Multifocal extramural venous invasion detected with an elastin stain as a predictor of cancer-specific outcomes in stage I-III resected colorectal cancer (CRC).
Authors: Cyr David Patrick , Kirsch Richard , Brar Amanpreet , Shivji Sameer , Brar Mantaj , Gryfe Robert , MacRae Helen , Kennedy Erin , Connor James , Swallow Carol Jane , Akder Aysegul 
Published: January 2021

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Background: ExtraMural Venous Invasion (EMVI) is considered an indicator of poor prognosis in patients who have undergone resection of primary CRC, but its use has not been widely adopted in staging systems or nomograms. Staining for elastin may facilitate the accurate detection of EMVI and minimize interobserver variability, as well as enable the assessment of specific features of EMVI including focality and size. We examined the prognostic potential of EMVI detected by elastin staining at a tertiary center that performs a high volume of CRC resections. Methods: This is a single-institution, observational study of consecutive patients who underwent resection of primary CRC between 01/2011 and 12/2016 (n=556). All pathology specimens were re-assessed by expert reviewers who were blinded to patient outcomes. Venous invasion was detected using an elastin trichrome stain and classified as IntraMural or ExtraMural. The number of VI foci, as well as the maximum foci width and length, were also determined. Disease-specific and recurrence-free survival (DSS, RFS) were estimated using the Kaplan-Meier method and group differences were assessed using the log-rank test. Cox proportional-hazard models were used to calculate hazard ratios (HR) and 95% CI. For the present analysis, patients with stage IV (n=86) CRC were excluded. Results: The cohort for analysis included 470 patients (264M, 206F; TNM 8th edition Stage I/II n=291; Stage III n=179) with a median follow-up time of 63 months (0.1-114). EMVI was detected in 33% of all cases (20% in Stage I/II vs. 55% in Stage III; p<0.0001). For the entire cohort, DSS and RFS at 5 years were 86% and 76%, respectively. The presence of EMVI was associated with significantly worse DSS and RFS at 5-years (73% and 54%) compared to patients with no VI (92% and 85%) or IMVI alone (93% and 89%; p<0.0001). The majority of EMVI was multifocal (69%) vs. unifocal (31%). Interestingly, multifocal EMVI was prognostic for worse 5-year DSS (65%), whereas unifocal EMVI was similar to the absence of EMVI (91% and 92%, respectively; p<0.0001). A Cox-proportional hazards model showed worsening DSS with increasing number of detected EMVI foci (1 focus: HR 1.1, 2-4 foci: HR 3.3, >4 foci: HR 7.9; p<0.0001). A similar trend was observed for RFS. Neither the maximum width or length of EMVI foci were prognostic of DSS or RFS. Conclusions: To our knowledge, the prognostic role of EMVI focality in CRC has not been previously explored. In this cohort of Stage I - III CRC patients, multifocal EMVI as assessed by elastin staining was a powerful predictor of cancer-specific death and recurrence-free survival. Elastin staining, which improves the accuracy and objectivity of EMVI detection, may allow validation of EMVI as an independent prognostic variable that should be incorporated into staging systems and nomograms.