.9%）发生在躯干。35例BCC患者中，男性13例（37.1%），女性22例（62.9%）。年龄20~78岁，平均年龄（59.5±13.3）岁，所有BCC病例均发生于头颈部。35例BCC中24例为结节型BCC，4例为微结节型BCC，2例为腺样型BCC，4例为硬化型，1例为浅表型。
2.2　免疫组织化学染色结果
使用免疫组化标记CK20、CD10、PHLDA1 、CD34、AR、Ber-EP4和Ki-67检测TB以及BCC表达情况。TB与BCC肿瘤细胞CD10阳性模式（P<0.001）及阳性比例（P<0.001）、任意CD20阳性（P=0.028），肿瘤间质CD10阳性比例（P<0.001）均存在表达差异。而间质细胞CD34阳性（P=0.247）、基底样细胞AR阳性（P=0.794），基底样细胞Ber-EP4阳性（P=0.156）、基底样细胞Ki-67阳性计数（P=0.280）、基底样细胞Ki-67阳性模式（P=0.897）在TB以及BCC表达差异均无统计学意义。CD10、CK20、CD34、PHLDA1、AR、Ber-EP4和Ki-67在35例TB与35例BCC中阳性表达差异及统计结果见表1。
2.3　基于多因素Logistic回归分析的免疫组化标记组合及其诊断效能
在单因素分析基础上，所有P<0.1的免疫组化标记均纳入Logistic多因素分析。CD10、CK20、PHLDA1的Logistic多因素分析结果显示，间质CD10阳性［Exp（B） 0.013，95%CI：0.013~0.304，P<0.001］以及基底样细胞PHLDA1阳性［Exp（B） 0.091，95%CI： 0.009~0.914，P=0.042］是TB的独立预测因子，与BCC呈负相关，而基底样细胞CK20阳性［Exp（B） 0.184，95%CI：0.006~5.947，P=0.340］在TB和BCC中表达差异无统计学意义。CD10、CK20、PHLDA1的多因素Logistic回归分析详见表2。随后，按照多因素Logistic回归的显著性由小到大排序，在免疫组化标记组合中按顺序逐一纳入标记，并设置不同的判定条件。最终，间质CD10、肿瘤基底样细胞巢团PHLDA1、CK20中任意两个标记阳性的约登指数为0.74，具备最好的诊断性能。CD10、CK20、PHLDA1的不同免疫组化组合对诊断效能的影响见表3。
3　讨论
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BCC起源于皮肤表皮及其附属器的多能表皮干细胞，具有多种组织学分型和多向分化的特点［2］。TB是一种向毛囊分化的良性肿瘤，具有双向分化的特点，即肿瘤既包含毛囊生发上皮成分又包含特定的毛源性间叶组织，这种上皮-间叶组织关系与早期毛囊胚胎发育过程相似，可形成特征性的乳头间质体样的组织结构［4-5］。当组织病理诊断难以区分BCC与TB时，应用免疫组化标记鉴定肿瘤中基底样细胞及间质组织的来源，有助于二者的鉴别诊断。
3.1　BCC与TB的免疫组化标记特征
CD10是一种分子量为100 kD的细胞膜金属蛋白酶，生长早期的毛母质细胞与生长晚期的内毛根鞘、毛周的间叶组织均表达CD10［6-8］。与既往研究结果一致［3，7-8］，CD10在癌巢周边细胞阳性更加支持BCC的诊断，间质CD10阳性更加支持TB的诊断。值得注意的是，本研究观察到部分BCC病例间质散在CD10阳性，这可能与局灶的反应性纤维化间质有关［3］。
CK20是一种低分子量角蛋白，特异性表达于正常表皮基底层和毛囊上皮中的Merkel细胞［10］。组织学研究表明，良性毛源性肿瘤因保留正常组织结构，其瘤巢内可见Merkel细胞存在，而BCC则普遍缺乏此类细胞。与既往研究结果类似［3，9，11-12］，本组病例中CK20在单因素分析中具有统计学意义。值得注意的是，BCC样本中毳毛毛囊残留的Merkel细胞可能造成假阳性判读，该现象在既往文献中已有报道，需引起警惕［13］。
CD34是一种高度糖基化的单链跨膜蛋白，主要表达于毛囊隆突以下、毛母质以上的外毛根鞘上皮细胞以及毛周的间叶组织［14-15］。既往有文献报道CD34在BCC瘤周间质呈阴性染色而在TB瘤周间质呈阳性染色［16］，但在本组病例以及既往的其他研究中CD34在两种肿瘤周围间质阳性细胞比例相当［9，17-18］。我们猜测，CD34作为毛囊干细胞标记物，其相对原始的生物学特性使其在BCC以及TB的基底样细胞巢团均呈现阴性表达［15］。
PHLDA1（pleckstrin homology-like domain，family A，member 1）是一种富含丙氨酸和谷氨酰胺的蛋白质，可表达于毛囊隆突部最外层、次级毛芽、内毛根鞘下段；同时，PHLDA1在黑素细胞以及外泌汗腺的导管部亦有分布［19-20］。本研究显示，肿瘤细胞巢团PHLDA1阳性表达对TB具有诊断提示价值，该结果与既往研究基本一致［11-12，21］。既往文献报道，PHLDA1在BCC中可呈局灶阳性表达，伴有毛囊分化的漏斗部囊性BCC以及微结节型BCC都可能出现PHLDA1阳性［12，21］，但在本组病例中并未观测到上述现象。需要特别指出的是，瘤巢中散在分布的树突状黑素细胞以及溃疡周围的表皮均可表达PHLDA1，这对免疫组化判读存在干扰［11，21］，因此需结合肿瘤形态学特征进行综合判断.
AR是一种核内配体依赖型的类固醇转录因子，主要分布在毛囊皮脂腺单位的上皮及毛囊间表皮［22］。在皮肤肿瘤中，AR的表达常提示皮脂腺/汗腺分化特征，而成熟的毛囊肿瘤少见表达［4］。文献显示BCC的AR阳性率高于TB［12-13，23-24］。但在本组研究中，AR的表达差异没有统计学意义。这可能是由于BCC中AR阳性细胞比例本身相对较低［23］，而且其染色强度会受肿瘤结构影响［13］。
Ber-EP4是一种可识别人类上皮细胞表面糖蛋白肽的单克隆抗体，在多种上皮细胞和癌细胞中均有表达［25］。在正常皮肤组织中，Ber-EP4在汗腺的分泌部、生长期早期毛发下段以及退行期毛囊生发细胞下段阳性，但在毛囊的其他部位、表皮以及汗腺均呈阴性，因而常用于BCC与原鳞位癌、汗孔瘤、脂溢性角化症的鉴别诊断［26］。个别研究报道Ber-EP4在BCC阳性细胞比例和阳性病例均高于TB［9］，但同既往多数报道一致［26-28］，本研究认为Ber-EP4对于BCC和TB的鉴别诊断作用有限。
Ki-67作为细胞增殖标志物，既往研究显示BCC的阳性计数显著高于TB，且BCC中阳性细胞呈弥漫分布，而TB多局限于瘤巢周边［3，24，29］，但本组病例中二者Ki-67阳性计数及分布模式均无显著差异，且部分生长活跃的TB呈现较高增殖活性。文献报道BCC的Ki-67阳性计数存在亚型差异，侵袭性亚型显著高于惰性亚型［30-33］。本组病例中BCC的Ki-67均值较低（68.57%为结节型亚型），这与结节性BCC的低增殖特性相符。基于此，本研究认为Ki-67在两者的鉴别诊断中参考价值有限。
3.2　多因素分析及免疫组化标记组合
基于单因素χ2分析的结果，将间质CD10阳性、基底样细胞巢团CK20以及PHLDA1阳性的指标纳入多因素Logistic回归分析。最终，本研究发现CD10以及PHLDA1在两种肿瘤中的表达水平差异具有统计学意义，相反，CK20的表达水平则没有统计学意义。这可能与本组病例中CK20的阳性率相对较低有关。有文献报道，CK20阳性细胞数量本身有限，体积较小的活检标本往往需要连续切片技术提高阳性细胞的识别率［13］，因此CK20的检验效能有赖于更大样本量的研究结果。
合理设置免疫组化标记组合可以提升诊断实验的效能，因此进一步评估了联用CK20、PHLDA1、CD10的效果。本研究发现，在免疫组化组合中，当间质CD10阳性、基底样细胞巢团CK20以及PHLDA1阳性这3个标记中的任意2个呈阳性时，能够实现最优的诊断效果。
综上所述，本研究发现了免疫组织化学染色标记在TB与BCC的鉴别诊断中的应用价值。本研究并未发现具有完美特异性的标记，这与既往研究结果相似，一方面这是由于本研究领域内既往研究样本量均相对较小，另一方面，这反映了TB与BCC是起自同一细胞系分化过程中不同时间节点的肿瘤，因而两者在蛋白表达上具有一定重合［9］。此外，不同TB以及BCC组织学亚型免疫组化表达可能有差异，因而相关结论还有待进一步的验证。我们认为CD10和PHLDA1在TB以及BCC的鉴别诊断中具有相对可靠的应用价值，尽管如此，仍然有部分病例不能单独通过进行免疫组化标记进行确诊，因而临床医师需结合临床特点、组织病理学形态特征，合理运用和解读免疫组织化学标记，才能更好地鉴别这两种疾病。

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2025年第47卷第12期
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doi: 10.16016/j.2097-0927.202311128
  • 接收时间：2024-11-27
  • 首发时间：2026-10-28
  • 出版时间：2025-06-30
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  • 收稿日期：2024-11-27
  • 修回日期：2025-02-13
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    1四川大学华西医院皮肤科，四川 成都

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