Clinicopathological heterogeneity between primary and metastatic sites of gastroenteropancreatic neuroendocrine neoplasm

Abstract

Background Chromogranin A (CgA), synaptophysin (Syn) and the Ki-67 index play significant roles in diagnosis or the evaluation of the proliferative activity of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, little is known about whether these biological markers change during tumor metastasis and whether such changes have effect on prognosis. Methods We analyzed 35 specimens of both primary and metastatic tumor from 779 patients who had been diagnosed as GEP-NENs at Wuhan Union Hospital from August 2011 to October 2019. The heterogeneity of CgA, Syn and Ki-67 index was evaluated by immunohistochemical analysis. Results Among these 779 patients, the three most common sites of NENs in the digestive tract were the pancreas, rectum and stomach. Metastases were found in 311 (39.9%) patients. Among the 35 patients with both primary and metastatic pathological specimens, differences in the Ki-67 level were detected in 54.3% of the patients, while 37.1% showed a difference in CgA and only 11.4% showed a difference in Syn. Importantly, due to the difference in the Ki-67 index between primary and metastatic lesions, the WHO grade was changed in 8.6% of the patients. In addition, a Kaplan–Meier survival analysis showed that patients with Ki-67 index variation had a shorter overall survival (p = 0.0346), while neither Syn variation nor CgA variation was related to patient survival (p = 0.7194, p = 0.4829). Conclusions Our data indicate that primary and metastatic sites of GEP-NENs may exhibit pathological heterogeneity. Ki-67 index variation is closely related to the poor prognosis of patients with tumor metastasis, but neither Syn variation nor CgA variation is related to patient prognosis. Therefore, clinicopathologic evaluation of the primary tumor and metastatic sites could be helpful for predicting the prognosis.

High rate of Ki‐67 increase in entero‐pancreatic NET relapses after surgery with curative intent

“…Previous data have reported different histopathological features among different primary lesions in cases of multifocal tumors, as well as between primary tumor site and distant metastases. [6][7][8][9][10][11][12][13][14] These intra-individual differences can be more frequently observed for metachronous than synchronous lesions, thus supporting the indication of histological reassessment during disease course. 6,7,15 Studies published to date have mainly analyzed series of patients with metastatic disease observed over a relatively long follow-up period, who had received several therapy lines in this time interval.…”

“…This heterogeneity can be observed inter‐individually among patients affected by NENs, but also intra‐individually over time. Previous data have reported different histopathological features among different primary lesions in cases of multifocal tumors, as well as between primary tumor site and distant metastases 6–14 . These intra‐individual differences can be more frequently observed for metachronous than synchronous lesions, thus supporting the indication of histological reassessment during disease course 6,7,15 .…”

Single-cell RNA sequencing reveals spatiotemporal heterogeneity and malignant progression in pancreatic neuroendocrine tumor

“…In addition, pNETs have high intra- and intertumor heterogeneity, not only across patients, but also in different lesions of a single patient and have a complex tumor microenvironment (TME). 6 Although studies based on bulk-sequencing have facilitated understanding of the molecular nature of pNETs, it is challenging to explore a heterogenous disease based on bulk mRNA sequencing.…”

Glucose Metabolism Modification Induced by Radioligand Therapy with [177Lu]Lu/[90Y]Y-DOTATOC in Advanced Neuroendocrine Neoplasms: A Prospective Pilot Study within FENET-2016 Trial

“…Despite radiopeptides being selectively accumulated by those cells overexpressing SSTr, they can also damage nearby undifferentiated cells with less SSTr expression by the crossfire effect. In this context, [ 90 Y]Y-DOTATOC β-particles could be more effective than [ 177 Lu]Lu-DOTATOC ones, thanks to their higher emission energy and tissue penetration, which enhances the crossfire effect [ 32 , 33 , 34 , 35 ]. As a result, we can speculate that DUO-scheme RLT might be able to clear-cut NEN lesions from FDG-positive cell clones.…”