Prognostic Significance of Lymphatic, Venous and Perineural Invasion After Neoadjuvant Chemotherapy in Patients with Gastric Adenocarcinoma

Between June 2003 and June 2016, 252 patients underwent either total or subtotal gastrectomy after neoadjuvant therapy for adenocarcinoma of the stomach. Multiple treatment regimens were used in the present study determined by the standard of care and recruiting trials in progress at the time of each patient’s treatment. All patients received neoadjuvant therapy, although not all completed all planned cycles. Seven patients underwent surgery with palliative intent and/or underwent palliative resections due to intraoperative findings of incurable disease and were excluded from analysis. Two patients died within 90 days (both during their index hospital admission for surgery) and were excluded. LI, VI and PNI were reported in all specimen samples.

Clinicopathological characteristics of the study population are presented in Table 1. Of the 243 patients included, 171 (70%) were male; median age was 67 years (24–81 years). Total gastrectomy was carried out in 146 patients (60%) due to proximity of tumour to gastro-oesophageal junction or because of a diffuse-type cancer. The remaining 97 patients underwent subtotal gastrectomy. All patients in the present study were diagnosed with adenocarcinoma. Clinical staging indicated that 224 patients (92%) were assessed as being cT3 or greater, with 204 (84%) suspected to have lymph node involvement (cN1 +).

After neoadjuvant therapy and surgical resection with D2 lymphadenectomy, pathological examination revealed that eight patients (3%) had received an R1 (microscopic presence of tumour at the resection margin) resection. A median number of 32 (10–142) nodes were resected. Overall, 117 tumours (48%) were regarded as ypT3 or worse and 136 patients (56%) had nodal involvement (ypN1 +).

Gastric cancer is an aggressive malignancy in which most patients treated with surgical resection develop disease recurrence, with a recent meta-analysis showing that 5-year survival for patients undergoing surgery is 42% if given neoadjuvant therapy and only 30% if not.13 The present study indicates that presence of LI, VI and/or PNI is associated with poorer survival in patients with gastric adenocarcinoma who are treated with neoadjuvant therapy followed by gastrectomy with D2 lymphadenectomy, with PNI having prognostic significance independent of lymph node status. The reported prevalence of LI, VI and PNI is widely distributed, with PNI being reported between 2% and 48%, VI 7–44% and LI 10–91%. However, these values correspond to chemotherapy-naïve patients.14^–16

Patients with gastric cancer who undergo surgery are staged by the TNM system. The importance of the number of involved nodes is reported in the 7th4 and 8th9 editions of the TNM system, and our data reflect this, as seen in Fig. 1. Pre-treatment clinical staging guides prognostication and choice of treatment options that are discussed with patients; however, our analysis demonstrates minimal association between clinical staging and presence of LI, VI and PNI. There is an association between ypT and ypN stage and LI, VI and PNI post-neoadjuvant therapy. A combination of these factors is associated with poorer survival, an important finding given that this study demonstrates that presence of one form of invasion increases the risk of other forms being present. This study suggests that presence of LI, VI and/or PNI in the surgical specimen is an indicator for aggressive disease behaviour that should be taken into consideration along with ypT and ypN stage. Evaluation of survival curves in those with N0 disease demonstrated similar, albeit less pronounced, outcomes to those in the entire cohort. Whilst a statistical significance remains with each factor (except VI), the change in significance may be due to the smaller dataset of these patients. The present study provides an insight into the survival outcomes associated with LI, VI and PNI in a large series of gastric adenocarcinoma patients who have undergone neoadjuvant therapy followed by surgery. Many previous studies have reported that LI, VI and PNI are adverse prognostic factors in other cancers, such as in colorectal,17 gynaecological,18 breast19 and pancreatic20 cancers. In gastric cancer, LI,21 VI22 and PNI23 have all been reported as adverse prognostic factors, although this is predominately in patients who have not received neoadjuvant therapy. Jhawer et al.24 reported that perineural invasion was associated with worse outcomes in a study of 38 post-neoadjuvant patients, and Zhu et al.25 reported LI and PNI (but not VI) data for 192 post-neoadjuvant patients, showing worse survival if one factor was present, but with no assessment of the additive risk of multiple factors. The present study confirms and expands on these previous findings by establishing that LI, VI and PNI are individually associated with poorer survival outcomes, with PNI acting independently of other predictors of survival. The present study also demonstrates that survival worsens as the total number of these histopathological factors increases. This is in good agreement with what has been seen in oesophageal adenocarcinoma.5

In addition, the association between combined LVPNI and survival occurs even in patients with no tumours detected in the surgically resected lymph nodes (ypN0 subgroup). Patients in this subgroup have substantially better survival than those with even small numbers of positive nodes. In the present study, 44% of patients had no residual nodal disease, and our analysis of this subgroup suggests that survival outcomes can be further stratified using LVPNI (Fig. 1). The present study demonstrates that, in the ypN0 subgroup, presence of multiple LVPNI factors (despite no positive nodes) is associated with significantly worse survival outcomes. Patient compliance with adjuvant therapy is often poor, and multi-disciplinary teams may find the additional prognostic information provided by LVPNI factors to be useful in encouraging take-up of adjuvant therapy, especially in what might otherwise be considered low-risk disease on a purely TNM basis.

Presence of LVPNI may be useful when stratifying patient populations in future studies assessing the efficacy of adjuvant regimens. These factors also have prognostic potential in pre-operative patients for whom this information exists, for example in patients who have had endoscopic mucosal resection biopsies22,26,27 or in those whose simple biopsies happen to include evidence of LVPNI. Further, these factors may help identify patients with poorer prognosis. In those for whom neoadjuvant treatment has had apparently little impact (e.g. TRG 4/5), it may help support a different adjuvant modality such as chemoradiotherapy. However, this highlights a potential area for future work.

In conclusion, these findings suggest that presence of LI, VI and PNI after neoadjuvant therapy followed by gastrectomy is associated with poorer prognosis. These factors should be incorporated in standard pathology reports and should be considered by multi-disciplinary teams when identifying patients at higher risk of disease recurrence or when considering the need for adjuvant therapy. This may be particularly useful in decision-making, when multiple factors are present, for node-negative patients who otherwise might be considered relatively low risk for recurrence.