Difference in types of <i>EGFR</i> mutations between tumors with mPAP and without mPAP element.

<p>Difference in types of <i>EGFR</i> mutations between tumors with mPAP and without mPAP element.</p

Representative appearances of the major histological subtypes of lung adenocarcinoma (hematoxylin and eosin stain, ×200).

<p>A, The lepidic subtype is characterized by the extension of neoplastic cells along the surface of the alveolar walls; B, The acinar subtype is characterized by tubular or glandular structures invading a fibrous stroma; C, The papillary subtype is characterized by the extension of neoplastic cells on the surfaces of fibrovascular cores; D, The micropapillary subtype is characterized by the formation of tufted papillary structures that lack a central fibrovascular core and float in the alveolar space; E, The solid subtype is characterized by the formation of solid nests consisting of neoplastic cells.</p

Representative histological appearances of the biopsy specimens (A, <i>EGFR</i>-mutated lung adenocarcinoma (LADC); B, <i>EGFR</i> wild-type LADC).

<p>The micropapillary element, which is composed of papillary structures lacking fibrovascular cores, floats in alveolar spaces (A, hematoxylin and eosin (HE) stain, ×200). The acinar element (and some crush artifacts) grows in collapse fibrosis (B, HE stain, ×200).</p

Proportions of the micropapillary (mPAP) element in different stages of surgically resected lung adenocarcinomas (LADCs).

<p>A, stage I <i>EGFR</i>-mutated LADCs (n = 103) versus (vs) stage II-IV <i>EGFR</i>-mutated LADCs (n = 39); B, stage I <i>EGFR</i> wild-type LADCs (n = 106) vs stage II-IV <i>EGFR</i> wild-type LADCs (n = 88); n, number of tumors examined mPAP element proportions are displayed as a box-and-whiskers plot with median (thick line), 25th to 75th percentile (box) and 10th to 90th percentile (whiskers) and outliers (circles). <i>P</i>-values were calculated using the Mann-Whitney test.</p

Differences in the histological elements between the <i>EGFR</i>(+)/LN(+) group and the other groups.

<p>Differences in the histological elements between the <i>EGFR</i>(+)/LN(+) group and the other groups.</p

Kaplan-Meier recurrence-free survival curves of the association between the proportion of micropapillary (mPAP) element and disease recurrence in patients with stage I <i>EGFR</i>-mutated lung adenocarcinomas.

<p>A, tumors in which the mPAP element accounted for ≥5% of the tumor versus (vs) those in which the mPAP element accounted for <5% of the tumor (<i>P</i> = 0.028 in the Log-rank test); B, tumors in which the mPAP element accounted for ≥10% of the tumor vs those in which the mPAP element accounted for <10% of the tumor (<i>P</i> = 0.005 in the Log-rank test); C, tumors in which the mPAP element accounted for ≥20% of the tumor vs those in which the mPAP element accounted for <20% of the tumor (<i>P</i> = 0.102 in the Log-rank test); n, number of tumors examined; asterisk(*), statistically significant.</p

Hypothetical schema for histogenesis of the <i>EGFR</i>-mutated and the <i>EGFR</i> wild-type lung adenocarcinomas (LADCs).

<p>In early stages, <i>EGFR</i>-mutated LADC, which may develop from terminal respiratory units (TRU) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166795#pone.0166795.ref022" target="_blank">22</a>], exhibits lepidic patterns consisting of neoplastic cells with hobnail or spheroid morphology. In advanced stages, they progress to form papillary and micropapillary patterns (upper panel). <i>EGFR</i> wild-type LADC, which may develop from the central airway compartment (CAC) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166795#pone.0166795.ref022" target="_blank">22</a>], exhibits a lepidic pattern consisting of neoplastic cells with columnar morphology, and progresses to form acinar and solid patterns (lower panel). Magnification of all photographs is ×200.</p

Clinical characteristics of inoperable lung adenocarcinomas.

<p>Clinical characteristics of inoperable lung adenocarcinomas.</p

Multivariate analysis performed using the Cox proportional hazards model.

<p>Multivariate analysis performed using the Cox proportional hazards model.</p

Clinicopathological characteristics and disease recurrence in patients with stage I <i>EGFR</i>-mutated lung adenocarcinomas (univariate analyses).

<p>Clinicopathological characteristics and disease recurrence in patients with stage I <i>EGFR</i>-mutated lung adenocarcinomas (univariate analyses).</p