EGFR突变型肺绒毛膜癌合并腺癌

SCI

2 September 2022

EGFR-mutated pulmonary choriocarcinoma combined with adenocarcinoma

（Journal of Thoracic Oncology, IF: 20.121）

• Shigematsu Y, Nakano K, Uchibori K, Inamura K. EGFR-mutated pulmonary choriocarcinoma combined with adenocarcinoma. J Thorac Oncol 2022. DOI: 10.1016/j.jtho.2022.07.1146.

• Corresponding author: Kentaro Inamura, MD, PhD，Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research，3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan，Tel: +81-3-3570-0111 (ext. 5604); Fax: +81-3-3570-0558，E-mail: kentaro.inamura@jfcr.or.jp

A 78-year-old woman with no history of smoking presented to our hospital with complaints of wet cough and exertional dyspnea that had worsened progressively over 1 week.  Physical examination revealed reduced air entry into the right side of the chest.  Imaging by computed tomography revealed an 8.6 cm-sized mass in the right middle-to-lower lobes and multiple nodules in the bilateral lobes of the lung (Fig. 1).  Subsequently, multiple masses in the liver, vertebrae, and uterus were detected.  The patient could not undergo a pathological examination due to poor general condition and died 11 days after presentation.  Autopsy revealed the largest tumor mass, which occupied the right middle-to-lower lobes of the lung, to have “black” and “white” components, and diffuse alveolar injury was identified as the direct cause of death.  Pathological examination further revealed that the “black” and “white” areas represented choriocarcinoma and adenocarcinoma, respectively (Fig. 2). Microscopically, the choriocarcinoma component was composed of mononucleated and multinucleated trophoblastic cells and exhibited marked hemorrhage, which is characteristic of choriocarcinoma and caused the “black” macroscopic appearance.  Immunostaining revealed that this tumor component was positive for germ cell markers spalt like transcription factor 4 (SALL4) and human chorionic gonadotropin (hCG) but negative for pneumocyte markers thyroid transcription factor 1 (TTF-1; also known as NKX2-1) and Napsin A.  In contrast, the adenocarcinoma component of the tumor exhibited papillary morphology and immunostained positive for TTF-1 and Napsin A but not for SALL4 or hCG .  The “black” choriocarcinoma had metastasized throughout the body, resulting in the formation of malignant foci in the bilateral lungs, liver, vertebrae, and uterus, whereas the “white” adenocarcinoma was localized within the lung and mediastinal lymph node.  The spatial localization of the two components with distinct “black” and “white” phenotypes raised the question of whether the tumor was a collision carcinoma originating from different clones or a single carcinoma originating from an identical clone.

一位78岁的女性患者，无吸烟史，以湿咳和劳力性呼吸困难逐渐加重超过1周为主诉来我院就诊。体格检查显示胸腔右侧进气减少。CT示右肺中下叶一8.6 cm大小肿块，双肺多发结节(图1)。随后在肝脏、椎骨、子宫发现多发肿物。患者因全身状况不佳无法进行病理检查，于就诊11天后死亡。尸检发现最大肿瘤位于右肺中下叶，有“黑”和“白”成分，弥漫性肺泡损伤被确定为死亡的直接原因。病理检查进一步发现，“黑色”和“白色”区域分别为绒毛膜癌和腺癌(图2)。镜下，绒毛膜癌成分由单核和多核滋养细胞组成，并伴有明显出血，这是绒毛膜癌的特征，导致肉眼呈现“黑色”。免疫染色显示，该肿瘤成分生殖细胞标记物SALL4和hCG阳性，而肺细胞标记物TTF-1（也称为NKX2-1）和Napsin A阴性。与此相反，肿瘤的腺癌成分呈乳头状形态，TTF-1和Napsin A免疫染色呈阳性，而不是SALL4和hCG。“黑色”绒毛膜癌已全身转移，在双肺、肝脏、椎体和子宫形成恶性病灶，而“白色”腺癌则局限在肺和纵隔淋巴结内。这两种具有明显“黑”和“白”表型成分的空间定位提出了这样一个问题:该肿瘤是源自不同克隆的碰撞癌还是源自同一克隆的单一癌。

The putative relationship between the adenocarcinoma and choriocarcinoma in the context of tumorigenesis was deciphered by whole-exome sequencing of tissues from both components in the primary tumor lesion and from the metastatic foci, including those localized in the bilateral lungs, liver, and uterus (Supplementary materials and methods). This analysis revealed the EGFR L858R and TP53 C275G mutations in all the examined lesions, indicating that they originated from an identical progenitor clone.  The number of somatic mutations in any of the primary and metastatic tumors in the lungs was 402, and that of primary adenocarcinoma, primary choriocarcinoma, metastatic choriocarcinoma to the ipsilateral lung, and metastatic choriocarcinoma to the contralateral lung was 256, 171, 165, and 148, respectively (Fig. 3A, upper panel).  The multiregional tumor tree based on the 402 mutations supported the idea that adenocarcinoma and choriocarcinoma arose from the same origin (Fig. 3A, lower panel).  Notably, the adenocarcinoma component additionally harbored amplification of TTF-1 and demonstrated an elevation in its protein expression level, both of which are characteristic phenomena in lung adenocarcinoma with the EGFR mutation. Furthermore, EGFR amplification, often observed during the progression of EGFR-mutated lung adenocarcinoma, was detected only in the adenocarcinoma component (Fig. 3B).  The adenocarcinoma component harbored all the somatic mutations shared by intrapulmonary and extrapulmonary choriocarcinoma components, suggesting that the divergence into choriocarcinoma is unlikely attributable to specific mutations. Epigenetic and/or transcriptional regulation might be responsible for the morphological and protein-expression characteristics of choriocarcinoma.  These observations signify the emergence of a progenitor clone harboring the EGFR L858R and TP53 C275G mutations and its subsequent divergence into choriocarcinoma and adenocarcinoma by multiple mechanisms including the acquisition of differentiation-specific genomic aberrations and protein expressions (Fig. 3C).

腺癌和绒毛膜癌在肿瘤发生过程中假定的关系是通过原发肿瘤病变和转移灶组织的全外显子组测序来破译的，包括那些位于双肺、肝脏和子宫的组织(补充材料和方法)。该分析显示，在所有检查的病变中均存在EGFR L858R和TP53 C275G突变，表明它们来自同一个祖克隆。肺内原发性和转移性肿瘤的体细胞突变数为402，原发腺癌、原发性绒毛膜癌、绒毛膜癌同侧肺转移和绒毛膜癌对侧肺转移的体细胞突变数分别为256、171、165和148(图3A，上图)。基于402个突变的多区域肿瘤树支持腺癌和绒毛膜癌来源于同一起源的观点(图3A，下图)。值得注意的是，腺癌成分还存在TTF-1扩增，且其蛋白表达水平升高，这都是EGFR突变肺腺癌的特征现象。此外，在EGFR突变的肺腺癌进展过程中经常观察到的EGFR扩增，仅在腺癌成分中检测到(图3B)。腺癌成分包含所有肺内和肺外绒毛膜癌成分共有的体细胞突变，提示分化为绒毛膜癌不太可能归因于特定的突变。表观遗传学和/或转录调控可能与绒毛膜癌的形态和蛋白表达特征有关。这些观察表明出现了EGFR L858R和TP53 C275G突变的前体细胞克隆，并通过多种机制(包括获得分化特异性基因组畸变和蛋白表达)分化为绒毛膜癌和腺癌(图3C)。

Primary pulmonary choriocarcinoma is rare, with approximately 30 cases being reported to date, but it generally follows a rapid and devastating clinical course. Therapeutic strategies against this lethal malignancy remain unestablished because its pathogenesis is poorly understood and no driver mutations have been identified thus far.  The present case of combined choriocarcinoma and adenocarcinoma provides insights into its tumorigenesis and has therapeutic implications.  This is the first report to present a case of pulmonary choriocarcinoma originating from the same progenitor clone with adenocarcinoma and harboring the EGFR L858R mutation.  The presence of this mutation raises the possibility of employing EGFR inhibitors as potential therapeutic agents to improve the otherwise dismal prognosis of patients with pulmonary choriocarcinoma.  The present case underscores the importance of EGFR screening even in pulmonary choriocarcinoma, as is the case with conventional non-small cell lung carcinomas.  Further research is warranted to determine the frequency of EGFR mutations and the efficacy of treatment with EGFR inhibitors in pulmonary choriocarcinoma.

原发性肺绒毛膜癌是罕见的，至今大约报道了30例，但它通常遵循一个快速和毁灭性的临床过程。针对这种致命恶性肿瘤的治疗策略仍未建立，因为其发病机制尚不清楚，到目前为止还没有发现驱动突变。目前的情况下，合并绒毛膜癌和腺癌提供了深入了解其肿瘤发生和治疗的意义。这是第一例来自于腺癌和EGFR L858R突变的肺绒毛膜癌病例报告。该突变的存在提高了使用EGFR抑制剂作为潜在治疗药物的可能性，以改善肺绒毛膜癌患者惨淡的预后。本病例强调了EGFR筛查在肺绒毛膜癌中和传统非小细胞肺癌一样的重要性。需要进一步的研究来确定肺绒毛膜癌中EGFR突变的频率和EGFR抑制剂治疗的疗效。