Characterization of Small Intestinal Neuroendocrine Tumorlets

Small intestine neuroendocrine tumors (SI-NETs) frequently present as multifocal primaries. We commonly observe microscopic lesions in the superficial layer of the small intestine of SI-NET patients. We aimed to define them as small intestinal neuroendocrine tumorlets (SINTs), and explore their clinical and biological significance. Twenty multifocal and twenty unifocal SI-NETs patients who received resection at a single institution were retrospectively reviewed. 446 archived pathological slides were examined for microscopic lesions located in the lamina propria, muscularis mucosa, and superficial submucosa. Clinicopathological associations and progression-free survival (PFS) were analyzed. Previously published genomic data were re-analyzed. SINTs were identified in 50% of multifocal and 30% of unifocal SI-NET patients. Median SINT size was 95 µm, with a median distance of 2.2 mm from the nearest mass. Compared to 'true unifocal' group (unifocal without SINT), 'multifocal-spectrum' group (multifocal or unifocal with SINT) had higher BMI (median 27.6 vs 22.8, p = 0.0060), higher rates of perineural invasion (OR 5.5, p = 0.044), larger mesenteric mass (median 2.6 cm vs 1.6 cm, p = 0.034), and more advanced pT stage (pT3 or pT4, OR 7.2, p = 0.018). Genomic re-analysis suggested that 13% of cells in multifocal primary tumors could share clonal origins, possibly indicating clonal spread via SINTs. SINTs may serve as a new biomarker for multifocal spectrum with local aggressiveness. The actual frequency of multifocal SI-NET may be higher than currently recognized in clinical practice. Further studies are needed to validate their prognostic and biological significance.