p16 and MIB1 improve the sensitivity and specificity of the diagnosis of high grade squamous intraepithelial lesions: Methodological issues in a re-Tort of 447 biopsies with consensus diagnosis and HPVHCII testing
p16 and MIB1 improve the sensitivity and specificity of the diagnosis of high grade squamous intraepithelial lesions: Methodological issues in a re-Tort of 447 biopsies with consensus diagnosis and HPVHCII testing
复制标题
DOI：
10.1016/j.ygyno.2007.07.064
复制
发表时间：
2007-10-01
影响因子：
4.7
通讯作者：
MacAulay, Calum
中科院分区：
文献类型：
--
作者：
Van Niekerk, Dirk;Guillaud, Martial;MacAulay, Calum
Objective.许多研究者正在研究生物标志物的附加价值，以提高组织病理学的一致性，但很少有人使用相同的方法。我们在这项分析中区分高度鳞状上皮内病变（HGSIL）与低度鳞状上皮内病变（LGSIL）、鳞状上皮内病变和正常的目的是：（1）检查人乳头瘤病毒高危阳性（UPV HR+）的比率，（2）比较和分级每种标记物的基底层、副基底层、中间层和浅层染色，（3）确定标记物的最佳定性阈值;（4）比较p16和MIB 1的一致性;（5）检查单独和联合使用每种标记物的敏感性和特异性。从总共1850名患者中选择了208名患者的活检样本，并在正在进行的光学试验过程中获得了3735份活检样本。每次活检至少进行两次独立的盲态审查。如果两次审查之间存在分歧，则进行第三次审查。对宫颈内和宫颈外样本进行p16和MIB 1染色。文本中描述的分级系统范围为0 - 3，两种标记物和每个活检均按每个细胞层评分。使用Statistica计算频率、灵敏度和特异性。ANOVA用于比较上皮层中的p16和MIB 1染色。最后，对每种标记物单独和联合检测的敏感性和特异性进行了检测。选择来自208例患者的453份标本进行分析，这些患者的最终诊断为正常（n=244）、低级别（LG）（n= 59）和高级别（HG）（n= 144）。453份标本中有447份可用于染色。大部分LG和HG病变为HPV HR阳性。宫颈内样本染色阳性率低于宫颈外样本，且结果与宫颈外样本结果不一致。分层分析显示，随着病变从正常进展到LG再到HG，p16和MIB 1的染色均显著增加。p16的截止值或阈值为0与1-3，而MIB 1的截止值或阈值为0- 1与2-3。使用HPV高危阳性中的p16和MIB I的中间上皮层测量，通过统计学显著的边界（p < 0.05）将正常组织与LGSIL、正常组织与HGSIL以及LGSIL与HGSIL分开。每种标记物对HGSIL与LGSIL和正常诊断的敏感性和特异性相似，为85-90%，当一起使用时，敏感性和特异性均提高了5%（p 16敏感性90%，特异性85%; MIB 1敏感性89%，特异性87%;一起敏感性94%，特异性90%）。研究了几个重要的方法问题。总的来说，p16和MIB 1是帮助病理学家区分HG病变与其他病变的有希望的标志物。宫颈内膜和宫颈外膜的染色并不总是一致的，宫颈外膜在HGSIL的存在下更常染色阳性。每个标记都有帮助，两者都有帮助。总之，这两种标记物都有助于HG病变的确认。(C)2007年由Elsevier Inc.出版
Objective. Many investigators are studying the additional value of biomarkers to improve histopathologic agreement, but few are using the same methodologies. Our objectives in this analysis to differentiate High-grade Squamous Intraepithelial lesions (HGSIL) from Low Grade Squamous Intraepithelial Lesions (LGSIL), atypia, and normal were: (1) to examine the rate of Human Papilloma Virus High-Risk positivity (UPV HR+), (2) to compare and grade the basal, parabasal, intermediate, and superficial layer staining of each marker, (3) to determine the optimal qualitative threshold for markers, (4) to compare p16 and MIB 1 agreement, and (5) to examine the sensitivities and specificities using each markers alone and together.Methods. A sample of biopsies from 208 patients were chosen from a total of 1850 patients and 3735 biopsies obtained during the course of ongoing optical trials. At least two independent blinded reviews were performed for each biopsy. A third review was performed if there was a disagreement between the two reviews. Both endocervical and ectocervical samples were stained for p 16 and MIB 1. A grading system that is delineated in the text ranged from 0 to 3 for both markers and each biopsy was scored by each cell layer. Frequencies, sensitivities, and specificities were calculated using Statistica. An ANOVA was used to compare p16 and MIB 1 staining in the epithelial layers. Finally the sensitivity and specificity of each marker alone and together were examined.Results. 453 specimens from 208 patients whose final diagnoses were normal (n=244), low-grade (LG) (n= 59), and high-grade (HG) (n= 144) were selected for analysis. 447 of 453 specimens were available for staining. Most LG and HG lesions were HPV HR positive. Endocervical samples stained positive less often than ectocervix and often results were discordant from ectocervical results. The analysis by layers showed pronounced increases in staining of both p 16 and MIB 1 as lesions progressed from normal to LG to HG. The cutoff or threshold for p 16 was 0 versus 1-3 while for MIB 1 it was 0- 1 versus 2-3. Using the intermediate epithelial layer measurement of both p16 and MIB I in HPV High-Risk Positive separated the normal tissue from LGSIL, normal from HGSIL, and LGSIL from HGSIL by a statistically significant margin (p < 0.05). Each marker had sensitivities and specificities for the diagnosis of HGSIL versus LGSIL and normal of similar to 85-90% and this improved by 5% for both sensitivity and specificity when used together (p 16 sensitivity 90%, specificity 85%; MIB 1 sensitivity 89%, specificity 87%; together sensitivity 94%, specificity 90%).Conclusion. Several important methodological issues have been studied. Overall, p16 and MIB 1 are promising markers to help pathologists differentiate HG lesions from all else. The staining of the endocervix and the ectocervix do not always agree, and the ectocervix more often stains positive with the presence of HGSIL. Each marker is helpful and both are helpful together. In conclusion, both markers are useful for the confirmation of HG lesions. (C) 2007 Published by Elsevier Inc.