DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas

Abstract

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbor somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behavior and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥50%) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (P < 0.0001) and lymph node metastases (P < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behavior. DLL3 expression in ≥50% of tumor cells virtually excludes MTC without stromal desmoplasia. DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.

Keywords: DLL3; medullary thyroid carcinoma; notch pathway; stromal desmoplasia; thyroid cancer.

Figure 1

Expression of DLL3 in MTC with and without desmoplasia and its lymph node metastasis (A). Representative microphotographs of MTC with and without desmoplasia showing in H&E typical morphologic features. Immunohistochemistry for DLL3 shows a strong signal in tumors with desmoplasia as well in primary tumors as in lymphnode metastases. Tumors without desmoplasia are largely negative. (B) Bar chart divided into desmoplasia negative and positive tumors showing DLL3 expression of every single case. (C) Number of DLL3 positive tumor cells is significantly increased dependent on status of metastases and desmoplasia. ***P < 0.0001.

Figure 2

Immunohistochemical staining of DLL3 shows a widely homogenous distribution of the entire tumor with low or high expression in lower magnification in top row (200×). Bottom row shows the cytoplasmatic and membranous expression of DLL3 positive tumor cells in higher magnification (400×).