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Published on: September 18, 2020
DLL3 Expression in a Genotyped Cohort of Sporadic Medullary Thyroid Carcinomas
Maria Christina Riascos1,2, Fedaa Najdawi3, Sara Ahmadi2,4
1Department of Pathology, Mass General Brigham.
Abstract:
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.
Insights
Delta-like ligand 3 (DLL3) is frequently expressed in medullary thyroid carcinoma (MTC) and associated with advanced disease. DLL3 may represent a promising therapeutic target for MTC patients.
Area of Science:
- Oncology
- Molecular Pathology
- Endocrinology
Background:
- Delta-like ligand 3 (DLL3) is a validated therapeutic target in high-grade neuroendocrine carcinomas.
- Limited data exist on DLL3 expression in medullary thyroid carcinoma (MTC), and its correlation with MTC genotype is unexplored.
- Understanding DLL3 expression patterns in MTC is crucial for evaluating its potential as a therapeutic target.
Purpose of the Study:
- To evaluate DLL3 expression in a genotyped cohort of sporadic medullary thyroid carcinoma (MTC).
- To investigate the association between DLL3 expression and MTC clinicopathological features, including grade, genotype, lymph node metastasis, and disease progression.
Main Methods:
- Retrospective analysis of 39 genotyped sporadic MTC cases.
- Assessment of DLL3 expression using immunohistochemistry, evaluating staining intensity and percentage of positive cells.
- Correlation of DLL3 expression with tumor grade, RET/RAS mutational status, lymph node metastasis, and disease progression.
Main Results:
- DLL3 expression was detected in 69% (27/39) of MTC tumors, with 41% showing high expression.
- DLL3 positivity was significantly associated with high tumor grade (100% positive), presence of RET mutations (89% positive), lymph node metastasis at diagnosis (100% positive), and disease progression (100% positive).
- All tumors with disease progression (n=17) were DLL3 positive, irrespective of genotype.
Conclusions:
- The majority of medullary thyroid carcinomas express DLL3, particularly high-grade tumors and those with advanced disease characteristics.
- DLL3 expression is significantly correlated with adverse prognostic factors, including lymph node metastasis and disease progression.
- These findings suggest that DLL3 is a potential therapeutic target for medullary thyroid carcinoma.
