Sasaki Takahiro, Yuzawa Sayaka, Tanabe Hiroki, Ono Yusuke, Takahashi Keitaro, Ando Katsuyoshi, Ueno Nobuhiro, Kashima Shin, Moriichi Kentaro, Tanino Mishie, Mizukami Yusuke, Fujiya Mikihiro
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
Department of Diagnostic Pathology, Asahikawa Medical University Hospital, Asahikawa Medical University, Asahikawa, Japan.
Cancer Rep (Hoboken). 2025 Sep;8(9):e70338. doi: 10.1002/cnr2.70338.
Cancer of unknown primary (CUP) is a challenging malignancy characterized by metastatic tumors with an unidentified primary site, even after extensive pathological and radiographic evaluation. Recent advancements in gene expression profiling and comprehensive genomic profiling (CGP) using next-generation sequencing (NGS) have enabled the identification of potential tissue origins, thereby facilitating personalized treatment strategies. Although most cases of CUP present as adenocarcinomas or poorly differentiated tumors, the treatment remains largely empirical, with limited success from molecularly tailored therapies. However, advances in tumor DNA sequencing and targeted therapies hold great promise for enhancing patient outcomes.
A 72-year-old woman presented with epigastric pain and was diagnosed with a duodenal tumor and gastric ulceration via esophagogastroduodenoscopy. A histological evaluation revealed poorly differentiated adenocarcinoma in the duodenum, and the immunohistochemistry findings supported a pancreatobiliary origin. An endoscopic ultrasound-guided biopsy confirmed poorly differentiated adenocarcinoma in the duodenum, while a subsequent gastric examination revealed well-differentiated adenocarcinoma, suggesting dual malignancies. The patient underwent neoadjuvant chemotherapy, followed by pancreatoduodenectomy with distal gastrectomy. The CUP was staged as poorly differentiated adenocarcinoma (pStage IVB), while the gastric cancer was staged as well-differentiated adenocarcinoma (pStage IA). Despite adjuvant TS-1 therapy, lymph node metastasis near the superior mesenteric artery continued to progress. CGP revealed high microsatellite instability and a high tumor mutational burden, along with multiple actionable genetic mutations. Pembrolizumab monotherapy was initiated, leading to complete remission, with no recurrence observed at 1 year after treatment cessation. Genetic and immunohistochemical investigations have identified microsatellite instability in both CUP and gastric cancer tissues, suggesting a shared origin. Targeted gene sequencing confirmed common genetic variations, ultimately revealing that the CUP originated from gastric cancer cells.
This case highlights the critical role of CGP in the diagnosis and treatment of CUP. The use of advanced molecular techniques, including NGS, revealed the gastric origin of CUP and identified actionable biomarkers, leading to successful treatment with immune checkpoint inhibitors.
原发灶不明的癌症（CUP）是一种具有挑战性的恶性肿瘤，其特征是即使经过广泛的病理和影像学评估，转移瘤的原发部位仍不明确。使用下一代测序（NGS）的基因表达谱分析和综合基因组分析（CGP）的最新进展使得能够识别潜在的组织起源，从而促进个性化治疗策略。尽管大多数CUP病例表现为腺癌或低分化肿瘤，但治疗仍主要是经验性的，分子靶向治疗的成功率有限。然而，肿瘤DNA测序和靶向治疗的进展为改善患者预后带来了巨大希望。
一名72岁女性因上腹部疼痛就诊，经食管胃十二指肠镜检查诊断为十二指肠肿瘤和胃溃疡。组织学评估显示十二指肠为低分化腺癌，免疫组化结果支持胰胆管起源。内镜超声引导下活检证实十二指肠为低分化腺癌，随后的胃部检查显示为高分化腺癌，提示双重恶性肿瘤。患者接受了新辅助化疗，随后行胰十二指肠切除术加远端胃切除术。CUP分期为低分化腺癌（pStage IVB），胃癌分期为高分化腺癌（pStage IA）。尽管接受了辅助替吉奥治疗，肠系膜上动脉附近的淋巴结转移仍持续进展。CGP显示高微卫星不稳定性和高肿瘤突变负荷，以及多个可操作的基因突变。开始使用帕博利珠单抗单药治疗，导致完全缓解，停药1年后未观察到复发。基因和免疫组化研究在CUP和胃癌组织中均发现了微卫星不稳定性，提示共同起源。靶向基因测序证实了常见的基因变异，最终揭示CUP起源于胃癌细胞。
本病例突出了CGP在CUP诊断和治疗中的关键作用。使用包括NGS在内的先进分子技术揭示了CUP的胃起源，并识别出可操作的生物标志物，从而成功地使用免疫检查点抑制剂进行治疗。
