Diagnosis and prognostic significance of extramural venous invasion in neuroendocrine tumors of the small intestine.

Extramural venous invasion (EMVI) is an established independent prognostic factor in colorectal carcinoma where it is linked to hematogenous spread (i.e., liver metastases), influencing the decision for adjuvant chemotherapy. However, its prognostic significance in small intestinal neuroendocrine tumors (NETs) has not been studied, nor is it routinely assessed or reported. We reviewed primary small bowel NETs (14 jejunum, 82 ileum, 8 not specified) from 104 patients (52 women; median age 60.5, range: 24-84). EMVI was identified in 58 cases (55.8%), including in 13 of 21 equivocal cases using an elastin stain. In univariate analysis, EMVI was associated with lymphovascular and perineural invasion, tumor stage, and lymph node and distant metastases, whereas in multivariate analysis, only distant metastases remained significant (p < 0.001). Liver metastases were present in 55 cases (52.9%) and were significantly associated in univariate analysis with lymphovascular and perineural invasion, tumor stage, lymph node metastases, and EMVI, whereas in multivariate analysis, only EMVI remained significant (p < 0.001; odds ratio (OR) = 59.42). Eight patients developed metachronous liver metastases during follow-up (mean 22.9 ± 22.0 months, range: 4.7-73.2) and all (100%) were positive for EMVI. In contrast, of 49 patients who never developed liver metastases over significantly longer follow-up (mean 71.0 ± 32.4 months, range: 6.6-150.4; p < 0.001), only 7 (14.3%) had EMVI (p < 0.001). In Kaplan-Meier analysis, 8 of 15 patients with EMVI (53.3%) developed metachronous liver metastases, compared with 0 of 42 patients without EMVI (p < 0.001). In contrast, nonhepatic distant metastases, seen in 26 (25.0%) patients, were not associated with EMVI in multivariate or Kaplan-Meier analyses. Our data demonstrate that EMVI is common in small bowel NETs and strongly correlates with development of liver metastases. Therefore, its evaluation is critical and should be assessed in combination with adjuvant techniques such as elastin staining, if necessary. Moreover, inclusion of EMVI in pathology reporting guidelines should be considered.