Frequency and Prognostic Significance of Intertumoural Heterogeneity in Multifocal Jejunoileal Neuroendocrine Tumours

Simple Summary Well differentiated jejunoileal neuroendocrine tumors (SI-NETs) commonly present as multiple primaries, which are believed to be clonally unrelated. Our study aimed to explore whether these multifocal lesions show intertumoral differences between the most common histomorphological parameters and if so, whether these differences can be associated with patient prognosis. While WHO grade and standard neuroendocrine markers were found to be mostly stable, we observed intertumoral heterogeneity in the expression of SSTR2, CDX2, and serotonin, but observed no survival differences between the expression groups or in comparison to unifocal NETs. Although multifocal SI-NETs showed some degree of heterogeneity in their central morphological parameters, these findings do not appear to be of major clinical significance, rendering an extensive testing of all multifocal lesions as not necessarily required. Background: A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient survival. Methods: We separately assessed WHO grade (based on the Ki-67 index), expression of basal diagnostic markers (synaptophysin/chromogranin A/CDX2/serotonin), SSTR2a, and the contexture of the immunogenic microenvironment in 146 separate tumors from 28 patients with multifocal SI-NETs and correlated the results with clinicopathological factors and survival. Results: Synaptophysin and chromogranin A were strongly expressed in all tumors. WHO grade was concordant within all multifocal lesions in more than 80% of cases and the highest grade was usually found in the most advanced primary. Intertumoral expression of serotonin, SSTR2, and CDX2 was discrepant in 32%, 43%, and 50% of all patients, respectively. Neither heterogeneity of any of the aforementioned markers nor multifocality itself had any impact on patient survival (p = n.s.). Discussion: Multifocal SI-NET show considerable variability in some of the central diagnostic parameters. However, neither intertumoral heterogeneity of those parameters nor multifocality itself had any impact on patient survival, showing that extensive testing of all multifocal lesions is not necessarily required.