Micropapillary: A component more likely to harbour heterogeneous EGFR mutations in lung adenocarcinomas

Area of Science:

• Oncology
• Molecular Pathology
• Cancer Genomics

Background:

• The micropapillary (MP) subtype is a recognized marker of poor prognosis in lung adenocarcinomas (LACs).
• Accurate reporting of LAC constituents is crucial per the 2015 WHO classification.
• EGFR-TKI resistance is associated with T790M mutations and exon 20 insertions (E20ins).

Purpose of the Study:

• To investigate the association between EGFR mutations and histological subtypes in LAC.
• To analyze the EGFR status of primary LAC components and metastatic lesions.
• To understand the heterogeneity of EGFR mutations, particularly T790M, within MP components.

Main Methods:

• Analysis of 211 LAC patients using Amplification Refractory Mutation System (ARMS) for EGFR mutation determination.
• Comparison of clinical and pathological features between EGFR wild-type and mutant groups.
• Microdissection of specific tumor components, including MP and glomerulus-like structures, from 20 patients with naïve T790M or E20ins.

Main Results:

• Significant differences in sex, smoking history, lymph node status, and clinical stage were observed between EGFR wild-type and mutant groups (p < 0.05).
• EGFR mutations were more frequent in female, non-smokers, and LACs with papillary or MP components (p < 0.001).
• Metastatic constituents in lymph nodes mirrored the phenotype and EGFR status of primary tumor components. MP and glomerulus-like components showed consistent EGFR status, while acinar and papillary cells were heterogeneous. Naïve T790M mutants increased significantly after EGFR-TKI therapy.

Conclusions:

• Micropapillary components in lung adenocarcinoma are associated with EGFR mutations and portend a poor prognosis.
• EGFR mutation status is generally consistent within MP and glomerulus-like components but heterogeneous in acinar and papillary subtypes.
• The MP component exhibits intrinsic heterogeneity, with a notable increase in T790M mutations post-EGFR-TKI treatment, suggesting therapeutic implications.