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. Four hundred and forty six archived pathological slides were examined for microscopic lesions located in the lamina propria, muscularis mucosa, and superficial submucosa. Clinicopathological associations and progression-free survival 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 the 'true unifocal' group (unifocal without SINT), the '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 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.