DLL3 Expression in a Genotyped Cohort of Sporadic Medullary Thyroid Carcinomas

Delta-like ligand 3 (DLL3) has been identified as a therapeutic target in high-grade neuroendocrine carcinomas, particularly small cell lung carcinoma. Data on DLL3 expression in medullary thyroid carcinoma (MTC) are limited; moreover, the relationship between DLL3 expression and MTC genotype has not been explored. We evaluated DLL3 expression (based on staining intensity and percentage of positive cells) in a genotyped cohort of sporadic MTC. In our cohort of 39 cases, 27 (69%) tumors were positive for DLL3, including 1 (4%) with low DLL3 expression, 10 (26%) with moderate expression, and 16 (41%) with high expression. DLL3 expression was significantly associated with grade (P=0.036), presence of a RET mutation (P=0.014), presence of lymph node metastases at diagnosis (P<0.005), and disease progression (P<0.005). All 9 (100%) high-grade tumors were positive for DLL3. In contrast, 18 (60%) of 30 low-grade tumors were DLL3 positive. DLL3 was positive in 17 (89%) of 19 RET-mutated tumors, 4 (50%) of 8 RAS-mutated tumors, and 6 (50%) of 12 RET/RAS wild-type tumors. All 24 primary tumors with associated lymph node metastases at diagnosis were positive for DLL3. Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET-mutated tumors, 1 RAS-mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.