Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
Histopathology. 2021 Jun;78(7):987-999. doi: 10.1111/his.14311. Epub 2021 Mar 11.
In the evolving era of precision medicine, increasing emphasis is placed on detecting molecular alterations driving the development of specific cancers and targeting them with matched therapies that can yield the best outcomes for patients. Lung adenocarcinomas with uncommon actionable alterations, including MET exon 14 skipping (METex14), ERBB2 and BRAF mutations, are rare and poorly characterised cancers.
To more clearly understand the histopathological features of lung adenocarcinoma with uncommon actionable alterations, we compared the histological features of 678 cases with mitogenic driver alterations from 996 surgically resected lung adenocarcinomas. Genomic data from our cohort revealed METex14, ERBB2 and BRAF mutations in 13, 16 and 15 cases, respectively. Patients who had lung adenocarcinoma with METex14 were often elderly females. Histological features such as clear cell features (23%), hyaline globules (31%) and nuclear pleomorphism (39%) were the most frequently identified in METex14-positive cases; among those, three cases (23%) had tumour cells with bizarre giant or multilobulated nuclei. Additionally, the micropapillary pattern was the most frequently identified in ERBB2-mutated lung adenocarcinoma (31%). Lung adenocarcinoma with BRAF mutations tended to be less invasive, and the BRAF V600E mutation was identified in only one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2 and BRAF-positive tumours, except for invasive mucinous adenocarcinoma, were positive for thyroid transcription factor 1 (TTF-1).
Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumour cells with marked nuclear pleomorphism, hyaline globules and expression of TTF-1 in elderly women who never or lightly smoked.
在精准医学的发展时代，越来越重视检测驱动特定癌症发展的分子改变，并针对这些改变采用匹配的治疗方法，从而为患者带来最佳的疗效。罕见的可靶向改变（如 MET 外显子 14 跳跃（METex14）、ERBB2 和 BRAF 突变）的肺腺癌是罕见且特征不明确的癌症。
为了更清楚地了解罕见可靶向改变的肺腺癌的组织病理学特征，我们比较了 996 例手术切除的肺腺癌中 678 例具有促分裂原驱动改变的病例的组织学特征。我们队列的基因组数据显示，METex14、ERBB2 和 BRAF 突变分别见于 13、16 和 15 例患者。METex14 阳性患者通常为老年女性。最常发现的 METex14 阳性病例的组织学特征包括透明细胞特征（23%）、透明小体（31%）和核多形性（39%）；其中，3 例（23%）的肿瘤细胞具有奇异的巨核或多叶核。此外，微乳头状模式是 ERBB2 突变肺腺癌中最常见的（31%）。BRAF 突变的肺腺癌侵袭性较低，并且仅在 1 例贴壁腺癌中发现 BRAF V600E 突变。免疫组化染色显示，除了浸润性黏液腺癌外，所有 METex14、ERBB2 和 BRAF 阳性肿瘤均表达甲状腺转录因子 1（TTF-1）。
我们来自日本患者的数据表明，METex14 阳性的肺腺癌具有独特的临床病理特征：在从不或很少吸烟的老年女性中，肿瘤细胞具有明显的核多形性、透明小体和 TTF-1 表达。
