Evaluation of Pathologic Prognostic Factors in Neuroendocrine Tumors of the Small Intestine

The precise contributions of histopathologic features in the determination of stage and prognosis in small intestinal neuroendocrine tumors (NETs) are still under debate, particularly as they pertain to primary tumor size, mesenteric tumor deposits (TDs), and number of regional lymph nodes with metastatic disease. This single-institution series reviewed 162 patients with small bowel NETs (84 females, mean age: 60.3 +/- 12.0 y). All cases examined (100%) were immunoreactive for both chromogranin A and synaptophysin. Primary tumor size >1 cm (P=0.048; odds ratio [OR]=3.06, 95% confidence interval [CI]: 1.01-9.24) and lymphovascular invasion (P=0.007; OR=4.85, 95% CI: 1.53-15.40) were associated with the presence of lymph node metastasis. Conversely, TDs (P=0.041; OR=2.73, 95% CI: 1.04-7.17) and higher pT stage (P=0.006; OR=4.33, 95% CI: 1.53-12.28) were associated with the presence of distant metastasis (pM). A cutoff of >= 7 positive lymph nodes was associated with pM (P=0.041), and a thusly defined modified pN stage (pNmod) significantly predicted pM (P=0.024), compared with the prototypical pN (cutoff of >= 12 positive lymph nodes), which did not. Over a median follow-up of 35.7 months, higher pNmod (P=0.014; OR=2.15, 95% CI: 1.16-3.96) and pM (P<0.001; OR=11.00, 95% CI: 4.14-29.20) were associated with disease progression. Proportional hazards regression showed that higher pNmod (P=0.020; hazard ratio=1.51, 95% CI: 1.07-2.15) and pM (P<0.001; hazard ratio=5.48, 95% CI: 2.90-10.37) were associated with worse progression-free survival. Finally, Kaplan-Meier survival analysis demonstrated that higher pNmod (P=0.003), pM (P<0.001), and overall stage group (P<0.001) were associated with worse progression-free survival, while higher pM also predicted worse disease-specific survival (P=0.025). These data support requiring either chromogranin or synaptophysin, but not both, for small bowel NET diagnosis, the current inclusion of a 1 cm cutoff in primary tumor size and the presence of TDs in staging guidelines, and would further suggest lowering the cutoff number of positive lymph nodes qualifying for pN2 to 7 (from 12).