Lotan Tamara L, Carvalho Filipe Lf, Peskoe Sarah B, Hicks Jessica L, Good Jennifer, Fedor Helen, Humphreys Elizabeth, Han Misop, Platz Elizabeth A, Squire Jeremy A, De Marzo Angelo M, Berman David M
Department of Pathology, Johns Hopkins University School of Medicine.
Department of Oncology, Johns Hopkins University School of Medicine.
Mod Pathol. 2015 Jan;28(1):128-137. doi: 10.1038/modpathol.2014.85. Epub 2014 Jul 4.
When distinguishing between indolent and potentially harmful prostate cancers, the Gleason score is the most important variable, but may be inaccurate in biopsies due to tumor under-sampling. This study investigated whether a molecular feature, PTEN protein loss, could help identify which Gleason score 6 tumors on biopsy are likely to be upgraded at radical prostatectomy. Seventy one patients with Gleason score 6 tumors on biopsy upgraded to Gleason score 7 or higher at prostatectomy (cases) were compared with 103 patients with Gleason score 6 on both biopsy and prostatectomy (controls). A validated immunohistochemical assay for PTEN was performed, followed by fluorescence in situ hybridization (FISH) to detect PTEN gene deletion in a subset. PTEN protein loss and clinical-pathologic variables were assessed by logistic regression. Upgraded patients were older than controls (61.8 vs 59.3 years), had higher pre-operative PSA levels (6.5 vs 5.3 ng/ml) and a higher fraction of involved cores (0.42 vs 0.36). PTEN loss by immunohistochemistry was found in 18% (13/71) of upgraded cases compared with 7% (7/103) of controls (P=0.02). Comparison between PTEN immunohistochemistry and PTEN FISH showed the assays were highly concordant, with 97% (65/67) of evaluated biopsies with intact PTEN protein lacking PTEN gene deletion, and 81% (13/16) of the biopsies with PTEN protein loss showing homozygous PTEN gene deletion. Tumors with PTEN protein loss were more likely to be upgraded at radical prostatectomy than those without loss, even after adjusting for age, preoperative PSA, clinical stage and race (odds ratio=3.04 (1.08-8.55; P=0.035)). PTEN loss in Gleason score 6 biopsies identifies a subset of prostate tumors at increased risk of upgrading at radical prostatectomy. These data provide evidence that a genetic event can improve Gleason score accuracy and highlight a path toward the clinical use of molecular markers to augment pathologic grading.
在区分惰性和潜在有害的前列腺癌时， Gleason评分是最重要的变量，但由于肿瘤采样不足，活检时可能不准确。本研究调查了一种分子特征——PTEN蛋白缺失，是否有助于识别活检时Gleason评分为6分的肿瘤在根治性前列腺切除术中可能被升级的情况。将71例活检时Gleason评分为6分但在前列腺切除术中升级为Gleason评分7分或更高的患者（病例组）与103例活检和前列腺切除术时Gleason评分均为6分的患者（对照组）进行比较。对PTEN进行了验证的免疫组织化学检测，随后对一部分患者进行荧光原位杂交（FISH）以检测PTEN基因缺失。通过逻辑回归评估PTEN蛋白缺失和临床病理变量。升级患者比对照组年龄更大（61.8岁对59.3岁），术前PSA水平更高（6.5对5.3 ng/ml），且受累核心的比例更高（0.42对0.36）。免疫组织化学检测发现，升级病例中有18%（13/71）存在PTEN缺失，而对照组为7%（7/103）（P=0.02）。PTEN免疫组织化学与PTEN FISH的比较显示，两种检测方法高度一致，97%（65/67）PTEN蛋白完整的活检样本缺乏PTEN基因缺失，81%（13/16）PTEN蛋白缺失的活检样本显示PTEN基因纯合缺失。即使在调整年龄、术前PSA、临床分期和种族后，PTEN蛋白缺失的肿瘤在根治性前列腺切除术中比无缺失的肿瘤更有可能被升级（优势比=3.04（1.08 - 8.55；P=0.035））。Gleason评分为6分的活检样本中PTEN缺失可识别出根治性前列腺切除术中升级风险增加的一部分前列腺肿瘤。这些数据提供了证据，表明一个基因事件可以提高Gleason评分的准确性，并突出了一条临床应用分子标记物来加强病理分级的途径。
