Grade Increases in Gastroenteropancreatic Neuroendocrine Tumor Metastases Compared to the Primary Tumor

Abstract

Background/Aim: The neuroendocrine tumor (NET) proliferation-based grading system (ENETS/WHO) for gastroenteropancreatic (GEP) tumors has proved reliable for prognostic stratification. To date, concerns exist regarding Ki-67 heterogeneity within the tumor and little is known on whether grade varies between primary and secondary sites. As tumor heterogeneity may have a significant impact on clinical management, our aim was to retrospectively evaluate Ki-67 on a series of GEP NETs in order to establish whether there is variability in different samples of the same lesion or between primary and metastatic disease (local/distant, synchronous/metachronous). Methods: Sixty patients with multiple samples of tumor were accrued from a total of 338 GEP NETs; 44 of them also had tissue from local/distant metastases and a further 5 had multiple metastatic foci from unknown primary tumors. Immunohistochemistry for Ki-67 was performed on all paraffin blocks from both primary and metastatic tumors. Results: Intratumor Ki-67 heterogeneity sufficient to change grade at first diagnosis was seen in 3/60 cases (5%). Out of 49 patients with primary NETs and/or multiple metastases, discrepancy in grade between sites was identified in 19 (39%) cases and in particular in 11/47 (23%) and in 10/12 (83%) patients with synchronous and metachronous metastases, respectively (p = 0.0002). Change in grade was more frequent in distant compared to locoregional metastases (p = 0.024) and in particular in distant sites other than the liver (p = 0.006). Conclusions: NETs show frequent differences in grade between primary sites and their synchronous/metachronous metastases; assessment of Ki-67 at all sites may prove to be significant for patient management.

Tissue heterogeneity contributes to suboptimal precision of WHO 2010 scoring criteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreascriteria for Ki67 labeling index in a subset of neuroendocrine neoplasms of the pancreas

“…This examination and previous studies [10,12,15,24] showed that pancreatic NEN (in particular NET) may show heterogeneous distribution of Ki67 LI. Unfortunately, adherence to WHO 2010 scoring criteria did not allow providing precise reports of tumour grade in a subset of pancreatic NET, at least from a single patient perspective.…”

“…Grillo et al reported that 37% (22/60) of gastro-entero-pancreatic NEN showed different Ki67 LI between tissue blocks of primary tumour (2-5 paraffin block were examined per case). However, only in 5% (3/60) of cases this resulted in change of grade from G1 to G2 [15]. This value could be underestimated, since higher grade component may form a minor portion of the tumour [9].…”

“…Carlinfante et al showed that Ki67 LI in cytological sample had poor sensitivity for detection of G2 NET, but allowed perfect distinction of NET and NEC [83]. Change of grade of NET is not rare at the stage of synchronous and especially metachronous metastatic disease [15]. Ki67 LI heterogeneity of different extent may be also found in some metastases of pancreatic NET [16,17].…”

“…Ki67 LI heterogeneity was observed not only within primary tumour tissue [9,10,11,12], but also between primary and metastatic lesions [13,14,15] and within and between metastases [16,17].…”

Morphological classification of digestive neuroendocrine neoplasms: the current concepts and controversies

“…В связи с внутриопухолевой гетерогенностью данного параметра и возможным несовпадением мито-тического индекса и индекса Ki-67 важно оценивать заболевание с учетом наиболее высокого показателя пролиферативной активности опухолевых клеток. По-следние исследования показали, что индекс Ki-67 яв-ляется непостоянным параметром, который может зна-чительно меняться в процессе опухолевой прогрессии, поэтому его определение рекомендуется проводить не только в первичной опухоли, но и в биопсиях мета-стазов [46][47][48].…”