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摘要: 原发灶不明肿瘤（cancer of unknown primary，CUP）是一种细胞异质性显著并且具有高度恶性表型的转移性疾病，并且很难通过常规的检查手段被检测出其原发灶。一些新的检测手段，如基因表达谱检测、肿瘤表观遗传学检测、液体活检等手段逐渐应用于CUP原发灶的确定上，基于此出现的器官特异性治疗、靶向治疗、免疫治疗等也均有较大的应用前景，其有望提高CUP患者诊断的精确性和特异性，延长患者生存时间，改善患者生存质量。本文针对CUP的前沿诊断技术和治疗选择及其进展进行综述。Abstract: Cancer of unknown primary (CUP) is a metastatic disease with significant cell heterogeneity and a highly malignant phenotype. It is difficult to detect the primary affected sites of CUP using routine medical examinations. Gene expression profiling, tumor epigenetics, and liquid biopsy are gradually being employed to identify the primary sites of CUP. Organ-specific therapy, targeted therapy, and immunotherapy based on these assays may have clinical applicability. They are expected to improve diagnostic accuracy and specificity in patients with CUP and increase their life expectancy. This article reviews the progress and prospect of advanced diagnostic techniques and treatment options for CUP.
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表 1 CUP患者常规检查项目
临床病理资料 实验室检查（所有患者） 实验室检查（特定患者） 组织学证实的转移性癌 全血细胞计数 乳腺X线摄影（适用于所有女性） 详细病史 生化检查 乳腺MRI 全面体格检查（包括盆腔和直肠） 尿液检查 睾丸超声检查 组织病理学检查和特异性免疫组织化学研究 大便潜血检测 PET或CT扫描 胸片 血清甲胎蛋白和β-人绒毛膜促性腺激素浓度 胸部、腹部和骨盆CT扫描 血清前列腺特异性抗原浓度（所有男性） 内镜检查 
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表 2 IHC诊断流程
标志物 诊断 1）确定肿瘤类型 AE1/AE3 癌 LCA 淋巴瘤 S100， HMB-45 黑色素瘤 S100， vimentin 肉瘤 2）确定亚型 CK7/CK20， PSA 腺癌 PLAP、 OCT4、 HCG 生殖细胞肿瘤 chromogranin、 synaptophysin、 CD56 神经内分泌癌 CK5/CK6， P63 鳞癌 3）确定原发部位 PSA， PAP 前列腺癌 TTF1 肺癌 CDX2， CK20 结肠癌 CDX2 (intestinal epithelium)、 CK20、 CK7 小肠癌 ER、CA-125、 mesothelin、 WT1 卵巢癌 mammaglobulin， ER 乳腺癌 AE1/AE3:泛癌角蛋白；LCA:白细胞共同抗原； vimentin:波形蛋白； PSA:前列腺特异性抗原； PLAP:胎盘碱性磷酸酶； OCT4:八聚体结合转录因子4； HCG:人绒毛膜促性腺激素； chromogranin:嗜铬蛋白；synaptophysin:突触素； PAP:前列腺酸性磷酸酶； TTF1:甲状腺转录因子-1； CDX2:尾型同源盒基因转录因子-2； mesothelin:间皮素； ER:雌激素受体； HMB-45：黑色素瘤相关抗原； CA-125：糖类抗原125
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表 3 目前正在开展的CUP免疫治疗相关临床试验
临床试验编号 试验分期（期） 试验状态 研究药物/方案 主要终点 NCT05241132 Ⅱ 招募中 替雷利珠联合化疗（铂+紫杉醇） 完全缓解、部分缓解 NCT05024968 Ⅱ 招募中 信迪利单抗 客观缓解率、安全性 NCT04131621 Ⅱ 招募中 纳武单抗联合伊匹单抗 无进展生存期、安全性 NCT03752333 Ⅱ 招募中 帕博利珠单抗 无进展生存期、总生存期 NCT03391973 Ⅱ 招募中 帕博利珠单抗 客观缓解率、治疗相关不良事件 NCT03053466 Ⅰ 招募中 APL-501 治疗相关不良事件、客观缓解率
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