The influence of tumor stage on the prognostic value of Ki-67 index and mitotic count in small intestinal neuroendocrine tumors

Tumor cell proliferation rate determined by either Ki- 67 index or mitotic count (MC) has shown to be a prognostic factor for gastrointestinal neuroendocrine tumors in general, and after its incorporation in the 2010 World Health Organization tumor grading system, it has become essentially mandatory in pathology reports for all gastrointestinal neuroendocrine tumors, regardless of tumor location. Nevertheless, clinical significance for the Ki-67 index or MC has not been well demonstrated in small intestinal neuroendocrine tumor (SINET), especially those without distant metastasis, the majority of which have very low proliferation rates. We assessed the clinical behavior of 130 SINETs in relation to stage, Ki-67 index, MC, and other pathologic features. Most SINETs (86%) were grade 1 and 14% were grade 2. There were no grade 3 tumors or poorly differentiated neuroendocrine carcinomas. On multivariate analysis, age, Ki-67 index > 5%, MC > 10/50 high-power field, stage IV, and liver metastases were associated with increased risk of death in all patients. When both stage and grade were considered, Ki-67 index > 5% was associated with a nearly 4-fold increased risk of death in stage IV cases (n= 60). In contrast, Ki-67 index did not show prognostic value for patients with stages I to III disease (n= 70), although MC > 1/50 high-power field was significantly associated with death on multivariable analysis. Our study confirms that liver metastasis and increased tumor cell proliferation rate are independent prognostic factors for SINETs, but shows that most SINETs have a very low proliferation rate, which limits its value for predicting tumor behavior. By combining staging and grading information, we demonstrate different roles and cutoff values of Ki-67 index and MC in SINET with different stages.