Karolina S. Jabbar, Liisa Arike, and Gunnar C. Hansson, University of Gothenburg; Karolina S. Jabbar and Riadh Sadik, Sahlgrenska University Hospital, Gothenburg, Sweden; and Caroline S. Verbeke, University of Oslo, Oslo, Norway.
J Clin Oncol. 2018 Feb 1;36(4):367-375. doi: 10.1200/JCO.2017.73.7288. Epub 2017 Nov 22.
Purpose Pancreatic cystic lesions are common incidental findings on imaging, but up to half may be forerunners of pancreatic cancer. Therefore, accurate differential diagnosis is crucial for correct patient management. Unfortunately, currently available diagnostic methods cannot robustly identify premalignant and malignant pancreatic cystic lesions. Methods Cyst fluid samples obtained by routine endoscopic ultrasound-guided aspiration were used for the analyses. In a cohort of 24 patients, eight biomarker candidates for malignant potential and high-grade dysplasia/cancer were identified by an explorative proteomic approach. Subsequently, a quantitative analysis, using 30 heavy-labeled peptides from the biomarkers and parallel reaction monitoring mass spectrometry, was devised, tested in a training cohort of 80, and prospectively evaluated in a validation cohort of 68 patients. End points were surgical pathology diagnosis/clinical follow-up. Diagnostic assessments were blinded to mass spectrometry results. Results The optimal set of markers for detecting malignant potential was a panel of peptides from mucin-5AC and mucin-2, which could discriminate premalignant/malignant lesions from benign with an accuracy of 97% (95% CI, 89% to 99%) in the validation cohort. This result compared favorably with the accuracy of standard analyses: cyst fluid carcinoembryonic antigen (61%; 95% CI, 46% to 74%; P < .001) and cytology (84%; 95% CI, 71% to 92%; P = .02). A combination of proteins mucin-5AC and prostate stem-cell antigen could identify high-grade dysplasia/cancer with an accuracy of 96% (95% CI, 90% to 99%), and detected 95% of malignant/severely dysplastic lesions, compared with 35% and 50% for carcinoembryonic antigen and cytology ( P < .001 and P = .003, respectively). Conclusion Targeted mass spectrometry analysis of just three cyst fluid biomarkers provides highly accurate identification and assessment of cystic precursors to pancreatic adenocarcinoma. Additional studies should determine whether the method can facilitate timely cancer diagnosis, successful intervention, and prevention.
目的
胰腺囊性病变在影像学检查中较为常见，但其中一半可能是胰腺癌的前驱病变。因此，准确的鉴别诊断对于正确的患者管理至关重要。不幸的是，目前可用的诊断方法无法可靠地识别癌前和恶性胰腺囊性病变。
方法
使用常规内镜超声引导下抽吸获得的囊液样本进行分析。在 24 名患者的队列中，通过探索性蛋白质组学方法鉴定了 8 种恶性潜能和高级别异型增生/癌症的生物标志物候选物。随后，设计了一种定量分析方法，使用来自 8 个生物标志物的 30 个重标记肽和并行反应监测质谱法，并在 80 名训练队列中进行了测试，并在 68 名验证队列中进行了前瞻性评估。终点是手术病理诊断/临床随访。质谱结果对诊断评估进行了盲法处理。
结果
用于检测恶性潜能的最佳标志物组合是粘蛋白-5AC 和粘蛋白-2 的一组肽，在验证队列中，该组合能够以 97%的准确率（95%CI，89%至 99%）区分癌前/恶性病变与良性病变。这一结果优于标准分析的准确性：囊液癌胚抗原（61%；95%CI，46%至 74%；P<0.001）和细胞学（84%；95%CI，71%至 92%；P=0.02）。粘蛋白-5AC 和前列腺干细胞抗原的组合可以以 96%的准确率（95%CI，90%至 99%）识别高级别异型增生/癌症，并检测到 95%的恶性/重度异型增生病变，而癌胚抗原和细胞学的检测率分别为 35%和 50%（P<0.001 和 P=0.003）。
结论
仅对三种囊液生物标志物进行靶向质谱分析即可提供高度准确的胰腺腺癌囊性前体的识别和评估。进一步的研究应确定该方法是否可以促进及时的癌症诊断、成功的干预和预防。
