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. 2024 Oct;31(10):7001-7011.
doi: 10.1245/s10434-024-15632-y. Epub 2024 Jul 2.

Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols

Ozgur Can Eren  1 , Pelin Bagci  2 , Serdar Balci  3 , Nobuyuki Ohike  4 , Burcu Saka  1 , Cenk Sokmensuer  5 , Can Berk Leblebici  5 , Yue Xue  6 , Michelle D Reid  7 , Alyssa M Krasinskas  7 , David Kooby  8 , Shishir K Maithel  8 , Juan Sarmiento  8 , Jeanette D Cheng  9 , Orhun Cig Taskin  1 , Yersu Kapran  1 , Zeynep Cagla Tarcan  10 , Claudio Luchini  11 , Aldo Scarpa  11 , Olca Basturk  10 , N Volkan Adsay  12
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Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols

Ozgur Can Eren et al. Ann Surg Oncol. 2024 Oct.

Abstract

Background: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach.

Methods: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed.

Results: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001).

Conclusions: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Keywords: Grade; Ki-67 proliferative index; Metastasis; Pancreatic neuroendocrine tumor.

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Conflict of interest statement

Authors declare that they have no conflict of interest to disclose.

Figures

Fig. 1
Fig. 1
Macroscopic and microscopic correlations of categories non/minimal infiltrative (A, D); moderately infiltrative (B, E), and highly infiltrative (C, F)
Fig. 2
Fig. 2
PanNETs with Ki67 index 1.2% (A), 5.6% (B), 12.4% (C), and 29.4% (D) corresponding to G1, G2a, G2b, and G3, respectively
See this image and copyright information in PMC

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