Hansel D E, DeMarzo A M, Platz E A, Jadallah S, Hicks J, Epstein J I, Partin A W, Netto G J
Department of Pathology, The Johns Hopkins University, Baltimore, Maryland 21231, USA.
J Urol. 2007 May;177(5):1736-40. doi: 10.1016/j.juro.2007.01.013.
Early prostate cancer antigen is a nuclear matrix protein that was recently shown to be expressed in prostate adenocarcinoma and adjacent benign tissue. Previous studies have demonstrated early prostate cancer antigen expression in benign prostate tissue up to 5 years before a diagnosis of prostate carcinoma, suggesting that early prostate cancer antigen could be used as a potential predictive marker.
We evaluated early prostate cancer antigen expression by immunohistochemistry using a polyclonal antibody (Onconome Inc., Seattle, Washington) on benign biopsies from 98 patients. Biopsies were obtained from 4 groups that included 39 patients with first time negative biopsy (group 1), 24 patients with persistently negative biopsies (group 2), 8 patients with initially negative biopsies who were subsequently diagnosed with prostate carcinoma (group 3) and negative biopsies obtained from 27 cases where other concurrent biopsies contained prostate carcinoma (group 4). Early prostate cancer antigen staining was assessed by 2 of the authors who were blind to the group of the examined sections. Staining intensity (range 0 to 3) and extent (range 1 to 3) scores were assigned. The presence of intensity 3 staining in any of the blocks of a biopsy specimen was considered as positive for early prostate cancer antigen for the primary outcome in the statistical analysis. In addition, as secondary outcomes we evaluated the data using the proportion of blocks with intensity 3 early prostate cancer antigen staining, the mean of the product of staining intensity and staining extent of all blocks within a biopsy, and the mean of the product of intensity 3 staining and extent.
Primary outcome analysis revealed the proportion of early prostate cancer antigen positivity to be highest in group 3 (6 of 8, 75%) and lowest in group 2 (7 of 24, 29%, p=0.04 for differences among groups). A relatively higher than expected proportion of early prostate cancer antigen positivity was present in group 1 (23 of 39, 59%). Early prostate cancer antigen was negative in 41% of group 4 who were known to harbor prostate carcinoma. The proportion of early prostate cancer antigen positivity was statistically significantly lower in group 2 than in each of the other groups when compared pairwise. A lower proportion of early prostate cancer antigen positivity was encountered in older archival tissue blocks (p<0.0001) pointing to a potential confounding factor. Corrected for block age, group 3 was the only group to remain statistically significantly different in early prostate cancer antigen positivity compared to the reference group 2. Similar findings were obtained when adjustments for patient age were made and when analysis was based on secondary outcome measurements.
Our study showed a higher proportion of early prostate cancer antigen expression in initial negative prostate biopsy of patients who were diagnosed with prostate carcinoma on subsequent followup biopsies. We found a relatively high proportion of early prostate cancer antigen positivity (59%) in the group with first time negative biopsies and a potential 41% rate of false-negative early prostate cancer antigen staining in benign biopsies from cases with documented prostate carcinoma on concurrent cores. The lower early prostate cancer antigen positivity in cases with older blocks raises the question of a confounding effect of block age. Additional studies on the antigenic properties of early prostate cancer antigen in archival material are required to further delineate the usefulness of early prostate cancer antigen immunostaining on biopsy material.
早期前列腺癌抗原是一种核基质蛋白，最近研究表明其在前列腺腺癌及相邻良性组织中表达。既往研究显示，在前列腺癌确诊前长达5年的时间里，良性前列腺组织中就有早期前列腺癌抗原表达，提示早期前列腺癌抗原可作为一种潜在的预测标志物。
我们使用一种多克隆抗体（华盛顿州西雅图市Onconome公司），通过免疫组织化学方法评估了98例患者良性活检组织中早期前列腺癌抗原的表达情况。活检组织取自4组患者，包括39例首次活检结果为阴性的患者（第1组）、24例活检结果持续为阴性的患者（第2组）、8例最初活检结果为阴性但随后被诊断为前列腺癌的患者（第3组），以及从27例其他同期活检组织中发现前列腺癌的病例所获取的阴性活检组织（第4组）。由2名对所检查切片分组情况不知情的作者对早期前列腺癌抗原染色进行评估。分别给出染色强度（范围0至3）和范围（范围1至3）评分。在统计分析中，将活检标本任何一个组织块中出现强度为3的染色视为早期前列腺癌抗原阳性的主要结果。此外，作为次要结果，我们使用强度为3的早期前列腺癌抗原染色组织块的比例、活检组织内所有组织块染色强度与染色范围乘积的均值，以及强度为3的染色与范围乘积的均值来评估数据。
主要结果分析显示，第3组早期前列腺癌抗原阳性比例最高（8例中的6例，75%），第2组最低（24例中的7例，29%，组间差异p = 0.04）。第1组早期前列腺癌抗原阳性比例相对高于预期（39例中的23例，59%）。已知患有前列腺癌的第4组中，41%的患者早期前列腺癌抗原为阴性。两两比较时，第2组早期前列腺癌抗原阳性比例在统计学上显著低于其他各组。在较陈旧的存档组织块中，早期前列腺癌抗原阳性比例较低（p < 0.0001），提示存在潜在的混杂因素。校正组织块年龄后，与参照组第2组相比，第3组是唯一在早期前列腺癌抗原阳性方面仍存在统计学显著差异的组。在对患者年龄进行调整以及基于次要结果测量进行分析时，也得到了类似的结果。
我们的研究表明，在随后随访活检中被诊断为前列腺癌的患者，其最初前列腺活检为阴性时，早期前列腺癌抗原表达比例较高。我们发现首次活检结果为阴性的组中，早期前列腺癌抗原阳性比例相对较高（59%），而在同期活检证实患有前列腺癌的病例的良性活检组织中，早期前列腺癌抗原染色存在潜在41%的假阴性率。较陈旧组织块病例中早期前列腺癌抗原阳性率较低，这引发了关于组织块年龄混杂效应的问题。需要对存档材料中早期前列腺癌抗原的抗原特性进行更多研究，以进一步明确早期前列腺癌抗原免疫染色在活检材料上的实用性。
