Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis

Abstract

Tumor islands-large collections of tumor cells isolated within alveolar spaces-can be seen in lung adenocarcinomas. Recently we observed by 3-dimensional reconstruction that these structures were connected with each other and with the main tumor in different tissue planes, raising the possibility of tumor islands being a means of extension. However, the clinical and prognostic significance of tumor islands remains unknown. In this study, we compared clinicopathologic and molecular characteristics and prognosis of stages I to II lung adenocarcinomas with tumor islands (n=58) and those without (n=203). Lung adenocarcinomas with tumor islands were more likely to occur in smokers, exhibit higher nuclear grade and a solid or micropapillary pattern of growth, and harbor KRAS mutations. In contrast, lung adenocarcinomas without tumor islands were more likely to present as minimally invasive adenocarcinoma, show a lepidic pattern of growth, and harbor EGFR mutations. Although there was no difference in stage, the prognosis of lung adenocarcinomas with tumor islands was significantly worse than those without. The 5-year recurrence-free survival for patients with tumor islands and those without was 44.6% and 74.4%, respectively (log rank P=0.010). The survival difference remained significant (P <0.020) by multivariate analysis, and the presence of tumor islands was associated with almost 2-fold increase in the risk of recurrence. Even in the stage IA cohort, more than half of the patients with tumor islands experienced recurrence within 5 years. Thus, aggressive surveillance and/or further intervention may be indicated for patients whose tumors exhibit tumor islands.

Figure 1

(A) Top view of 3D-reconstructed image of lung adenocarcinoma showing tumor islands. (B–J) Fifty whole-slide images of a serial-sectioned paraffin embedded specimen were combined and a 3D image was obtained to study the structure of the tumor islands and its relation with surrounding structures. (B–D) Different planes of view are shown depicting the islands running deep into the tissue (arrows). (B, E–J) Neighboring islands tend to connect (arrow heads and asterisks) and at certain points merge with the main solid tumor (white arrow heads).

Figure 2

(A) An example of lung adenocarcinoma with tumor islands. The islands are isolated within airspaces (arrows) and are several alveoli away from the main tumor (arrow heads). (B) A high-power view shows clusters of atypical cells with necrosis (arrows). The arrowheads indicate a collection of benign alveolar macrophages in the adjacent air space with significant difference in cytology between the two groups. (C) Another example of lung adenocarcinoma with tumor islands. The islands are present in the alveoli adjacent to the blue-inked wedge resection margin (arrowheads). (D) Keratin stain highlights the tumor islands confirming an epithelial origin. Conversely, a cluster of alveolar macrophages (arrows) are negative for keratin. (Immuno stain for pan-keratin on a deeper section of C).

Figure 3

(A) For all stages, median recurrence-free survival was 55 months after resection among subjects with tumor islands (n=56) and undefined among those without tumor islands (n=174). The five-year recurrence-free survival for subjects with tumor islands and those without was 44.6% and 74.4%, respectively (log-rank p = 0.010). (B) For cases with frank invasive carcinomas, median recurrence-free survival was 58 months after resection among subjects with tumor islands (n=56) and undefined among those without tumor islands (n=174). The five-year recurrence-free survival for patients with tumor islands and those without was 46.5% and 70.7%, respectively (log-rank p = 0.046). (C) For Stage IA cases, median survival was 55 months after resection among patients with Stage IA lung adenocarcinomas exhibiting tumor islands (n=35) and undefined among those without tumor islands (n=116). Five-year recurrence-free survival for patients with tumor islands and those without was 44.1% and 77.8%, respectively (log-rank p = 0.011). (D) For subjects who underwent isolated wedge resections, the median survival was undefined among those with tumor islands (n=16) as well as among those without tumor islands (n=66). There was no difference in the five-year recurrence-free survival between subjects with tumor islands and those without (59.3% vs. 68.8%, log-rank p = 0.317); however, the presence of tumor islands was associated with early recurrence (< 2 years) after resection.