Association of lymph node metastases, grade and extent of mesenteric lymph node dissection in locoregional small intestinal neuroendocrine tumors with recurrence-free survival

Abstract

We aimed to assess the prognostic impact of tumor- and patient-related parameters in patients with stage I-III small intestinal neuroendocrine tumors (SI-NETs), who underwent locoregional resective surgery (LRS) with curative intent. We included 229 patients with stage I-III SI-NETs diagnosed from June 15, 1993, through March 8, 2021, identified using the SI-NET databases from five European referral centers. Mean ± SD age at baseline was 62.5 ± 13.6 years; 111/229 patients were women (49.3%). All tumors were well-differentiated; 160 were grade 1 (G1) tumors, 51 were G2, two were G3 and 18 tumors were of unspecified grade (median Ki-67: 2%, range 1%-50%). One-hundred and sixty-three patients (71.2%) had lymph node (LN) involvement. The median number of retrieved lymph nodes was 10 (0-63), whereas the median number of positive LNs was 2 (0-43). After a mean ± SD follow-up of 54.1 ± 64.1 months, 60 patients experienced disease recurrence at a median (range) of 36.2 (2.5-285.1) months. The 5- and 10-year recurrence-free survival (RFS) rates were 66.6% and 49.3% respectively. In univariable analysis, there was no difference in RFS and overall survival (OS) between LN-positive and LN-negative patients (log-rank, p = .380 and .198, respectively). However, in stage IIIb patients who underwent mesenteric lymph node dissection (MLND) with a minimum of five retrieved LN (n = 125), five or more LN metastases were associated with shorter RFS (median RFS [95% CI] = 107.4 [0-229.6] vs. 73.7 [35.3-112.1] months; log-rank, p = .048). In addition, patients with G2 tumors exhibited shorter RFS compared to patients with G1 tumors (median RFS [95% confidence interval (CI)] = 46.9 [36.4-57.3] vs. 120.7 [82.7-158.8] months; log-rank, p = .001). In multivariable Cox-regression RFS analysis in stage IIIb patients, the Ki-67 proliferation index (hazard ratio = 1.08, 95% CI = 1.035-1.131; p < .0001) and the number of LN metastases (hazard ratio = 1.06, 95% CI = 1.001-1.125; p = .047) were independent prognostic factors for RFS. In conclusion, LRS with a meticulous MLND and a minimum number of five harvested LNs appears to be critical in the surgical management of SI-NET patients with locoregional disease. In patients who underwent LRS and MLND, the Ki-67 proliferation index and the LN metastases count were independent predictors of RFS.

Keywords: Ki-67 proliferation index; locoregional resective surgery; lymph node metastases; recurrence; small intestinal neuroendocrine tumors.

FIGURE 1

(A) Overall survival analysis and (B) recurrence‐free survival analysis of stage I–III small intestinal neuroendocrine tumor patients, who underwent locoregional resective surgery with curative intent

FIGURE 2

(A) Mantel–Cox overall survival analysis and (B) recurrence‐free survival analysis of stage I–III small intestinal neuroendocrine tumor patients, stratified by mesenteric lymph node positivity. LN, lymph node

FIGURE 3

(A) Mantel–Cox recurrence‐free survival analysis of stage IIIb small intestinal neuroendocrine tumor patients with five or more harvested lymph nodes at primary resective locoregional surgery stratified by lymph node metastases count at a cut‐off of five metastases and (B) Recurrence‐free survival analysis of stage I–III small intestinal neuroendocrine tumor patients, stratified by grade (grade 1 vs. grade 2). LN, lymph node; mets, metastases; WHO, World Health Organization