Case report: TP53 and RB1 loss may facilitate the transformation from lung adenocarcinoma to small cell lung cancer by expressing neuroendocrine markers

Abstract

Introduction: Transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is one of the mechanisms responsible for acquired EGFR-TKIs resistance. Although it rarely happens this event determines a rapid disease deterioration and needs specific treatment.

Patient and method: We report a case of 75-year-old LUAD female with a p.L858R mutation in Epidermal Growth Factor Receptor (EGFR) who presented with SCLC transformation after responding to first line osimertinib treatment for only 6 months. To understand the underlying molecular mechanism, we retrospectively sequenced the first (LUAD) and the second (SCLC) biopsy using a 56 multi-gene panel. Immunohistochemistry (IHC) staining and Fluorescence In Situ Hybridization (FISH) was applied to confirm the genetic aberrations identified.

Results: EGFR p.E709A and p.L858R, Tumor Protein p53 (TP53) p.A159D and Retinoblastoma 1 (RB1) c.365-1G>A were detected in both the diagnostic LUAD and transformed SCLC samples. A high copy number gain for Proto-Oncogene C-Myc (MYC) and a Phosphoinositide 3-Kinase Alpha (PIK3CA) p.E545K mutation were found in the transformed sample specifically. Strong TP53 staining and negative RB1 staining were observed in both LUAD and SCLC samples, but FISH only identified MYC amplification in SCLC tissue.

Conclusion: We consider the combined presence of MYC amplification with mutations in TP53 and RB1 as drivers of SCLC transformation. Our results highlight the need to systematically evaluate TP53 and RB1 status in LUAD patients to offer a different therapeutic strategy.

Keywords: MYC amplification; TP53 and RB1 loss; lung adenocarcinoma; osimertinib; small cell lung cancer transformation.

Figure 1

Pathology features and genetic aberrations present before and after SCLC transformation. (A) A brief history of the disease diagnosis and treatment in this patient. (B) HE and IHC staining of the tumor tissue before (first biopsy) and after (second biopsy) the SCLC transformation (10×). Scale bar indicates 200μm. (C) Genetic aberrations detected in the first and second tumor biopsy tissue using the targeted sequencing covering 56 lung cancer related genes. (D) MYC copy number (CN=55, upper) and EGFR copy number (CN=4.2) determined by modeling copy number variation and aneuploidy across the genome, the Y axis is indicated as log2 scale. (E) Example of MYC amplification detected by FISH in the primary LUAD (upper) and transformed SCLC (lower) tissue (40×). (F) IHC staining pattern of TP53 and RB-1 in the LUAD biopsy before transformation (10×). Scale bar indicates 200μm.