Case presentation

A 63-year-old woman who was a former smoker with a past medical history of hypertension and gastroesophageal reflux disease initially presented with upper abdominal pain. Her family history was notable for breast cancer in her mother, lung cancer in her father, and renal cell carcinoma in her sister. An ultrasound showed a heterogenous mass in the left lobe of the liver measuring 8.7 × 7.0 × 5.1 cm that was abutting the common bile duct and concerning for a neoplasm (Figure 1A). On laboratory testing, her alpha fetoprotein (AFP) was elevated (15.7 ng/mL), carbohydrate antigen 19-9 (CA 19-9) was normal (<15 U/ml), and carcinoembryonic antigen (CEA) was slightly elevated (0.6 ng/ml). She underwent an ultrasound-guided biopsy that demonstrated cytokeratin 7 (CK7)-positive, poorly differentiated adenocarcinoma with nonmucinous gland formation and papillary architecture within sclerotic stroma. Given that the biopsy was positive for CK7 with negative hepatocellular (hepatocyte-specific antigen, arginase, glypican), CDX2, TTF1, and synaptophysin markers, the mass was diagnosed as an intrahepatic cholangiocarcinoma (iCCA). A computed tomography (CT) scan of the chest, abdomen, and pelvis did not show any extrahepatic metastatic disease but did show a central left hepatic lobe mass in segment 4a/4b that measured 7.7 × 6.7 cm with calcifications suggestive of iCCA (Figure 1B,C). A CT scan also revealed potential tumor thrombus within the middle hepatic vein and distal left portal vein branches, extrahepatic (periportal, gastrohepatic, peripancreatic, portacaval) lymphadenopathy, left intrahepatic biliary ductal dilation, and common bile duct dilation.

The patient was started on gemcitabine, cisplatin, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). After 3 months of chemotherapy, the patient's AFP increased to 43.8 ng/ml and her CA 19-9 increased to 21.4 U/ml. On repeat CT scan, the size of the tumor was stable, but there was suspected intraductal extension toward the central inferior aspect of segment 4b. Given her suboptimal response to chemotherapy, radiation oncology was consulted. Approximately 4 months after starting chemotherapy, the patient underwent yttrium-90 radioembolization (Y90 RE) to the left hepatic hemiliver and subsequently was resumed on a gemcitabine, cisplatin, and nab-paclitaxel regimen (Figure 2A). A CT scan 5 months after starting treatment and 1 month after Y90 RE demonstrated a stable left hepatic lobe mass with interval necrosis. However, this effect was mostly seen in the tumor in the left lobe of the liver, whereas there was still some residual arterial enhancement along the right side of the mass because where the tumor extended into the right lobe was not treated given concern of toxicity to the remaining liver. After nine cycles of chemotherapy and the Y90 RE treatment, re-staging CT scans did not demonstrate any metastatic disease, and the tumor in the left lobe of the liver had a seemingly good response to the Y90 RE (Figure 2B). In addition, the periportal, portacaval, and gastrohepatic lymphadenopathy had decreased in size, and there was no new or progressive adenopathy.

At this point, the patient was taken to the operating room, and an extended left hepatectomy, cholecystectomy, and extensive lymphadenectomy, including skeletonizing of the hilum, left hepatic artery, bile ducts, and common hepatic artery, was performed. On postoperative day 5, the patient was tachycardic, a CT scan showed a large fluid collection in the resection bed, and the patient was brought back to the operating room. A bile leak from a small dehiscence along the left hepatic duct staple line was found and oversewn. The patient underwent endoscopic retrograde cholangiopancreatography postoperatively with placement of a biliary stent and, on cholangiogram, there was no evidence of a continued bile leak. The patient was discharged home on postoperative day 9. Final pathology demonstrated a poorly differentiated cholangiocarcinoma (CCA), small duct type, that had approximately 30% focal necrosis/70% persistent viable tumor with lymphovascular invasion and perineural invasion; carcinoma extended focally to the cauterized resection margin/edge, and there were no metastatic lymph nodes (n = 0 of 3).

Postoperative circulating tumor DNA (ctDNA) levels remained low but slightly positive, and her AFP came down to a normal range. Because of the close resection margin, it was recommended that the patient proceed with chemoradiation to the resection margin with adjuvant capecitabine. After completion of her chemoradiation, her ctDNA level was zero. Five months after completion of her radiation therapy, her ctDNA level was positive. A magnetic resonance image showed new liver lesions in the right lobe concerning for metastatic disease. Given the magnetic resonance imaging findings and positive ctDNA, there was high suspicion of recurrence of a fibroblast growth factor receptor-2 (FGFR2) fusion CCA. She tested positive for an FGFR2–AHCYL1 fusion iCCA and is currently on an FGFR inhibitor (pemigatinib) through a clinical trial.

中文翻译：

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多学科综合治疗肝内胆管癌

案例展示

一名 63 岁女性曾吸烟，有高血压和胃食管反流病病史，最初出现上腹部疼痛。她的家族史值得注意，其中母亲患有乳腺癌，父亲患有肺癌，姐姐患有肾细胞癌。超声检查显示肝左叶有一个大小为 8.7 × 7.0 × 5.1 cm 的异质肿块，毗邻胆总管，疑似肿瘤（图 1A）。实验室检查显示，她的甲胎蛋白 (AFP) 升高 (15.7 ng/mL)，碳水化合物抗原 19-9 (CA 19-9) 正常 (<15 U/ml)，癌胚抗原 (CEA) 轻微升高（ 0.6 纳克/毫升）。她接受了超声引导活检，结果显示细胞角蛋白 7 (CK7) 呈阳性，低分化腺癌，具有非粘液腺形成和硬化基质内的乳头状结构。鉴于活检呈 CK7 阳性，肝细胞（肝细胞特异性抗原、精氨酸酶、磷脂酰肌醇蛋白聚糖）、CDX2、TTF1 和突触素标记物阴性，肿块被诊断为肝内胆管癌 (iCCA)。胸部、腹部和骨盆的计算机断层扫描 (CT) 扫描未显示任何肝外转移性疾病，但确实显示 4a/4b 段中央左肝叶肿块，尺寸为 7.7 × 6.7 cm，钙化提示 iCCA（图 1B） ，C）。CT 扫描还显示肝中静脉和左门静脉远端分支内潜在的肿瘤血栓、肝外（门静脉周围、胃肝、胰周、门腔静脉）淋巴结肿大、左侧肝内胆管扩张、

患者开始服用吉西他滨、顺铂和纳米颗粒白蛋白结合紫杉醇（nab-紫杉醇）。化疗3个月后，患者的AFP升至43.8 ng/ml，CA 19-9升至21.4 U/ml。重复 CT 扫描时，肿瘤大小稳定，但疑似向 4b 段中央下方延伸至导管内。鉴于她对化疗的反应不佳，因此咨询了放射肿瘤科。开始化疗后约 4 个月，患者对左肝半肝进行钇 90 放射栓塞 (Y90 RE)，随后恢复吉西他滨、顺铂和白蛋白结合型紫杉醇治疗方案（图 2A）。开始治疗后 5 个月和 Y90 RE 后 1 个月进行的 CT 扫描显示，左肝叶肿块稳定，伴有间歇性坏死。然而，这种效果主要见于肝左叶的肿瘤，而沿肿块右侧仍有一些残留的动脉增强，因为考虑到对其余部分的毒性，肿瘤延伸到右叶的地方没有得到治疗肝。经过九个周期的化疗和 Y90 RE 治疗后，重新分期 CT 扫描未显示任何转移性疾病，肝左叶肿瘤对 Y90 RE 的反应似乎良好（图 2B）。此外，门静脉周围、门腔静脉和胃肝淋巴结肿大缩小，并且没有新的或进行性淋巴结肿大。而沿肿块右侧仍有一些残留的动脉强化，因为考虑到对剩余肝脏的毒性，肿瘤延伸到右叶的地方没有得到治疗。经过九个周期的化疗和 Y90 RE 治疗后，重新分期 CT 扫描未显示任何转移性疾病，肝左叶肿瘤对 Y90 RE 的反应似乎良好（图 2B）。此外，门静脉周围、门腔静脉和胃肝淋巴结肿大缩小，并且没有新的或进行性淋巴结肿大。而沿肿块右侧仍有一些残留的动脉强化，因为考虑到对剩余肝脏的毒性，肿瘤延伸到右叶的地方没有得到治疗。经过九个周期的化疗和 Y90 RE 治疗后，重新分期 CT 扫描未显示任何转移性疾病，肝左叶肿瘤对 Y90 RE 的反应似乎良好（图 2B）。此外，门静脉周围、门腔静脉和胃肝淋巴结肿大缩小，并且没有新的或进行性淋巴结肿大。肝左叶的肿瘤对 Y90 RE 似乎有良好的反应（图 2B）。此外，门静脉周围、门腔静脉和胃肝淋巴结肿大缩小，并且没有新的或进行性淋巴结肿大。肝左叶的肿瘤对 Y90 RE 似乎有良好的反应（图 2B）。此外，门静脉周围、门腔静脉和胃肝淋巴结肿大缩小，并且没有新的或进行性淋巴结肿大。

此时，患者被送往手术室，进行了扩大的左肝切除术、胆囊切除术和广泛的淋巴结切除术，包括肺门、左肝动脉、胆管和肝总动脉的骨架化。术后第5天，患者出现心动过速，CT扫描显示切除床上有大量积液，患者被带回手术室。发现沿左肝管钉线的小裂口有胆汁泄漏并进行了缝合。患者术后接受内镜逆行胰胆管造影并放置胆管支架，胆管造影未发现持续胆漏的证据。患者于术后第 9 天出院回家。最终病理结果显示为低分化胆管癌 (CCA)，小导管型，约 30% 局灶性坏死/70% 持续存活肿瘤，伴有淋巴管侵犯和神经周围侵犯；癌局部扩展至烧灼切除边缘，并且没有转移淋巴结（n  = 0（共 3））。

术后循环肿瘤 DNA (ctDNA) 水平仍然较低，但呈轻微阳性，AFP 降至正常范围。由于切除边缘较近，建议患者对切除边缘进行放化疗，并辅助卡培他滨。放化疗结束后，她的 ctDNA 水平为零。完成放射治疗五个月后，她的 ctDNA 水平呈阳性。磁共振图像显示右叶出现新的肝脏病变，与转移性疾病有关。鉴于磁共振成像结果和 ctDNA 阳性，高度怀疑成纤维细胞生长因子受体 2 ( FGFR2 ) 融合 CCA 复发。她的FGFR2-AHCYL1融合 iCCA检测呈阳性，目前正在接受治疗FGFR抑制剂（pemigatinib）通过临床试验。