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. 2016 Apr 21;468:639–649. doi: 10.1007/s00428-016-1935-8

The effects of implementing synoptic pathology reporting in cancer diagnosis: a systematic review

Caro E Sluijter 1,2,, Luc R C W van Lonkhuijzen 3, Henk-Jan van Slooten 2,4, Iris D Nagtegaal 1,2, Lucy I H Overbeek 2
PMCID: PMC4887530  PMID: 27097810

Abstract

Pathology reporting is evolving from a traditional narrative report to a more structured synoptic report. Narrative reporting can cause misinterpretation due to lack of information and structure. In this systematic review, we evaluate the impact of synoptic reporting on completeness of pathology reports and quality of pathology evaluation for solid tumours. Pubmed, Embase and Cochrane databases were systematically searched to identify studies describing the effect of synoptic reporting implementation on completeness of reporting and quality of pathology evaluation of solid malignant tumours. Thirty-three studies met the inclusion criteria. All studies, except one, reported an increased overall completeness of pathology reports after introduction of synoptic reporting (SR). Most frequently studied cancers were breast (n = 9) and colorectal cancer (n = 16). For breast cancer, narrative reports adequately described ‘tumour type’ and ‘nodal status’. Synoptic reporting resulted in improved description of ‘resection margins’, ‘DCIS size’, ‘location’ and ‘presence of calcifications’. For colorectal cancer, narrative reports adequately reported ‘tumour type’, ‘invasion depth’, ‘lymph node counts’ and ‘nodal status’. Synoptic reporting resulted in increased reporting of ‘circumferential margin’, ‘resection margin’, ‘perineural invasion’ and ‘lymphovascular invasion’. In addition, increased numbers of reported lymph nodes were found in synoptic reports. Narrative reports of other cancer types described the traditional parameters adequately, whereas for ‘resection margins’ and ‘(lympho)vascular/perineural invasion’, implementation of synoptic reporting was necessary. Synoptic reporting results in improved reporting of clinical relevant data. Demonstration of clinical impact of this improved method of pathology reporting is required for successful introduction and implementation in daily pathology practice.

Electronic supplementary material

The online version of this article (doi:10.1007/s00428-016-1935-8) contains supplementary material, which is available to authorized users.

Keywords: Pathology, Synoptic reporting, Narrative reporting, Checklist, Template, Proforma, Guideline, Completeness, Quality, Colorectal carcinoma, Breast cancer

Introduction

The ever increasing complexity of cancer treatment requires a high-quality diagnostic process, in which anatomic pathology plays a central role. A complete and clear anatomic pathology report forms the basis for optimal treatment decisions [1]. Depending on cancer type, an increasing number of parameters need to be reported by pathologists [25].

The way anatomic pathology reports are constructed needs to adapt to the continuous increase in complexity of reported diagnostic data [6]. There is a spectrum in the way pathology results are reported. This spectrum is divided into six levels by Srigley et al. [6]. Traditionally, a report consists of the following three paragraphs: macroscopy, microscopy and conclusion all completed with free text and without any further guidelines. These traditional narrative pathology reports (NRs) are considered level 1 reporting. NRs are still the standard in most jurisdictions, even though they are prone to misinterpretation [7] and do not always contain all mandatory information [816]. Level three consists of a synoptic-like structured format. With this method, the pathologist follows a checklist per cancer type to ensure that all mandatory parameters are reported. The layout of this type of reporting can still be narrative. More recently, synoptic reporting (SR) has been introduced in pathology. With SR, an electronic reporting module is used with standardised reporting language, multiple-choice answering of mandatory pathology parameters and automated generation of the conclusion (such as TNM stage). Generating a diagnostic report using such a system is much more comparable to filling out a form in an internet browser than it is to narrative reporting using speech recognition software. The result is a well-structured overview of the mandatory parameters for the pathology report (level 6). All levels are described in detail by Srigley et al. [6].

SR has been implemented in several settings all over the world [17]. However, an overview of the effect of SR on the completeness of pathology reports and quality of pathology evaluation in cancer diagnosis is lacking. In the current review, we evaluated the impact of the introduction of SR. We hypothesised that the implementation of SR improved both the completeness of anatomic pathology reports (per parameter and overall) as well as the inherent quality of anatomic pathologic evaluation of cancer specimens.

Materials and methods

To identify studies that described the effect of SR on completeness of reporting and quality of pathology evaluation of solid malignant tumours, a systematic literature search was performed.

Literature search

A combination of search terms in Pubmed, Embase and Cochrane was used to perform the literature search. For the search, we included variations of the following terms: ‘synoptic’, ‘checklist’, ‘template’, ‘pathologic’, ‘histopathology’ and ‘report’. In addition, reference lists of selected papers were manually searched (Online resource 1 describes the search terms in detail). The literature search was performed on September 30, 2015.

Studies were included if studies investigated human subjects, pathology, solid tumours, SR and histology. Selection was first based on title and subsequently on abstract. Only original studies evaluating the effect of SR versus NR of solid malignant tumours were selected. (Conference) abstracts, case reports, editorials, letters and studies for which the full text was not available were excluded. Only studies describing quantitative outcomes of the comparison of SR with NR were included. Therefore, we excluded studies that only described a format of pathology reporting before implementation of SR that described the development of a SR module or the implementation strategy for SR. Two independent investigators (CS and LvL) reviewed each full text report for eligibility.

From each included article, data was extracted on country of study, year and period of study, study design, cancer type, level of reporting before and after the implementation of SR [6], origin of guideline on which the synoptic data parameters are based, outcome measures, results and authors’ conclusion. The format or level of SR as described by Srigley et al. [6] was determined to categorise the studies.

Outcome measures

The outcome measures evaluated in this systematic review were completeness of the pathology reports and the quality of pathology evaluation. We used two definitions for completeness of pathology reports: (1) overall completeness, the proportion of pathology reports containing all mandatory pathology parameters in a given time frame, and (2) parameter-specific completeness, the proportion of pathology reports in which an individual parameter was present in a given time frame. Both definitions were applied to the selected studies.

Quality of pathology evaluation was defined as the proportion of pathology reports in which the informational content corresponds to established quality indicators, such as lymph node numbers, presence of extramural vascular invasion and resection margins.

Data evaluation

The studies were categorised based on cancer type and the implemented level of SR (level 3 versus ≥level 4). To compare completeness, absolute numerical data in studies were converted into percentages. We included parameters that were reported in at least two independent studies. For readability, in the tables, we included only parameters that were reported in at least three independent studies. There is no established definition for sufficient reporting of a parameter. We considered a parameter sufficiently reported if the proportion of pathology reports containing the parameter was greater than 90 % in all the studies that studied the parameter, per cancer type. This percentage was based on definitions used in a number of other studies [1822].

Results

A total of 3252 potentially relevant studies were retrieved by the database search. After removing duplicates, 2338 studies remained (Fig. 1). We excluded 2156 studies based on title, another 111 studies based on abstract or full text and 38 studies because the full-text article was not available. The remaining 33 studies were included for this review [6, 1821, 2352].

Fig. 1.

Fig. 1

Flowchart of search strategy

Characteristics of studies

Table 1 summarises the characteristics of the 33 included studies. Twenty-three studies had a cross-sectional design and ten a case-control design. The studies originated from the following countries: the UK (n = 7), Australia (n = 6), Canada (n = 5), the USA (n = 4), Norway (n = 4), Germany (n = 2), the Czech Republic, Ireland, Italy, Sri Lanka and Sweden (all n = 1). Ten different types of cancer were covered in the studies. Most covered cancer types were colorectal (n = 16), breast (n = 9) and prostate cancers (n = 6). Twenty-three out of the 33 studies implemented a checklist format (level 3); the other ten studies implemented a higher SR level (≥level 4). Some studies described a two-step process of implementing SR level 4 or higher [6, 18, 2325, 31, 35, 42, 47]. The SR modules were based on different guidelines, the College of American Pathologists (CAP; n = 12), the Royal College of Pathologists (RCP; n = 9) and other guidelines (n = 5). Some SR modules were based on expert opinion of a pathologist (n = 7).

Table 1.

Characteristic of included studies

Article Country Cancer type Number of subjects (n) Study design (CC or CS) Level synoptic reporting Origin guidelines
Before Step 1 Step 2
Appleton [23] UK Breast 40 CS 1 2 3 NHSBSP
Aumann [24] Germany Prostate 1049 CS 1 3 5 CAP
Aumann [25] Germany Lung 878 CS 1 3 5 CAP
Austin [19] Australia Breast 402 CS 1 3 ACN
Beattie [26] Ireland Colorectal 171 CC 1 3 RCP
Branston [28] UK Breast and colorectal 2042 CC 1 4 RCP
Buchwald [29] Sweden Colon 302 CC 1 3 Own
Casati [30] Norway Colorectal 1221 CC 1 1 and 5 RCP
Chan [18] Canada Colorectal 407 CS 1 3 4 CAP
Cross [31] UK Colorectal 272 CS 1 2 3 RCP
Gill [20] Australia Pancreatic 177 CC 1 3 CAP
Hammond [32] USA Breast 796 CS 1 3 Own
Hassel [33] USA Breast, prostate and melanoma 368 CC 1 4 CAP
Haugland [34] Norway Colorectal 650 CS 1 5 RCP
Haydu [35] Australia Melanoma 3784 CS 1 3 1 and 3 2008 Melanoma Guidelines
Idowu [36] USA Breast, colorectal and prostate 2125 CS 1 3 CAP
Ihnat [37] Czech Republic Colorectal 177 CC 1 3 CAP
Kahn [38] Australia Thyroid 448 CS 1 3 RCPA
Karim [39] Australia Melanoma 1692 CC 1 3 Own
Mathers [40] UK Breast 100 CC 1 3 RCP
McEvoy [41] Australia Breast 1649 CS ? 3 NHMRC
Messenger [42] Canada Rectal 498 CS 1 3 6 CAP
Porter, 2013 [43] Canada Rectal 197 CS 1 3 Own
Reid, 2000 [44] UK Uterine and cervix 349 CS 1 3 Own
Renshaw, 2014 [45] USA All synoptic pathology reports 6193 CS 1 2 3 CAP
Rigby, 2000 [46] UK Colorectal 98 CS 1 3 RCP
Siriwardana [21] Sri Lanka Colorectal 168 CS 1 3 RCP
Srigley [47] Canada Breast, lung, endometrium, colorectal, and prostate 7594 CS 1 3 6 CAP
Srigley [6] Canada Colorectal and prostate All reports CS 1 3 6 CAP
Ventura [48] Italy Prostate 70 CC 1 3 CAP
Westgaard [49] Norway Pancreatic 506 CS 1 3 Own
Westgaard [50] Norway Pancreatic 218 CS 1 3 Own
Woods [51] UK Colorectal 953 CS 1 3 RCP

UK United Kingdom, USA United States of America, CC case-control, CS cross sectoral, NHSBSP National Health Service Breast Screening Programme, CAP College of American Pathologists, ACN Australian Cancer Network, RCP Royal College of Pathologists, RCPA Royal College of Pathologists Australasia, NHMRC National Health and Medical Research Council

Completeness of pathology reports

Overall completeness

Out of the 14 studies [21, 2325, 28, 30, 32, 33, 36, 38, 40, 4547] that reported the effect of SR on the overall completeness of a pathology report, 13 showed an increased overall completeness, for several cancer types and SR levels (Fig. 2). SR was associated with an increased probability of providing information on the mandatory parameters [2325] and a decrease in the number of missing parameters in a pathology report [36, 48]. The study that failed to show improved completeness [33] commented on the restricted list of parameters in the SR as defined by CAP. For example, in the guidelines as defined by CAP, SR description of specimen type lacked specific histological codes, whereas in NR, these histological codes could be included.

Fig. 2.

Fig. 2

Impact of synoptic reporting on overall completeness of a pathology report. Fourteen studies [21, 2325, 28, 30, 32, 33, 36, 38, 40, 4547] reported the effect of synoptic reporting on the overall completeness of a Pathology report (definition 1). Thirteen studies showed an increased overall completeness, independent of cancer type or synoptic reporting level of the module. In contrast, only one article [33] described that the SR was less complete than the NR

Parameter-specific completeness

Five studies described the impact of SR on parameter-specific completeness in breast cancer. Four studies described the implementation of SR level 3 (Table 2). The results of the fifth article of Branston et al. [28], which implemented SR level 4, were calculated as the percentage change in minimum dataset completeness; these data are excluded from the table. ‘Tumour type’ and ‘lymph node status’ were already reported sufficiently in NR. The ‘oestrogen receptor’ and ‘progesterone receptor’ were already reported sufficiently in NR according to two studies [19, 40], but for another study, implementation of SR was needed to achieve a sufficient reporting [41]. McEvoy et al. reported increased completeness of the oestrogen receptor from 84 to 99 %; however, a decrease was seen for the progesterone receptor [41]. The implementation of SR led to an increased completeness of four parameters (‘resection margins’, ‘DCIS size’, ‘location: quadrant’ and ‘calcification’). Three parameters increased significantly in the majority of the studies ‘histological grade’ [19, 23, 40, 41], ‘lymphovascular invasion’ [19, 23, 41] and ‘lesion size’ [19, 23] or already showed sufficient completeness in NR [19, 40]. The parameters ‘distance tumour to resection margin’, ‘type of specimen’, ‘location side’, ‘multiple tumour foci’ and ‘CIS in specimen’ showed diverse results; in some studies, the parameters were already sufficiently reported in NR, whilst in other studies, implementation of SR was necessary.

Table 2.

Parameter-specific completeness of the breast cancer pathology report

Article Appleton [23] Austin [19] Mathersa [40] McEvoy [41]
Level SR Level 3 Level 3 Level 3 Level 3
Origin Guideline NHSBSP ACN RCP NHMRC
Reporting format NR SR NR SR NR SR NR SR2 SR
Number of reports 30 10 95 307 50 50 385 584 680
Individual parameters (%)
 Lesion size 63.3 100* 98.9 100 80 88
 Tumour type 93.3 100 97.9 100 100 98 100 100 100
 Histological grade 70 100* 86.3 100* 96 100 50.1 86.1 97.5*
 Lymph node status 100 100 100 99.6 100 100 100 100 100
 Resection margins 80 100 89.5 96.1* 93.2
 Lymphovascular invasion 70 100 89.5 99.7* 98 98 31.2 66.8 96.9*
 CIS in specimen 80 100* 95.8 98.1 84 100* 100 95.7 99.7
 DCIS size 23.67 100* 43.9 65.9
 Type of specimen 46.67 100* 100 100
 Location, side 43.33 100* 100 100
 Location, quadrant 76.67 100* 30.5 46.6*
 Multiple tumour foci 22.1 74.3* 98.2 97.4 100
 Calcification 36.8 91.9* 82 100
 ER status 94.5 94.1 90 100 83.9 67.6 98.7*
 PR status 93.4 88.5 90 98 83.6 67.3 71.8*

NHSBSP National Health Service Breast Screening Programme, ACN Australian Cancer Networ, RCP Royal College of Pathologists, NHMRC National Health and Medical Research Council, NR narrative report, SR synoptic report; SR2 approximately 50 % reported synoptically, ER oestrogen receptor, PR progesterone receptor

*Significant improvement in completeness according to the article

aMastectomy and biopsy merged together

Fourteen studies on SR of colorectal cancer described a quantitative effect on parameter-specific completeness. Of these 14 studies, 13 are represented in Table 3. For colorectal cancer, we merged colon and rectal cancer data if reported separately. The results of the 14th article by Branston et al. [28], which implemented SR level 4, were calculated as the percentage change in minimum dataset completeness. These were excluded from the table. Nine studies described the effect of implementing SR level 3, and five studies described the effect of implementing SR level 4 or higher. Four individual parameters were already reported sufficiently in NR (tumour type (Fig. 3a), ‘depth of invasion’, ‘total lymph nodes’ and ‘lymph nodes with metastasis’). ‘Tumour size’ was adequately reported in the NR of three studies [18, 42, 46] but lacking in a fourth [21]. ‘Histological grade’ was sufficiently reported in the majority of studies (n = 9) but not in three other studies [26, 28, 36]. The completeness of both parameters was increased to 96–100 % after the introduction of SR. The implementation of SR led to increased completeness for the reporting of the ‘circumferential resection margin’ (Fig. 3b), ‘distant resection margins’, ‘perineural invasion’ and ‘vascular and lymphovascular invasion’. The parameters ‘stage’, ‘resection margin’ and ‘nodal status’ showed diverse results; in some studies, NR was already very good, whilst in other studies, the implementation of SR was necessary.

Table 3.

Completeness of the colorectal carcinoma pathology report per individual parameter

Article Beattie [26] Buchwald [29] Cross [31] Idowu [36] Ihnatb [37] Porter [43] Rigby [46] Siriwardana [21] Woodsb [51] Chan [18] Casati [30] Haugland [34] Messenger [42]
Level SR Level 3 Level 3 Level 3 Level 3 Level 3 Level 3 Level 3 Level 3 Level 3 Level 4 Level 5 Level 5 Level 6
Guideline RCP Own RCP CAP CAP Own RCP RCP RCP CAP RCP RCP CAP
Localisation CRC CRC CRC CRC CRC Rectum CRC CRC CRC CRC CRC CRC Rectum
Reporting format NR SR NR SR NR SR NR SR NR SR NR SR NR SR NR SR NR SR NR SR SR3 NR SR NR SR4 SR5 NR SR
Number of reports 85 86 97 205 43 68 414 665 84 93 177 20 54 44 82 68 549 404 108 116 113 123 1089 368 112 170 183 315
Individual parameter (%)
Tumour size 100 100 88 100* 100 100 100 98.8 99.4
Tumour type 100 100 98.9 100 100 100 100 100 100 100 100 100 100 100 100 100 98.9 99.4
Histological grade 86 100* 100 100 76.8 96* 100 100 94.4 100 100 100 98 100 98 100 100 98.4 99.9 96.7 100 99.4 91.8 97.5
Resection margins 54 100* 41.5 84* 100 100 91 100* 50 99* 100 80.5 99.7* 84 90.2 97.1*
CRM 79 95 74 100* 86 100* 0 93.3* 24.3 85* 70.4 93.2* 45 90* 14 64* 78 75 100* 73.3 94.9 95.5* 86.3 97.4*
Invasion
Vascular 68 100* 52 98* 88 100* 44 76.3 98.2 97.7 80 100* 30.6 40.3 18 88* 100 41 96.8*
Perineural 52 98* 23.8 52.7 7 88* 100 13.7 94.0*
Lymphovascular 55.9 90* 81 97* 100 39.3 98.1*
Stagea 39 100* 100 100 100 100 14.1 80* 98.2 100 77 100* 58.2 100* 24 96.2*
Depth invasion 100 100 100 100 100 100 100 96.7 100 100
Ln status 85 99* 60.5 82.4* 100 100 100 99.8 100
Total LN 91 100 98.4 99.9 97.6 99.1 100
LN with metastasis 91 100 99.2 99.7 97.6 99.1 100

RCP Royal College of Pathologists, CAP College of American Pathologists, CRC colorectal carcinoma, NR narrative report, SR synoptic report, SR3 synoptic reporting 15 months after implementation, SR4 local synoptic report, SR5 national synoptic report, CRM circumferential margin (only on rectum tumours)

*Significant improvement in completeness according to the article

aTNM, but in Beattie [26] and Cross [31], Dukes was used

bColon and rectum are merged

Fig. 3.

Fig. 3

Impact of synoptic reporting on individual parameters in a colorectal specimen pathology report. a The effect of synoptic reporting on the proportion of pathology reports containing information on tumour type in colorectal cancers. b The effect of synoptic reporting on the proportion of pathology reports containing information on circumferential margin in rectal cancers. c The effect of synoptic reporting on the absolute mean number of lymph nodes resected per resection specimen. d The effect of synoptic reporting on the proportion of pathology reports reported 12 or more lymph nodes resected

Eight studies on SR described other cancer types, as shown in the tables (Online resources 26). Common parameters ‘tumour size’, ‘histological type’ and ‘histological grade’ were already reported sufficiently in NR, whereas for ‘resection margins’ and ‘(lympho)vascular/perineural invasion’, implementation of SR was necessary for an increased completeness to 96–100 %.

Quality of pathology evaluation

Implementation of SR is also expected to affect the quality of pathology evaluation. One aspect of quality is the accurate ascertainment of nodal tumour metastasis. If more lymph nodes are being resected, the N stage will be reported more accurately. For colorectal cancer, it is advised internationally to resect at least 12 lymph nodes [53]. The mean number of lymph nodes identified in the surgical specimen for colorectal cancer was evaluated in 5 of the 14 included studies [18, 29, 37, 46, 51]. All studies showed improvement in mean number of lymph nodes after implementation of SR (Fig. 3c), and more frequently, the minimum number of 12 lymph nodes was achieved. Three studies also showed an improvement of the proportion of pathology reports with a minimum of 12 lymph nodes reported after implementation of SR (Fig. 3d).

Discussion

In this systematic review, we showed that SR results in more complete pathology reports. Whilst traditional parameters such as ‘tumour type’, ‘grade’, ‘invasion depth’ and ‘nodal status’ are in general well reported with NR, other clinical relevant features such as resection margins and ‘type of local spread (vascular, lymphovascular and perineural invasion)’ are frequently lacking. The introduction of SR results in improved reporting of these parameters. SR also improves the mean number of lymph nodes reported and the proportion of pathology reports with 12 or more lymph nodes [53].

Besides these favourable quantitative outcomes, pathologists found that SR was quick and easy to complete and that reports included all essential parameters [28]. Even though SR appears to be more time-consuming in the beginning, implementation actually resulted in a significant reduction time spent on the production of the report by pathologists [54, 55]. For multidisciplinary meetings, both pathologists and clinicians appreciated consistency of the reports [56]. Necessary information for patient management was quick and unambiguous to find [28, 56].

SR can be implemented in different ways. In the studies included in the present review, the following six different implementation strategies were described: combined implementation of SR with clinical audits [23, 31, 47], organisation of SR education or meetings [18, 28, 32, 37], attachment of SR hard copy to the request form of the resection specimen [21, 31, 44], addition of explanatory notes to the SR [20, 24], mandated inclusion of essential parameters according to guidelines [33, 36, 51] or introduction of the SR module without any special attention [19, 26, 29, 30, 38, 41, 42, 46]. The implementation strategy could partially explain the success of implementation of SR. Srigley et al. described the implementation of SR in Ontario, Canada, where pilots and audits were used to ensure proper implementation of SR. In 2012, they achieved successful implementation in 92 % of all hospitals in Ontario [6]. In addition, funding for hospitals, as was used in Ontario [6, 47], could also have added to the successful implementation of SR.

To date, SR has not been widely adopted in anatomic pathology reporting. The main barriers preventing successful implementation are the personal preference of pathologists, who like the flexibility and work flow of NR [57]. Whilst indeed initially, introduction is likely to disrupt the work flow, this seems a temporary situation. Flexibility is sometimes necessary to express uncertainty about a diagnosis; this can in most cases be solved by addition of free text fields to a SR. For instance, Hassel et al. [58] reported that pathologists found the SR more difficult and inflexible and they missed parameters. Another factor hampering implementation is the introduction of the new reporting format in existing work environments, such as the electronic patient files and software systems used throughout the hospital [57, 59]. As reported by Bjugn et al. [27], the development of the SR in Norway was delayed considerably because of alterations in the mandatory diagnostic criteria of the SR and because of alterations in the user interface for the SR.

There are some potential limitations to our study. We are confident that with our search, we found the majority of published papers, minimising the risk of selection bias. However, publication bias may cause an overrepresentation of positive study outcomes.

All studies in this review were observational. The design was either case-control or cross-sectional. No randomised controlled trial has been conducted on the effect of SR on pathology reporting. However, in our opinion, a retrospective study is suitable to investigate the effect of SR in practice. Eight studies reported the effect of SR in less than 200 reports [20, 21, 23, 37, 40, 43, 46, 48]; this is partly due to manually auditing the data for completeness. Preferably, future studies would include much higher number of pathology reports to get a better understanding of the impact of SR on pathology reporting. The fact that these studies cover different tumour types and are conducted in different countries and continents increases the generalisability. Even though most articles investigated the effect of breast and/or colon cancer, we expect that the results reported in this review are transferable to implementation of SR for other cancer types and countries not yet investigated.

Based on the current data, we can conclude that SR results in improved reporting of clinical relevant data. For this reason, it is our opinion that SR is already at present the best clinical practice for anatomic pathology cancer reporting. Ongoing innovation in SR software will likely further improve the value of SR in anatomic pathology, as well as improve the ease of use and efficiency of reporting with SR modules.

Electronic supplementary material

Supplementary information is available at Virchows Archive website.

ESM 1 (44KB, docx)

(DOCX 43 kb)

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This study was funded by Dutch Cancer Society/Alpe d’huzes (grant number KUN 2013–6354).

Human and animal rights

Not applicable.

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