Delta-like protein 3 and seizure-related 6 homolog expressions are largely confined to neuroendocrine neoplasms, with strong positivity in high-grade tumors such as lung neuroendocrine carcinomas, Merkel cell carcinomas, and medullary thyroid carcinomas, according to a recent study.

Researchers conducted an immunohistochemical analysis to characterize the expression of Delta-like protein 3 (DLL3) and seizure-related 6 homolog (SEZ6) across a broad spectrum of neuroendocrine neoplasms (NENs) and non-neuroendocrine neoplasms (non-NENs). The investigators examined 213 formalin-fixed, paraffin-embedded specimens—160 NENs from diverse anatomical sites and 53 non-NENs—retrieved from the pathology archives of University Hospitals Cleveland Medical Center. Tumors were classified according to the 2022 World Health Organization criteria. Immunostaining for DLL3 and SEZ6 was performed using validated antibodies on a Ventana Benchmark Ultra platform, and expression was assessed semi-quantitatively by multiplying staining intensity (1–3) by the percentage of positive tumor cells to generate a histoscore (H-score) ranging from 0 to 300. Two pathologists independently reviewed all slides, with discrepancies resolved by consensus.

DLL3 expression was most prominent in high-grade neuroendocrine carcinomas. All lung NECs demonstrated positivity (mean H-score, 180), as did all Merkel cell carcinomas (n = 13; mean H-score, 178) and 10 of 11 medullary thyroid carcinomas (mean H-score, 199). Pancreatic NECs (n = 2) exhibited strong staining (mean H-score, 200), whereas pancreatic NETs were largely negative, with only 2 of 11 grade 3 tumors showing weak focal positivity (H-score, 50). DLL3 positivity was rare in gastrointestinal NETs, limited to single cases among gastric and appendiceal tumors. Pituitary neuroendocrine tumors (n = 18) showed variable expression, with 8 cases (44.4%) positive (H-score range, 10–180). In non-NENs, DLL3 staining was limited to focal weak reactivity in 5 cases.

SEZ6 expression was more broadly distributed among NENs. Medullary thyroid carcinomas showed the highest frequency (91%; mean H-score, 224), followed by duodenal NETs (80%; mean H-score, 206), appendiceal NETs (80%; mean H-score, 109), and pituitary neuroendocrine tumors (61%; mean H-score, 65). Merkel cell carcinomas expressed SEZ6 in 77% of cases (mean H-score, 128), and pancreatic NETs in 54.5% (mean H-score, 45). SEZ6 positivity was less consistent in NECs and infrequent in gastrointestinal NETs outside the duodenum. Expression in non-NENs was rare and weak, with only 1 or 2 cases per tumor type demonstrating focal positivity.

The authors reported no competing interests related to this study.

Source: Endocrine Pathology