Sonzogni Angelica, Bianchi Fabrizio, Fabbri Alessandra, Cossa Mara, Rossi Giulio, Cavazza Alberto, Tamborini Elena, Perrone Federica, Busico Adele, Capone Iolanda, Picciani Benedetta, Valeri Barbara, Pastorino Ugo, Pelosi Giuseppe
Department of Pathology and Laboratory MedicineFondazione IRCCS Istituto Nazionale TumoriMilanItaly.
Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies (ISBreMIT)IRCCS Casa Sollievo della SofferenzaSan Giovanni RotondoItaly.
J Pathol Clin Res. 2017 Mar 22;3(2):139-152. doi: 10.1002/cjp2.67. eCollection 2017 Apr.
Whether invasive mucinous adenocarcinoma (IMA) and colloid adenocarcinoma (ICA) of the lung represent separate tumour entities, or simply lie within a spectrum of phenotypic variability, is worth investigating. Fifteen ICA, 12 IMA, 9 -rearranged adenocarcinomas (ALKA), 8 non-mucinous -mutated adenocarcinomas (KRASA) and 9 mucinous breast adenocarcinomas (MBA) were assessed by immunohistochemistry for alveolar (TTF1, cytoplasmic MUC1), intestinal (CDX-2, MUC2), gastric (membrane MUC1, MUC6), bronchial (MUC5AC), mesenchymal (vimentin), neuroendocrine (chromogranin A, synaptophysin), sex steroid hormone-related (oestrogen and progesterone receptors), pan-mucinous (HNF4A) and pan-epithelial (keratin 7) lineage biomarkers and by targeted next generation sequencing (TNGS) for 50 recurrently altered cancer genes. Unsupervised clustering analysis using molecular features identified cluster 1 (IMA and ICA), cluster 2 (ALKA and KRASA) and cluster 3 (MBA) ( < 0.0001). Cluster 1 showed four histology-independent sub-clusters (S1 to S4) pooled by HFN4A and MUC5AC but diversely reacting for TTF1, MUC1, MUC2, MUC6 and CDX2. Sub-cluster S1 predominantly featured intestinal-alveolar, S2 gastrointestinal, S3 gastric and S4 alveolar differentiation. In turn, KRASA and ALKA shared alveolar lineage alongside residual MUC5AC expression, with additional focal CDX2 and diffuse vimentin, respectively. A proximal-to-distal scheme extending from terminal (TB) and respiratory (RB) bronchioles to alveolar cells was devised, where S3 originated from distal TB (cellular mucinous adenocarcinoma), S2 from proximal RB (secreting mucinous adenocarcinoma), S1 from intermediate RB (mucin lake-forming colloid adenocarcinoma), S4 from distal RB (colloid alveolar adenocarcinoma), KRASA from juxta-alveolar RB (KRAS-mutated non-mucinous adenocarcinoma) and ALKA from juxta-bronchial alveolar cells (ALK-translocated adenocarcinoma). TNGS analysis showed , , , and mutation predominance. In conclusion, IMA and ICA are basket categories, which likely originate from distinct domains of stem/progenitor cells spatially distributed along bronchioles upon common molecular features and genetic alterations.
肺侵袭性黏液腺癌（IMA）和胶样腺癌（ICA）是代表不同的肿瘤实体，还是仅仅处于表型变异范围内，这值得研究。通过免疫组织化学检测15例ICA、12例IMA、9例ALK重排腺癌（ALKA）、8例KRAS突变非黏液腺癌（KRASA）和9例黏液性乳腺腺癌（MBA）的肺泡（TTF1、细胞质MUC1）、肠（CDX-2、MUC2）、胃（膜MUC1、MUC6）、支气管（MUC5AC）、间充质（波形蛋白）、神经内分泌（嗜铬粒蛋白A、突触素）、性类固醇激素相关（雌激素和孕激素受体）、泛黏液（HNF4A）和泛上皮（角蛋白7）谱系生物标志物，并通过靶向二代测序（TNGS）检测50个反复改变的癌症基因。使用分子特征的无监督聚类分析确定了簇1（IMA和ICA）、簇2（ALKA和KRASA）和簇3（MBA）（P<0.0001）。簇1显示出四个不依赖组织学的亚簇（S1至S4），由HFN4A和MUC5AC汇集，但对TTF1、MUC1、MUC2、MUC6和CDX2的反应不同。亚簇S1主要表现为肠-肺泡分化，S2为胃肠道分化，S3为胃分化，S4为肺泡分化。反过来，KRASA和ALKA除了残留MUC5AC表达外，还共享肺泡谱系，分别额外有局灶性CDX2和弥漫性波形蛋白表达。设计了一个从终末细支气管（TB）和呼吸性细支气管（RB）到肺泡细胞的近端到远端模式，其中S3起源于远端TB（细胞黏液腺癌），S2起源于近端RB（分泌性黏液腺癌），S1起源于中间RB（黏液湖形成性胶样腺癌），S4起源于远端RB（胶样肺泡腺癌）,KRASA起源于肺泡旁RB（KRAS突变非黏液腺癌），ALKA起源于支气管旁肺泡细胞（ALK易位腺癌）。TNGS分析显示，、、、和突变占优势。总之，IMA和ICA是笼统的类别，它们可能起源于沿细支气管空间分布且具有共同分子特征和基因改变的干/祖细胞的不同区域。
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