Delta-like protein 3 (DLL3) is a
protein of the Notch pathway, and it is a potential therapeutic target for high-grade lung
neuroendocrine tumors (NETs), i.e.,
small cell lung carcinoma (SCLC) and large cell neuroendocrine
carcinoma (LCNEC). However, DLL3 prevalence in lung NETs and its association with clinicopathological characteristics and prognosis remained unclear. We analyzed the immunohistochemical expression of DLL3 and its prognostic role in a consecutive series of 155 surgically resected lung NETs, including typical
carcinoid (TC), atypical
carcinoid (AC), LCNEC, and SCLC patients. The DLL3 expression was categorized as high (>50% positive
tumor cells) or low (<50%). In addition,
tumors were categorized by H-score (i.e., percentage of positive cells by staining intensity, ≥150 vs. <150). DLL3 staining was positive in 99/155 (64%) samples, and high DLL3 expression was frequently observed in high-grade
tumors. In detail, 46.9% and 75% of SCLC and 48.8% and 53.7% of LCNEC specimens showed a high DLL3 expression by using H-score and percentage of positive
tumor cells, respectively. Regarding low-grade NETs, only 4.9% and 12.2% TCs and 19.5% and 24.4% ACs had high DLL3 expression considering H-score and percentage of positive
tumor cells, respectively. High DLL3 expression was associated with advanced American Joint Committee on
Cancer (AJCC) stage, peripheral location, and
chromogranin A expression in high-grade
tumors (p < 0.05). In low-grade NETs, high DLL3 expression was associated with female sex, peripheral location, a higher number of mitoses, higher Ki-67 index, presence of
necrosis, and pleural infiltration (p < 0.05). No association was observed between high DLL3 expression and overall survival (OS) and disease-free survival (DFS) in high-grade NETs, whereas high DLL3 expression was associated with lower DFS in ACs (p = 0.01). In conclusion, our study demonstrated a high prevalence of DLL3 expression in high-grade lung NET patients and its association with aggressive clinicopathological features. These findings confirm that DLL3 could represent a useful
biomarker for target
therapy in high-grade
tumors. Our results also suggest that the DLL3 expression could identify a subset of AC
tumors with more aggressive behavior, thus providing the basis for new therapeutic options in this group of patients.