# A Comprehensive Evaluation of Clinicopathologic Characteristics, Molecular Features and Prognosis in Lung Adenocarcinoma with an Acinar Component

## TL;DR

This study shows that even small acinar components in lung adenocarcinoma can worsen patient outcomes when combined with more aggressive tumor patterns.

## Contribution

The study reveals that minor acinar components, when present with other aggressive patterns, significantly impact prognosis in lung adenocarcinoma.

## Key findings

- Tumors with a minor acinar component had worse recurrence-free survival compared to acinar-predominant tumors.
- EGFR exon 19 deletions were more common in acinar-predominant tumors than in those with a minor acinar component.
- Patients with an acinar component who received EGFR TKIs had better post-recurrence survival.

## Abstract

Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its prognosis often depends on the tumor’s microscopic structure. Acinar-predominant, the most frequent histological pattern, is associated with an intermediate prognosis. However, it remains unclear how minor acinar components influence patient outcomes. In this study, we examined over 1200 LUAD cases to compare patients with acinar-predominant tumors to those with tumors containing a minor acinar component. We analyzed the clinical characteristics, common driver mutations, and recurrence-free survival. We also evaluated the effect of EGFR tyrosine kinase inhibitors (TKIs) on post-recurrence survival in EGFR-mutated LUAD patients harboring an acinar component. Our results show that even small acinar components can worsen outcomes when combined with more aggressive patterns. This research suggests that looking beyond the predominant histological pattern and integrating molecular information may improve prognostic assessments and help guide personalized treatment decisions for patients with LUAD.

Introduction: Lung adenocarcinoma (LUAD) is the leading cause of cancer-related mortality worldwide. Acinar is the most prevalent architectural pattern and is associated with an intermediate prognosis. Several studies have investigated the prognosis of acinar-predominant LUAD patients. Here, we aimed to move beyond the acinar-predominant classification and gain a more comprehensive understanding of how acinar minor components influence prognosis specifically when accompanying other histological patterns in LUAD. Methods: Patients were grouped by the proportion of acinar patterns in their tumors: acinar-predominant (AP), and acinar component (AC; non-acinar predominant LUAD with an acinar component of ≥5%). The clinicopathologic characteristics, recurrence-free survival (RFS), and a panel of well-characterized driver mutations, including KRAS, EGFR, BRAF, MET, and PIK3CA, were investigated in the two groups of patients. Results: Among 1263 LUAD patients, 716 (56.7%) were AP, and 547 (43.3%) were AC. In AP, the frequency of EGFR exon 19 deletions (EGFR-Del 19) was significantly higher than in AC (p = 0.014). AC demonstrated a worse RFS than AP in the unadjusted analysis (log-rank p: 0.006). In stage I, the difference in the RFS of AC in comparison to AP remained significant (p = 0.048). In the multivariable analysis, AC was significantly associated with a worse RFS in comparison to AP (hazard ratio [HR] AC vs. AP: 1.240, 95% CI: 1.103–1.312, p: 0.04), even after adjusting for other histological patterns, the mutational status, and relevant clinicopathological features. The post-recurrence survival was significantly better in patients with an acinar component of ≥5% who received EGFR tyrosine kinase inhibitors (TKIs) compared to those who did not receive TKIs (p = 0.033). Conclusions: While the predominant pattern primarily dictates prognosis in LAUD, the presence of an acinar minor component alongside other high-grade patterns may further worsen outcomes. This underscores the necessity of considering the broader histological landscape rather than focusing solely on predominant patterns, as our findings show that minor acinar components can impact RFS alongside other histological patterns.