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Introduction
Venous invasion (VI) has been shown to be an independent predictor for haematogenous disease recurrence (typically liver and lung metastasis) and decreased survival in colorectal cancer.1–7 This has prompted its inclusion as a mandatory element in the College of American Pathologists' (CAP) protocol for the examination of colorectal cancer specimens.8 The CAP protocol provides the basis for most synoptic pathology reports throughout Ontario.
The identification of VI is subject to widespread variability among studies, with reported detection rates ranging from 9% to 90%.2 9–14 The most recently published dataset for colorectal cancer from the Royal College of Pathologists (RCPath) in the UK states that extramural VI should be detected in at least 25% of all specimens,15 although anecdotal reports suggest that in routine practice this figure is usually closer to 10%.5 Detection of adverse prognostic features, such as VI, is of particular relevance in patients with stage II tumours, as it may encourage oncologists to offer adjuvant chemotherapy. Studies of interobserver variation have demonstrated only poor to moderate agreement in the detection of VI, even among subspecialist gastrointestinal (GI) pathologists within the same department.16 Reproducibility in other centres may be lower, especially if the reporting of colorectal cancer specimens is undertaken as part of a general pathology rota.
Factors believed to contribute to the variation in the detection of VI include: selection bias in centres undertaking more advanced cases, a lack of consensus over reporting criteria, the use of special stains, and the experience or subspecialist interest of the reporting pathologist. The RCPath have suggested that extramural VI is recorded according to Talbot's criteria, where ‘tumour is present within an extramural endothelium-lined space that is either surrounded by a rim of muscle or contains red blood cells’.17 The explanatory notes of the current CAP protocol make reference to VI as an ‘independent adverse prognostic factor’ with particular emphasis on the prognostic significance of extramural VI. Nevertheless, VI is not recorded as a separate entity in the CAP protocol and is instead incorporated under the collective heading of ‘lymph vascular invasion’. VI and lymphatic invasion may have different prognostic implications, although it is often difficult to distinguish between these two features in clinical practice.
Increasing numbers of studies have demonstrated that the use of elastic or immunohistochemical staining greatly facilitates the identification of blood vessels, by highlighting elastin or smooth muscle in vessel walls, and is associated with a higher detection rate of VI.18–22 In series where special staining techniques have been employed, VI detection rates of 27–52% have been reported for stage II tumours.10–12 23 As yet, the routine use of special stains is not currently advocated by either the CAP or the RCPath.
Therefore, this survey aimed to (1) clarify the current practice patterns of pathologists regarding the assessment of VI in colorectal cancer resections, and (2) identify the factors associated with an increased self-reported VI detection rate.
Materials and methods
Ethical approval for the study was obtained from the Research Ethics Board of Mount Sinai Hospital prior to commencement of the study. A survey was mailed to all pathologists in the province of Ontario, Canada. Ontario is the most populous province of Canada, with a population of approximately 13 million and 8100 new diagnoses of colorectal cancer each year.24
Pathologists currently practicing in Ontario were identified from the province's medical licensing body website, the College of Physicians and Surgeons of Ontario (CPSO), and the online Canadian Medical Dictionary. Pathologists were excluded from the study if they practiced outside Ontario, if no practice address was available, or if they exclusively practiced in a non-GI subspecialty. Email addresses were obtained from the databases of the Ontario Association of Pathologists and Cancer Care Ontario (CCO).
A 15-item survey was developed to assess practice patterns regarding the use of reporting criteria to detect VI (six items), the use of special stains (five items) and demographic information (four items) (figure 1). The survey was piloted on four pathologists involved in the reporting of colorectal cancer resections to ensure face validity and comprehension.
An example of the survey sent to pathologists in the province of Ontario.
The following definitions were provided on the front page of the survey to limit the effect of self-interpretation:
Venous invasion (VI): large vessel invasion and not angiolymphatic or lymphovascular invasion
Extramural venous invasion (EMVI): venous invasion in adipose tissue surrounding the muscularis propria
Intramural venous invasion (IMVI): venous invasion in the muscularis propria or submucosa.
Study packages were sent to all eligible pathologists and included a mailed cover letter, the survey, and a stamped, addressed return envelope. Three weeks after the initial mailing, an email reminder was sent to all non-responders with a link to an online version of the survey. Seven weeks after the initial mailing, a second package was sent to non-responders. Individual identifying information was removed from all surveys and a unique tracking number was assigned to each pathologist for the purposes of data analysis.
Descriptive data are presented as frequencies and percentages. Statistical analyses were performed using the χ2 test and Fisher's exact test where appropriate. Factors associated with a self-reported VI detection rate of above 10% on univariate analysis (p≤0.10) were entered into a stepwise logistic regression model. A p value ≤0.05 was considered statistically significant. All statistical analyses were performed using the SPSS statistical software program (SPSS for Windows release 16.0).
Results
A search of the CPSO and Canadian Medical Dictionary websites revealed that 597 general and anatomical pathologists were licensed to practice in Ontario. Of these, 236 pathologists were excluded from the initial mail out (that is, exclusive practice in a non-GI sub-specialty (n=160), no longer practicing in Ontario (n=53), or no practice address listed (n=23)).
The survey was mailed to 361 pathologists. Only four surveys were returned unopened, and these pathologists could not be located on subsequent telephone contact. Two hundred and fifty-three surveys were returned; of which 198 were complete and 56 were incomplete (that is, did not process colorectal cancer specimens (n=52), had retired (n=3), or had changed specialty (n=1)). Therefore, the corrected response rate, according to the American Association for Public Opinion and Research guidelines,25 was 64.9% (198 of 305 surveys). There were no significant differences between respondents (n=198) and non-respondents (n=107) in terms of gender (p=0.590) and duration of practice (p=0.737) based on information that was available on the CPSO website.
The majority of respondents were male (61.1%) and approximately half had been in practice for over 15 years (53.5%) (table 1). Most pathologists practiced in community-based centres (66.2%), with 43.9% estimating that they processed over 30 colorectal cancer resections each year. A subspecialist interest in GI pathology was declared by 27.3% of pathologists.
Demographic and practice characteristics of pathologists surveyed
The majority of pathologists (70.2%) estimated that they detected VI in less than 10% of colorectal cancer resections. Only 9.1% estimated that they detected VI in more than 20% of cases (figure 2). Nearly all pathologists (98.5%) reported the presence or absence of VI when issuing a pathology report, with 70.7% stating that they made the distinction between EMVI and IMVI. Standardised reporting criteria were used by 62.1% of pathologists, but only 4.0% employed a grading system to assess the degree of VI.
Self-reported venous invasion (VI) detection rate among pathologists responding to the survey.
Most pathologists stated that they would record VI as being present if tumour could be demonstrated in an endothelium lined space surrounded by a rim of muscle (89.4%) or if a well-circumscribed tumour nodule was adjacent to an artery where smooth muscle or elastin could be demonstrated within the nodule on routine or special stains (74.7%). Tumour within an endothelium-lined space containing red blood cells was considered sufficient evidence to record the presence of VI by 51.5% of pathologists.
Routine use of an elastin or immunohistochemical stain if VI could not be detected with a standard H&E stain was reported by 11.1% of pathologists. A further 57.6% would use a special stain if they suspected VI, but nearly all would restrict its use to those blocks they thought would yield a positive result. Only a small minority of pathologists (11.1%) advocated the introduction of routine elastin staining of all tumour blocks as a means of enhancing the detection of VI.
Predictors associated with a self-reported VI detection rate above 10% on univariate analysis included: accepting the criterion of a well-circumscribed tumour nodule adjacent to an artery where smooth muscle or elastin could be demonstrated within the nodule (p=0.001), routinely using special stains if VI could not be detected on a standard H&E stain (p=0.031), reporting by a pathologist with a GI subspecialist interest (p<0.001), and practicing within a university-affiliated centre (p<0.001) (table 2).
Univariate analysis of factors predictive for a self-reported venous invasion detection rate above 10%
Logistic regression revealed that acceptance of a tumour nodule adjacent to an artery where smooth muscle or elastin could be demonstrated within the nodule (OR 3.74 (95% CI 1.18 to 11.8), p=0.025), practice in a university-affiliated centre (OR 2.44 (95% CI 1.13 to 5.31), p=0.024) and a subspecialist interest in GI pathology (OR 2.24 (95% CI 1.01 to 4.99), p=0.048) were all independently associated with a self-reported detection rate above 10% (table 3).
Factors predictive of a self-reported venous invasion detection rate above 10% on logistic regression
The effect of type of hospital practice and the subspecialist interest of the reporting pathologist is shown in figure 3. Subspecialist GI pathologists practicing in a university-affiliated centre had the highest self-reported VI detection rates, with 61.1% reporting rates above 10% (p<0.001).
Pathologists reporting venous invasion (VI) detection rates above 10% according to specialty and type of hospital practice.
A comparison of reporting practices between specialist GI pathologists and non-gastrointestinal pathologists is displayed in table 4. Specialist GI pathologists were more likely to practice in a university-affiliated centre (p<0.001), to distinguish between EMVI and IMVI (p=0.013), and to accept the criterion of a tumour nodule adjacent to an artery where smooth muscle or elastin could be demonstrated within the nodule (p=0.041). There was a trend towards the increased use of standardised reporting criteria (p=0.074) and a trend towards less time in practice (p=0.062).
Comparison of reporting practices between specialist GI and non-GI pathologists
Discussion
This study is the first to explore the practice patterns of a large cohort of pathologists in the assessment of VI in colorectal cancer resections. Of note, 70% of pathologists estimated that they detected VI in less than 10% of cases, supporting the assumption that VI is a widely under-reported finding. In addition, provincial data from pathology reports submitted to CCO during the corresponding time period over which the study was conducted (April to July 2010) revealed that VI was reported in only 197 of 1371 reports (14.4%).26 If the guidelines of the RCPath for detection of 25% were to be taken as a reference standard, only a small minority of pathologists would be close to achieving this target.
Nearly all pathologists indicated that they routinely reported the presence or absence of VI when formulating a pathology report; this may be attributable to the successful implementation of synoptic reporting in pathology departments across Ontario.27 However, there was little uniformity in the use of specific reporting criteria and techniques to assess VI in this study.
Most pathologists stated that they employ a standardised set of reporting criteria in the assessment of VI, although the application of Talbot's criteria was not universal. While 90% of pathologists considered VI to be present if tumour could be demonstrated in an endothelium-lined space surrounded by a rim of smooth muscle, only half would report VI if tumour was present in an endothelium-lined space containing red blood cells. Three-quarters of pathologists were willing to accept a tumour nodule adjacent to an artery, the so-called ‘orphan arteriole’ sign, as long as smooth muscle or elastin could be demonstrated within the nodule on routine or special stains (figure 4). The orphan arteriole sign is commonly regarded as a less stringent criterion for the diagnosis of VI and has previously been shown to increase the frequency with which VI is detected.16 It is not surprising, therefore, that pathologists who accept this criterion were more likely to report a VI detection rate above 10%.
The ‘orphan arteriole’ sign. (A) Tumour nodule (between arrows) identified adjacent to an artery in a presumed vein (H&E, ×200). (B) Movat pentachrome stain highlights the residual elastin in the destroyed vein.
Evidence is now accumulating that the use of special staining techniques to identify smooth muscle and elastin in vessel walls increases the detection of VI (table 5).18–22
Detection of venous invasion in comparative studies of standard H&E and elastic staining
In this study, pathologists who routinely used a special stain if VI was absent on standard H&E staining were more likely to report detection rates above 10%, although this association was not significant on regression analysis. Pathologists who reserve special stains for equivocal cases on H&E staining reported similar detection rates to those pathologists who relied on H&E stains alone. It has been suggested that routine elastin staining of all tumour blocks prior to sectioning would result in the highest detection rate of VI, but there was little enthusiasm for this approach among respondents. Barriers to the routine uptake of the use of special staining were not specifically addressed, but it is possible that economic factors, workload pressures and the perceived benefit on patient outcome may all have an effect.
Practice in a university-affiliated centre and reporting by specialist GI pathologists were both associated with an increased likelihood of reporting a VI detection rate above 10%. Data from pathology reports submitted to CCO also demonstrated that pathologists practicing in university-affiliated centres reported a higher VI detection rate (90 of 433 reports; 20.8%) than their counterparts in community-based centres (107 of 938 reports; 11.4%).26 Although provincial data regarding the subspecialist interest of reporting pathologists were unavailable, a recent study at our own institute revealed that specialist GI pathologists reported the detection of extramural VI more than twice as frequently as non-specialist GI pathologists (24.4% vs 10.2%).28 It is particularly noteworthy that in the current study the combination of a specialist GI interest and university-affiliated practice was associated with the greatest likelihood of reporting a VI detection rate above 10%. Nevertheless, only 25% of this subgroup of pathologists reported detection rates in excess of 20%, highlighting that even among pathologists who could be considered ‘experts’ the RCPath standard seems to be rarely achieved. Selection bias may have also affected VI detection rates, as it is well recognised that advanced tumour stage is associated with an increased incidence of VI. Pathologists were not asked to provide details regarding their stage-related case mix and it is possible that the reporting of more advanced tumours was undertaken in university-affiliated centres or by specialist GI pathologists.
Differences in reporting practices may explain the higher VI detection rates reported by specialist GI pathologists. Specialist GI pathologists were more likely to accept the orphan arteriole criterion and to distinguish between EMVI and IMVI when compared with non-GI specialists. They were also more likely to practice in university-affiliated centres; this may reflect the clustering effect of subspecialist reporting practices.
Sternberg et al demonstrated that the use of tangential cut tissue sections at sites of known venous drainage increased the likelihood of detecting VI.29 This survey attempted to address the use of tangential sections, but apparent confusion regarding the distinction of tangential and perpendicular sections makes it difficult to draw any reliable conclusions. Approximately 60% of pathologists reported taking tangentially cut sections; this is likely to be a marked overestimation given current protocols for the grossing of colorectal cancer resections (data not shown). We recognise that an assessment of tissue sectioning techniques merits further investigation.
A 64.9% response rate was achieved; this is relatively high for a survey of physicians and compares favourably with previous surveys of pathologists within Ontario.30–32 Although there were no differences between respondents and non-respondents in terms of gender and duration of practice, the data could still be subject to response bias and may not be representative of the practice patterns of all pathologists involved in the assessment of colorectal cancer resections. Furthermore, analysing data based on self-reported rather than objective findings may not accurately reflect what practices were actually employed by pathologists. It is possible that pathologists overestimated VI detection rates, especially if they were aware of the standard recommended by the RCPath. However, there appeared to be good correlation with the VI detection rate obtained from pathology reports submitted to CCO at the time of the survey.
In summary, self-reported VI detection rates are low among most pathologists reporting colorectal cancer resections in Ontario. Few pathologists reported that they detected VI at a level close to that expected by the RCPath. Application of the orphan arteriole sign, university-affiliated hospital practice and reporting by a specialist GI pathologist were all associated with an increased self-reported VI detection rate. Despite partial verification of these findings with provincial data, further studies specifically addressing the issue of interobserver variability among a predefined set of cases are required. Nevertheless, it would appear that strategies to improve the detection of VI by pathologists may be warranted. Knowledge transfer may be facilitated by the issuing of explicit guidance on the application of reporting criteria, the use of special stains and specimen preparation techniques. Continuing medical education sessions led by expert pathologists may also be of benefit in the dissemination of best practice province-wide.
What this paper adds
This paper is the first to explore the practice patterns of a large cohort of pathologists in the assessment of VI in colorectal cancer specimens. It reveals that VI is a widely under-reported finding with most pathologists reporting detection rates below 10%. Pathologists who accept the ‘orphan arteriole’ sign are more likely to report higher VI detection rates, although there appears to be little uniformity in the application of specific reporting criteria and the use of special stains. University-affiliated practice and a subspecialist GI interest are associated with higher self-reported VI detection rates. Despite partial verification of these findings with provincial data, further studies specifically addressing the issue of interobserver variability among a predefined set of cases are required before strategies to improve the detection of VI can be implemented.
Take-home messages
Venous invasion (VI) is a widely under-reported finding, with most pathologists reporting detection rates below 10%.
Pathologists who accepted the ‘orphan arteriole’ sign were more likely to report higher VI detection rates, although there was little uniformity in the application of specific reporting criteria.
University-affiliated practice and reporting by a subspecialist gastrointestinal pathologist were independently associated with higher self-reported VI detection rates.
The implementation of standardised reporting criteria and the use of elastic staining may enhance the detection of VI, but will need to be verified by studies of interobserver variation.
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Acknowledgments
The authors also wish to thank Marilyn Raby at Cancer Care Ontario for providing provincial data regarding the reporting of venous invasion, and Harden Huang and Selina Schmocker for their technical and administrative support during the conduct of the survey.
References
Footnotes
Funding David Messenger was supported by The Joseph and Wolf Lebovic Research Fellowship.
Competing interests None.
Ethics approval Ethical approval for the study was obtained from the Research Ethics Board of Mount Sinai Hospital, Toronto, Canada.
Provenance and peer review Not commissioned; externally peer reviewed.