Comprehensive analysis of mutational profile and prognostic significance of complex glandular pattern in lung adenocarcinoma

Abstract

Background: Complex glandular pattern (CGP) was included as high-grade pattern in the new grading system proposed by The International Association for the Study of Lung Cancer. We aimed to investigate the mutational profile and validate the prognostic significance and proper cut-off value to distinguish the aggressive behavior of CGP.

Methods: CGP was defined as nests of tumor cells with sieve-like perforation, fused glands with irregular borders or back-to-back glands without intervening stroma. Patients were categorized into four groups according to the percentage of CGP component (0%, 1-19%, 20-49%, 50-100%). Cox's proportional hazards model was applied to analyze recurrence free survival (RFS) and overall survival (OS).

Results: A total of 950 patients with resected lung adenocarcinoma was enrolled. The most frequent driver mutation in this cohort was EGFR and was detected in 624 (65.7%) patients. EGFR mutation was more frequently observed in patients with <20% CGP than in patients with ≥20% CGP (73.6% vs. 60.2%), while KRAS mutation and ALK rearrangement was significantly associated with ≥20% CGP. Patients with 20% or greater CGP exhibited significant worse RFS (P<0.001) and OS (P<0.001) than their counterparts. Moreover, the multivariate Cox regression analysis confirmed that CGP (≥20%) was a risk factor for a worse RFS (P=0.001) and OS (P<0.001) independent of staging and gene mutation. Smaller portion of CGP (<20%) were comparable in RFS and OS to those without CGP (0%). There was also no significant difference in RFS and OS between the 20-49% and ≥50% group.

Conclusions: Our study provided mutational profile of patients with different CGP, validated CGP as a negative prognostic factor and provided extra evidences for the optimal cut-off value of CGP percentage.

Keywords: International Association for the Study of Lung Cancer grading system (IASLC grading system) grading system; complex glandular pattern (CGP); driver mutations; pulmonary adenocarcinoma.

Figure 1

Histological examples in hematoxylin and eosin (HE) staining of complex glandular patterns. Left: cribriform pattern: invasive tumor nests of tumors cells that produce glandular lumina without solid components. Right: fused gland pattern: invasive back-to-back fused tumor glands with poorly formed glandular spaces lacking intervening stroma.

Figure 2

Distribution of different CGP component (0%, 1–19%, 20–49% and 50–100%) in the whole cohort. CGP, complex glandular pattern.

Figure 3

Prognostic significance of different proportion of CGP, (A,B) RFS and OS curve of patients with 0–19% and 20–100% CGP; (C,D) RFS and OS curve of stage I patients with 0–19% and 20–100% CGP; (E,F) RFS and OS curve of stage II-III patients with 0–19% and 20–100% CGP; Error bars were displayed at 95% confidence limits; RFS, recurrence-free survival; OS, overall survival; CGP, complex glandular pattern.

Figure 4

Prognostic significance of different proportion of CGP in stage I patients: (A,B) RFS and OS curve of patients with 0%, 1–19%, 20–49% and 50–100% CGP; (C,D) RFS and OS curve of stage I patients with 0%, 1–19%, 20–49% and 50–100% CGP; (E,F) RFS and PRS in patients who recurred with 0–19% and 20–100% CGP; Error bars were displayed at 95% confidence limits; RFS, recurrence-free survival; OS, overall survival; PRS, post-recurrence survival; CGP, complex glandular pattern.

Figure 5

Mutational profile of patients with 0–19% and 20–100% CGP; CGP, complex glandular pattern; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma; ALK, anaplastic lymphoma kinase; HER2, human epidermal growth factor receptor 2.

Figure 6

Prognosis of patients with EGFR mutations, KRAS mutations, ALK-fusion and none above mutations (WT). (A,B) RFS and OS curve of patients with EGFR mutations, KRAS mutations, ALK-fusion and none above mutations (WT). RFS, recurrence-free survival; OS, overall survival; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma; ALK, anaplastic lymphoma kinase; WT, wild type.

Figure 7

Prognostic significance of different proportion of CGP in EGFR+ patients. (A,B) RFS and OS curve of EGFR+ patients with 0–19%, and 20–100% CGP; (C,D) RFS and OS curve of EGFR+ patients with 0%, 1–19%, 20–49% and 50–100% CGP. Error bars were displayed at 95% confidence limits. RFS, recurrence-free survival; OS, overall survival; EGFR, epidermal growth factor receptor; CGP, complex glandular pattern.