A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) vs mrEMVI-negative cases.

BACKGROUND: Pathological extramural vascular invasion (EMVI) is an independent prognostic factor in rectal cancer, but can also be identified on MRI-detected extramural vascular invasion (mrEMVI). We perform a meta-analysis to determine the risk of metastatic disease at presentation and after surgery in mrEMVI-positive patients compared with negative tumours.
METHODS: Electronic databases were searched from January 1980 to March 2016. Conventional meta-analytical techniques were used to provide a summative outcome. Quality assessment of the studies was performed.
RESULTS: Six articles reported on mrEMVI in 1262 patients. There were 403 patients in the mrEMVI-positive group and 859 patients in the mrEMVI-negative group. The combined prevalence of mrEMVI-positive tumours was 0.346(range=0.198-0.574). Patients with mrEMVI-positive tumours presented more frequently with metastases compared to mrEMVI-negative tumours (fixed effects model: odds ratio (OR)=5.68, 95% confidence interval (CI) (3.75, 8.61), z=8.21, df=2, P<0.001). Patients who were mrEMVI-positive developed metastases more frequently during follow-up (random effects model: OR=3.91, 95% CI (2.61, 5.86), z=6.63, df=5, P<0.001).
CONCLUSIONS: MRI-detected extramural vascular invasion is prevalent in one-third of patients with rectal cancer. MRI-detected extramural vascular invasion is a poor prognostic factor as evidenced by the five-fold increased rate of synchronous metastases, and almost four-fold ongoing risk of developing metastases in follow-up after surgery.

The link between histopathological extramural vascular invasion (EMVI) in specimens and metastatic disease was first reported in by Brown and Warren (1938) (Gibson ). Talbot , 1981) subsequently showed that tumour spread into ‘thick-walled vessels’ was evident in almost 52% of 703 rectal cancer specimens. Follow-up of their series showed a significantly worse 5-year survival rate and an almost four-fold risk of developing liver metastases (40%) in patients with EMVI compared to EMVI-negative tumours (14%). The prevalence of EMVI varies greatly and is underreported on histopathological specimens (Quasar Collaborative Group ; Messenger ). The reasons for this may include lack of specific definitions and inconsistent analysis techniques despite efforts to improve this (Messenger ; Kirsch ).

Magnetic resonance imaging is able to demonstrate normal veins within the mesorectum as distinctive low-signal serpiginous structures and when disrupted or expanded by tumour signal, this is strongly linked to the likelihood of pathological EMVI being detected in the specimen. This led to the standardisation of MRI-detected extramural vascular invasion (mrEMVI) definitions in the preoperative assessment of rectal cancer as ‘serpiginous extension of tumour signal within a vascular structure – resulting in contiguous or discontinuous expansion of a vein by tumour signal’ (Supplementary Figure 1; Brown ; Taylor , 2014a; Smith ; Shihab ; Nougaret ; Chand ). By comparing pre and post-treatment scans, magnetic resonance imaging (MRI) identifies the persistence of EMVI in a greater percentage of patients than histopathology (mrEMVI; Chand ) and has a high sensitivity even when enhanced histopathological techniques are used (Jhaveri ). Several studies have reported the prevalence of mrEMVI and its correlation to the development of metastatic disease (Smith ; Hunter ; Bugg ; Sohn ; Seehaus ; Chand ; Kim ). Given the standardised, reproducible and prognostically validated methods of describing tumour using MRI, it is considered a standard for preoperative risk stratification and treatment decision-making (Brown ; Ernst-Stecken ; Mercury Study Group, 2006; Smith ; NICE, 2011; Shihab ; Taylor , 2014b; Glimelius ; Yu ; Battersby ; National Comprehensive Cancer Network 2015; Chand ). Despite this, patients presenting with the finding of mrEMVI are treated in different ways with a lack of consensus on the use of adjuvant therapy. In a recent survey, only 55% of surgeons and 57% of oncologists considered it when deciding on post-operative treatment; this may lead to underestimation of the risks of metastatic disease and the consequent undertreatment of an MRI identified high-risk group (Chand ). Identifying the true overall prevalence of mrEMVI and the risk of metastatic disease will help in establishing the need, or lack thereof, for further treatment strategies and would certainly aid in patient discussions regarding the potential advantages or disadvantages of adjuvant therapy.

This meta-analyses aims to establish the true overall prevalence of rectal tumours with mrEMVI, its association with metastatic disease at the time of presentation and development of distant disease after surgery.

Materials and methods

Registration and protocol

This meta-analysis was registered on the PROSPERO database a priori with an outline of the proposed hypotheses and analysis (Siddiqui ).

Hypothesis

Tumours that are mrEMVI-positive demonstrate a higher incidence of synchronous and metachronous metastases compared with mrEMVI-negative tumours.

Searching and selection

All studies examining the outcomes in patients with rectal cancer and MRI-detected EMVI from January 1980 (first human publications regarding MRI) to July 2016 were identified. The MEDLINE, EMBASE and CINAHL databases available through the United Kingdom's National Health Service National Library of Health website, the Cochrane library and PubMed are available online. Text words ‘rectal cancer’, ‘vascular invasion’, ‘extramural’, ‘tumour in vessels’, ‘medical imaging’, ‘magnetic resonance’, ‘MRI’ were used in combination with the medical subject heading ‘rectal cancers’. Irrelevant articles, reviews and meta-analyses evident from the titles and abstracts were excluded. Relevant articles referenced in these publications were obtained and the references of identified studies were searched to identify any further studies. No language restriction was applied. A flow chart of the literature search according to PRISMA guidelines (Liberati ) is shown in Supplementary Figure 2. About 171 articles were screened for relevance. Of the 171 papers initially detected there were 55 duplicates leaving 116 records. Of these 116 records that were screened, most were pathology based and were excluded. Some of the studies were reviews and some studies captured by our search strategy were on unrelated subjects. On further scrutiny six studies comparing outcomes of rectal tumours with and without mrEMVI were found to have useful data for the summative outcome.

Quality assessment

The methodological quality of the trials included for meta-analysis is explained comprehensively in Table 3. Assessment was performed by two authors independently (MRSS and JB; Chalmers ; Jadad ; Rangel ).

Data extraction

Each included article according to our meta-analysis criteria (Supplementary Table 1) was reviewed by two researchers. This was performed independently and if any conflict arose, resolution was through discussion prior to analysis. Only papers examining outcomes in rectal cancer with and without mrEMVI were included. Where more specific data were required the authors of manuscripts were contacted. Our main outcome measures were synchronous and metachronous metastases. For the purposes of this meta-analysis, synchronous metastases were defined as the presence of metastatic disease prior to surgical intervention and metachronous disease was defined as the occurrence of metastases after surgery during the follow-up period.

Data synthesis

Statistical analyses were performed using Comprehensive Meta-Analysis 2006 for Windows XP (Borenstein ). A value of P<0.05 was chosen as the significance level for outcome measures. Binary data (number of metastases) were summarised as odds ratios (OR) and combined using the Mantel–Haenszel method (Egger ). Heterogeneity of the studies was assessed according to Q and I2. A random and fixed effects method was used. Studies were excluded on an individual basis to assess for influence on heterogeneity. In a sensitivity analysis, 1 was added to each cell frequency for trials in which no event occurred, according to the method recommended by Deeks . Forest plots were used for the graphical display.

Results

Six articles (Smith ; Hunter ; Bugg ; Sohn ; Seehaus ; Chand ) reporting on metastatic disease in patients with rectal cancer and EMVI that were retrieved from the electronic databases met the inclusion criteria (Supplementary Table 1). Two studies were from the same centre but evaluated different time cohorts (Smith ; Chand ). One study included a combination of synchronous and metachronous metastases (predominately synchronous), and was included in the analyses for both outcome measures; exclusion of this study did not alter the significance for both synchronous or metachronous metastases (Sohn ). For one study, the mrEMVI status in a cohort of patients was obtained after contacting the authors (Hunter ). A further study evaluated persistent ymrEMVI status after preoperative chemoradiotherapy (Chand ). Characteristics of each article are given in Tables 1 and 2. The methodological quality of the trials included for meta-analysis is shown in Table 3 (Chalmers ; Jadad ; Rangel ).

Table 1

Outcome measures

	Smith et al, 2008	Hunter et al, 2012	Bugg et al, 2014	Sohn et al, 2014	Chand et al, 2015	Seehaus et al, 2015
Patients (n)
EMVI+	24	90	53	98	99	39
EMVI−	97	146	149	349	89	29
Number with metachronous metastases
EMVI+	18	35	13	42a	36	15
EMVI−	41	18	10	37a	14	5
Number of local recurrences
EMVI+	ND	ND	ND	ND	5	ND
EMVI−	ND	ND	ND	ND	3	ND
Disease/recurrence-free survival (3 yr)
EMVI+	35% (s.d.=9.75)	ND	ND	ND	42.7% (s.d.=12.95)	ND
EMVI−	74.1% (s.d.=4.53)	ND	ND	ND	79.2% (s.d.=4.6)	ND
Number with synchronous metastases
EMVI+	7	21	ND	42a	ND	ND
EMVI−	4	11	ND	37a	ND	ND
Site of metachronous metastases
EMVI+(lung/liver/multi/other)	ND	4/15/12/4	ND	ND	5/4/4/23	ND/15/ND/ND
EMVI−(lung/liver/multi/other)	ND	1/6/11/0	ND	ND	7/1/2/4	ND/5/ND/ND
Site of synchronous metastases
EMVI+(lung/liver/multi/other)	ND	2/12/3/4	ND	ND	ND	ND
EMVI−(lung/liver/multi/other)	ND	4/4/2/1	ND	ND	ND	ND

Abbreviations: CRM=circumferential resection margin; EMVI=extramural vascular invasion; ND=no data.

Data were combined with synchronous and metachronous (6 months post surgery), most were synchronous but unable to extract breakdown.

Table 2

Characteristics of studies comparing patients with and without EMVI

	Smith et al, 2008	Hunter et al, 2012	Bugg et al, 2014	Sohn et al, 2014	Chand et al, 2015	Seehaus et al, 2015
Total number of patients (n)	121	236	202	447	188	68
Age of patients (range)	ND	64.5 (s.d.=13)	66 (32–84)	61.0 (36.6–75.4)	ND	64.3 (s.d.=14)
Gender (m : f)	77 : 65	161 : 69 (ND=6)	123 : 79	291 : 156	121 : 67	44 : 24
Tumour (MRI)
T-stage	T3	Overall stage	ND	T3	137 (Defined as >3c)	T3
Node positive	ND	III and IV: 89	ND	286	123	ND
CRM positive	ND	ND	ND	75	81	ND
Height	ND	Low – 100	ND	Below peritoneal	Low – 69	Low – 32
		Middle – 54		Reflection – 259	Middle – 62	Middle – 36
		High – 76		Above peritoneal	High – 7	High – 0
		ND – 6		Reflection – 61
Neoadjuvant/adjuvant therapy	+/+ (M)	+/−	Primary surgery only	Primary surgery/+ (M)	+/+	ND/ND
Follow-up	36 months	36 months	12 months	6 months	36 months	12 months
Study methodology
Country	UK cohort – London	Canadian cohort	UK cohort – E.Anglia	Korean cohort	UK cohort – London	South American cohort
Time period	2000–2004	2004–2008	2007–2012	2011–2012	2006–2013	2011–2012

Abbreviations: CRM=circumferential resection margin; EMVI=extramural vascular invasion; M=mix of cases; MRI=magnetic resonance imaging; ND=no data.

Table 3

Methodological qualities of comparative studies included (adapted from the Scottish Intercollegiate Guidelines National Comprehensive Cancer Network, 2015 and Rangel )

Quality measures	Smith et al, 2008	Hunter et al, 2012	Bugg et al, 2014	Sohn et al, 2014	Chand et al, 2015	Seehaus et al, 2015
Inclusion criteria	1	1	1	1	1	0.5
Exclusion criteria	1	1	1	1	1	1
Can the number of participating centres be determined	1	1	1	1	1	1
Can the number of radiologists who participated be determined	0	0	0	0	0	1
Can the reader determine where the authors are on the learning curve for the reported procedure	0	0	0	0	0	1
Are diagnostic criteria clearly stated for clinical outcomes if required	1	1	1	0	1	1
Is there any way that they have tried to standardise the radiological interpretation	1	1	1	0	1	1
Do authors address whether there is any missing data	1	1	1	1	1	1
Were patients in each group treated along similar timelines	1	1	1	1	1	1
Outcomes clearly defined?	1	1	1	0	1	1

Prevalence of MRI defined EMVI-positive rectal tumours

The combined prevalence of mrEMVI-positive tumours from the six studies (Smith ; Hunter ; Bugg ; Sohn ; Seehaus ; Chand ) was 0.346 (confidence interval (CI)=0.237–0.474) and is graphically portrayed in Figure 1.

Figure 1

The proportion of patients with rectal cancer who have extramural vascular invasion identified on MRI at the time of presentation.

Synchronous metastases

Three studies incorporating a total of 804 patients (Smith ; Hunter ; Sohn ) contributed towards a summative outcome. Seventy patients had metastases out of 212 patients with mrEMVI (33%). Fifty-two patients presented with metastases out of 592 patients without mrEMVI (9%).

Patients with mrEMVI-positive tumours presented more frequently with metastases at presentation compared to mrEMVI-negative tumours (fixed effects model: odds ratio (OR)=5.68, 95% CI (3.75, 8.61), z=8.21, P<0.001; Figure 2). There was no significant heterogeneity among trials (Q=1.85, df=2, P=0.40, I2=0) and the fixed effects model was used.

Figure 2

The proportion of patients with metastases at the time of presentation who have mrEMVI-positive tumours

In a sensitivity analysis, one study was excluded (Sohn ) due to clinical heterogeneity (inclusion of synchronous and metachronous metastases) although the heterogeneity was not reduced and the outcome remained significant (fixed effects model: OR=4.60, 95% CI (2.34, 9.07), z=4.41, P<0.001). Thus patients with mrEMVI were over four times more likely to present with metastases compared to patients without mrEMVI.

Metachronous metastases

Six studies incorporating 1262 patients (Stewart ; Smith ; Hunter ; Bugg ; Sohn ; Chand ) contributed towards a summative outcome. About 159 out of 403 patients had metastases and were mrEMVI-positive (39%). About 125 out of 859 patients had metastases and were mrEMVI-negative (15%).

Patients who had mrEMVI-positive tumours more often had metastases during follow-up compared with mrEMVI-negative tumours (fixed effects model: OR=4.02, 95% CI (2.99, 5.39), z=9.26, P<0.001; random effects model: OR=3.91, 95% CI (2.61, 5.86), z=6.63, P<0.001; Figure 3). There was no significant heterogeneity among trials (Q=8.53, df=5, P=0.129, I2=41), and the fixed and random effects models were used.

Figure 3

The proportion of patients who develop metastases after surgery who had mrEMVI-positive tumours before surgery

One study was excluded (Sohn ) due to clinical heterogeneity (inclusion of synchronous and metachronous metastases) and heterogeneity was reduced (Q=4.35, df=5, P=0.36, I2=8), but the outcome remained significant (fixed effects model: OR=3.26, 95% CI (2.29, 4.66), z=4.35, P<0.001). Therefore patients with mrEMVI, over three times, more likely to develop metastases than mrEMVI-negative tumours.

Discussion

The present analysis has shown that mrEMVI indicates poorer disease-free survival (DFS) (Chand ). Thus, identifying the burden of disease in the population and its almost four-fold increased risk of further metastatic disease may in future influence the use of neoadjuvant and adjuvant treatment strategies and certainly warrants future trial designs that take into account the presence of mrEMVI as a risk factor.

Main findings

This analysis of 804 patients has shown that those with mrEMVI are five times more likely to have metastases at presentation compared to those without. Analysis of 1262 with mrEMVI-positive tumours is almost four times more likely to develop metastases on follow-up. The meta-analysis has also shown that MRI-detected prevalence of EMVI in rectal cancer is 34.6% (CI: 23.7–47.4%) and thus amounts to over a third of all rectal cancers. Although the link between pathological EMVI and liver metastases is well-established (Talbot ), its reporting by individual pathologists is highly variable with documented pathological underreporting of pEMVI resulting in rates of only 9–21% in published audits (Stewart ; Courtney ; Messenger , 2012; Betge ; Bhangu ; Kirsch ; Gibson ). Furthermore pathological EMVI status is only available after surgery, thus limiting the ability to tailor preoperative therapy. Arguably, MRI assessment of EMVI can be justified as a gold standard as it has both a higher detection rate and represents an independent risk factor for recurrence.

Importance and clinical implications

MRI-detected extramural vascular invasion-positive tumours represent a large cohort (34.6%) within the rectal cancer population and carry a significantly high risk of metastatic disease. Its positive identification could lead to better surveillance of high-risk patients as well as future improvements in therapeutic strategies (Hunter ; Slesser ). This analysis has quantified the metastatic risk at presentation and after surgery following analysis of more than 800 patients who were identified as mrEMVI-positive thus enabling important prognostic information from the preoperative MRI assessment to be shared with patients. This is relevant because the current TNM classification and treatment policies largely fail to account for this prognostic group (Bujko ). Existing recommendations for patients with pEMVI are based on historical studies, which were limited by the low prevalence and underreporting of EMVI or misreporting vascular tumour deposits as ‘lymph nodes’ (Ueno , 2012). Node negative tumours in such studies showed a far greater overall survival and DFS rates than those currently observed in mrEMVI-positive node negative tumours (Quasar Collaborative Group ). The potential benefit of adjuvant chemotherapy in this previously unidentified group consequently remains uncertain (Quasar Collaborative Group ). The risk of metastatic disease associated with mrEMVI has implications for administration of long-course chemoradiotherapy (LCRT) with additional preoperative chemotherapy given either before or after LCRT, and this is currently under investigation in a number of clinical trials (Courtney ; Nilsson ; Slesser ).

Appraisal of evidence and heterogeneity

The overall incidence of mrEMVI in the individual studies was similar except for two studies that showed a prevalence of 53 (Chand ) and 57% (Seehaus ). One of these studies evaluated a population limited to advanced rectal tumours undergoing preoperative chemoradiotherapy, which accounts for the higher prevalence (Chand ). The other studies included both earlier and locally advanced stage tumours (Smith ; Sohn ; Thomson ). In this meta-analysis, one study included only mrEMVI-positive patients at baseline and compared patients who were persistently positive with EMVI that regressed. In this paper, those tumours that regressed to ymrEMVI-negative had similar low rates of metastatic disease as those who are mrEMVI-negative on baseline scans (Chand ). The link betweeen mrEMVI and metastatic disease has been further highlighted by studies showing that about 90% of patients with hepatic metastases are EMVI-positive (Slesser ). One limitation of this analysis is that the cohorts may not be truly comparable due to tumour-related factors; however most of our results did not identify significant heterogeneity between studies for the outcomes of interest, suggesting the cohorts are comparable. In the results where there was significant heterogeneity (clinical or statistical), it sets the stage for further research to identify the reasons for variability and inconsistency between studies. This meta-analysis has more power than individual studies to identify a true difference that exists between two groups, especially for outcomes that require larger sample sizes. In addition, our meta-analysis not only has more power to identify statistical difference, but also increases the precision in estimating the size of the effects of difference between the groups.

Quality assessment and limitations

Quality assessment of the studies (retrospective reviews of databases) included in this meta-analysis is shown in Table 3. It is too early to comment on publication bias.

The individual articles in our studies showed clinical heterogeneity when examining metastatic disease after surgery and this may be due to differing follow-up times. One study included synchronous and metachronous metastases (Sohn ) and when excluded from our analysis reduced the heterogeneity. Some studies (such as Smith ) included in our meta-analysis had small sample sizes that resulted in wide CIs and caution should be used when drawing conclusions. Despite the lack of statistical heterogeneity, the clinical differences need to be borne in mind as well as the relatively small number of patients retrieved from the literature. The small numbers involved also has the potential for overestimating the ORs of our overall outcome results and, therefore, although our results are strongly supportive of our conclusions, caution should be maintained and further trials would certainly be warranted. One potential area is that of tumour-related factors, which may affect the results; however all the preoperative variables assessed were comparable in the studies and while contributing to heterogeneity and to some extent the overall ORs, it is unlikely to affect the direction of the result. The MERCURY II study has also shown that nodal status did not predict for local or distant failure, in addition the mrEMVI positivity rate was greater than the CRM-positive rate therefore making mrEMVI likely to be a more predictive factor (Battersby ). Further studies should standardise follow-up of cases to add further to the literature.

Future studies

Further prospective matched cohort studies focusing on outcomes will help in risk stratification of mrEMVI-positive tumours. The clear definitions of EMVI identified on MRI, and confirmed in this meta-analysis, means that this imaging modality should be adopted as the gold standard in the assessment of this prognostic factor. This analysis has shown that mrEMVI is a likely precursor to metastatic disease and will be formally tested in a prospective study. With its greater detection of patients who are at high risk of developing metastatic disease than current methods, treatment with systemic chemotherapy may, in future, reduce the risk of recurrent disease. Further research into the biological processes of development of metastases and mrEMVI may be facilitated by study into release of tumour cells and DNA into the circulation (Talbot ).

Conclusion

Extramural vascular invasion is a poor prognostic factor in rectal cancer. It is now readily identified on MRI as an independent prognostic factor with a significant prevalence in rectal tumour population. This meta-analysis has shown that patients with mrEMVI-positive tumours are over five times more likely to have synchronous metastases and over three times as likely to develop metastases after surgery.