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Published online before print February 28, 2007, 10.1148/radiol.2431051825
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(Radiology 2007;243:132-139.)
© RSNA, 2007

Gastrointestinal Imaging

Extramural Depth of Tumor Invasion at Thin-Section MR in Patients with Rectal Cancer: Results of the MERCURY Study1

MERCURY Study Group

1 From the Department of Radiology, Royal Marsden Hospital, Downs Rd, Surrey SM2 5PT, England (Gina Brown, MD, FRCR). The complete list of the MERCURY Study Group members and the author contributions list are cited in Appendix E1 (http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC1). From the 2004 RSNA Annual Meeting. Received November 9, 2005; revision requested December 21; revision received June 8, 2006; accepted June 22; final version accepted August 30. Supported by the Pelican Cancer Foundation, with educational grants from Siemens Medical UK and the Wessex Cancer Trust. Address correspondence to G.B. (e-mail: gina.brown{at}rmh.nhs.uk).


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively evaluate the accuracy of magnetic resonance (MR) imaging in depicting the extramural depth of tumor invasion in patients who have rectal cancer, with histopathologic results as the reference standard.

Materials and Methods: The Magnetic Resonance Imaging and Rectal Cancer European Equivalence (MERCURY) Study received ethics approval from all participating centers, and all patients gave informed consent. Consecutive patients (n = 679) with adenocarcinoma of the rectum consented to participate. Imaging workshops for participating specialist gastrointestinal radiologists were held to ensure standardization of image acquisition techniques. Standardized MR image interpretation and data reporting were performed by using previously validated criteria. MR images were prospectively singly read by the specialist gastrointestinal radiologists. The maximal extramural depth (EMD) of tumor spread, defined at histopathologic analysis as the distance from the outer edge of the longitudinal muscularis propria to the outer edge of the tumor, was measured and recorded. The maximal EMD was the reference standard. The MR and histopathologic results were considered to be equivalent when the 95% confidence interval of the difference between them was within ±0.5 mm.

Results: Tumor EMD measurements obtained at both MR imaging and histopathologic analysis were available for 295 (95%) of 311 patients after primary surgery. Mean EMDs were 2.80 mm ± 4.60 (standard deviation) and 2.81 mm ± 4.28 at MR imaging and histopathologic analysis, respectively. The mean difference between the MR-derived and histopathologically derived EMDs was –0.05 mm ± 3.85 (95% confidence interval: –0.49 mm, 0.40 mm). Therefore, MR and histopathologic assessments of tumor spread were considered equivalent to within 0.5 mm.

Conclusion: Demonstration of accurate measurement of the depth of extramural tumor spread in the MERCURY Study enabled accurate preoperative prognostication.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC1
http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC2
http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC3

© RSNA, 2007

Results of several histopathologic studies have revealed the importance of extramural tumor spread and the influence of this spreading on prognosis (1–4). In one of the largest series published by a University of Erlangen group, T3 tumors with extramural spread of more than 5 mm were associated with a 5-year cancer-specific patient survival rate of only 54%, but T3 tumors with 5 mm or less of extramural spread—regardless of whether lymph node involvement was present—were associated with a 5-year cancer-specific survival rate of greater than 85% (5). Therefore, the benefit from preoperative therapy is likely to be minimal for patients who have tumors with less than 5 mm of spread but potentially huge for those who have tumors with more extensive extramural spread.

With the increasing availability of newer preoperative (neoadjuvant) therapy options (6–8), it is important that the preoperative staging system used is capable of enabling differentiation of good- versus poor-prognosis tumors and thus facilitating the appropriate intensification of therapy and optimized outcomes. An accurate and reproducible staging technique is therefore essential to enabling colorectal specialist multidisciplinary teams to consider potentially complex treatment options. Current preoperative staging techniques include digital rectal examination (9), endorectal ultrasonography (US) (10), and computed tomography (CT) (11,12). However, these modalities confer little knowledge about the relationship between the tumor and the circumferential resection margin, and they have not been shown to enable accurate measurement of the local depth of tumor spread.

Investigators in a single-center study focusing on optimal thin-section, small-field-of-view, pelvic phased-array coil magnetic resonance (MR) imaging; precise surgery; and meticulous whole-mount section histopathologic analysis achieved high accuracy in determining the extramural depth of tumor invasion, the nodal status, and the circumferential resection margin (13). However, this high degree of accuracy has not been achieved by others (11,14), and, thus, MR imaging has not been widely adopted for these applications. The MERCURY (Magnetic Resonance Imaging and Rectal Cancer European Equivalence) Study Group is a multicenter multidisciplinary collaboration formed in 2002 for the prospective evaluation of preoperative assessment in patients with rectal cancer. Therefore, the purpose of our study was to prospectively evaluate the accuracy of MR imaging in depicting the extramural depth of tumor invasion in patients who have rectal cancer, with histopathologic results as the reference standard.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Patients
Financial support for our study was provided by Siemens (Bracknell, Berkshire) and Wessex Cancer Trust (Hampshire, England) through the Pelican Cancer Foundation charity. The authors had control of the data and information submitted for publication. Our study received ethics approval from all participating centers. The trial was adopted within the United Kingdom National Cancer Research Network Portfolio of studies. Patient recruitment began in February 2002 and ended in November 2003. Between February 2002 and October 2003, 679 consecutive patients consented to participate in our study. Patients had to be older than 18 years, be able to give written informed consent, and have recently received a diagnosis of adenocarcinoma of the rectum. In our protocol, the rectum was defined as the distal 15-cm region of the large bowel.

Exclusion Criteria
Patients were excluded if they were pregnant or had a previous history of pelvic malignancy, pelvic radiation therapy, or pelvic floor surgery for fecal incontinence or rectal prolapse. Patients were also excluded if they were unable to undergo MR imaging owing to claustrophobia or to metal fragments or implanted metal devices in the body. Patients who were referred for palliative care only or who received treatment outside our study centers also were excluded. Patients who had or were scheduled to undergo local excision of the primary tumor were excluded. Patients who had or were scheduled to undergo combination chemotherapy–radiation therapy or long-course radiation therapy (but not short-course therapy) before the planned surgery were excluded from the primary end-point analysis of the depth of extramural tumor spread because of the likely treatment effects on extramural disease.

Preoperative Assessment
Initial clinical assessment was performed by a specialist colorectal surgeon. A total of 27 surgeons, with 7–30 years experience in colorectal surgery, participated in our study. MR imaging was then performed for local tumor staging. In addition, CT scanning was used to stage distant metastases. Patient cases were discussed at a multidisciplinary team meeting, and their treatment was planned on the basis of the preoperative assessment findings. The preoperative oncologic policies of the individual hospitals were followed. However, the focus of the preoperative policy at each center was the treatment of rectal cancers that extended to the potential surgical circumferential resection margin. One hundred seventy-four patients underwent combination chemotherapy–radiation therapy or long-course radiation therapy. Fifty-one patients underwent short-course radiation therapy (5 · 5 Gy) followed by immediate surgery at centers recruiting for the Medical Research Council CR07 Study or the Swedish Stockholm III Study. These patients were included in the primary surgery group because no tumor shrinkage is observed if surgery is performed within 7 days after short-course radiation therapy.

Imaging Technique
Imaging workshops for the 18 specialist gastrointestinal radiologists (5–20 years experience reporting abdominal and pelvic MR imaging data) who participated in our study were held to ensure standardization of imaging acquisition techniques before the study commenced (Appendix E2; http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC2). The interpretation and reporting criteria for MR imaging were standardized by using previously validated criteria (13,15,16). Before the multidisciplinary team meeting, each radiologist completed a comprehensive data-reporting form for each image (Fig 1). All images were singly read by a specialist gastrointestinal radiologist. Each radiologist used a workstation to interpret images and identify the image that depicted the maximal extramural tumor spread. For each tumor, the maximal extramural depth of spread, from the outer edge of the low-signal-intensity longitudinal muscularis propria to the outermost edge of the tumor, was measured and recorded by using the workstation calipers.


Figure 1
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  		Figure 1: Data-reporting form used by specialist gastrointestinal radiologists to stage rectal cancer. CRM = circumferential resection margin, Mel = tumor less than or equal to 1 mm of mesorectal fascia, MeLev = tumor at or below level of levator ani muscle, Me0 = tumor more than 1 mm from mesorectal fascia.

 
Surgery
The median time from MR imaging to surgery was 25 days (range, 1–120 days). Each colorectal surgeon in our study performed total mesorectal excision surgery (17). This procedure involves sharp dissection outside the mesorectal fascia, which results in the removal of the rectum and the surrounding fatty envelope enclosed by the mesorectal fascia. For tumors of the middle and lower regions of the rectum, the entire mesorectum and rectum are removed.

Histopathologic Analysis
Before our study, a pathology workshop was held to introduce the standardized protocols that would be used in the investigation. Histopathologic examinations were performed in the individual laboratories of the participating hospitals, and detailed pathologic data were reported on forms. Eighteen pathologists with 5–25 years experience in gastrointestinal pathology were involved in the data reporting. The quality of both the mesorectal excision and the perineal part of the abdominoperineal excision was graded (Appendix E3; http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC3) (18,19). The histopathologist embedded the tissue slices showing maximal tumor invasion in hematoxylin-eosin stain to prepare whole- or half-mount glass slides, and the maximal depth of extramural tumor spread was measured by using a 1-mm graticule overlaid on the glass-mounted section at microscopy. The maximal depth of extramural spread was defined at histopathologic analysis as the distance from the outer edge of the longitudinal muscularis propria to the outer edge of the tumor and served as the reference standard.

Statistical Analyses
The primary end point of our study was determination of the equivalence between preoperative MR imaging measurement of the extramural depth of tumor invasion and histopathologic measurement of the same parameter after primary surgery. The MR and histopathologic results were considered to be equivalent when the 95% confidence interval of the difference between them was within ±0.5 mm. Therefore, there would be a less than 5% probability of a false claim of equivalence if the true mean difference between the MR and histopathologic results exceeded ±0.5 mm. This tolerance range was based on previous single-center experiences (13,15) and on an expected standard deviation of the difference of ±2.121 mm (15). The required sample size was 277 patients (ß = .025, {alpha} = 2ß = .05). Agreement regarding the categorical assessment of tumor stage between MR imaging and histopathologic analysis and the corresponding weighted {kappa} scores were calculated by using the Fleiss method (20) (Table 1). Analyses were performed by using SPSS, version 11.0 (SPSS, Chicago, Ill), software. P < .05 was considered to indicate statistical significance. For any discrepancies of greater than 5 mm between the MR and histopathologic results regarding extramural tumor spread, the MR images were reviewed and compared with the histopathologic findings to determine the cause(s) of error.


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  		Table 1. MR versus Histopathologic Assessment of Tumor Stage in 311 Patients Who Underwent Primary Surgery

 

   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Histopathologic Findings
At analysis of 428 histopathologic specimens, values of tumor height, defined as the measured distance of the tumor from the anal verge, were 0–5.0 cm in 137 (32%), 5.1–10.0 cm in 152 (36%), and greater than 10.1 cm in 105 (24%) cases; measurements were missing in 34 (8%) cases. Three hundred eleven patients (183 men, 128 women; median age, 67 years; age range, 33–92 years) underwent primary surgery (Table 2), and 97 underwent surgery after combination chemotherapy–radiation therapy or long-course radiation therapy (Fig 2). Anterior resection was performed in 302 (71%) of 428 cases; abdominoperineal excision, in 101 (24%) cases; and the Hartmann procedure, in 25 (6%) cases. Overall, 266 (62%) mesorectal specimens were graded as complete (all fascial planes intact), 81 (19%) were graded as moderate (intramesorectal plane breached), and 23 (5%) were graded as incomplete (muscularis propria exposed). The specimen grade was missing in 58 (14%) cases. The median number of nodes found per specimen was 13 (range, 1–50). Three hundred eleven patients were eligible for primary end-point assessment of the extramural depth of tumor spread.


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  		Table 2. Characteristics of 311 Patients Who Underwent Primary Surgery

 

Figure 2
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  		Figure 2: Flow chart shows recruitment of patients.

 
MR versus Histopathologic Measurement of Extramural Depth of Tumor Invasion
Both MR and histopathologic measurements of the extramural depth of tumor invasion were available for 295 (95%) of the 311 patients who underwent primary surgery. Mean extramural depths of invasion at MR imaging and histopathologic analysis were 2.80 mm ± 4.60 (standard deviation) and 2.81 mm ± 4.28, respectively. The mean difference between the MR and histopathologic assessments of extramural depth of invasion was –0.05 mm ± 3.85 (95% confidence interval: –0.49 mm, 0.40 mm). Therefore, we were more than 95% certain that the mean difference between the MR and histopathologic assessments of extramural depth of tumor invasion was within our predefined 0.5-mm boundary and thus that the assessments were equivalent.

In 273 (92.5%) of the 295 patients, the depth of tumor spread depicted on the thin-section MR images was within 5 mm of the histopathologic measurement (Fig 3). In 22 (7.5%) patients, the MR image interpretation, as compared with the histopathologic measurement, resulted in an apparent overestimation of the extramural depth of invasion by more than 5 mm. In these cases, use of MR imaging would have resulted in patients being assigned to an incorrect prognostic group. In four of the 22 patients, the presence of transected tumor at the circumferential resection margin probably represented pathologic underestimation. At review of the images obtained in the remaining 18 patients, there were seven image interpretation errors and 11 overestimations due to incorrect angulation of the imaging plane in tumors in the very low region of the rectum and tumors above the peritoneal reflection. At both these levels, precise angulation of the imaging plane orthogonal to the rectal wall is critical (Fig 4) (15) owing to tapering of the lower rectal region and the tortuosity of the rectosigmoid.


Figure 3
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  		Figure 3: Extramural tumor spread. Oblique axial thin-section T2-weighted fast spin-echo MR images (top images and bottom left image; repetition time msec/echo time msec, 4080/85) obtained through tumor of midrectal region and corresponding axial whole-mount histopathologic section (bottom right). (Hematoxylin-eosin stain; original magnification, x1.) MR images and histopathologic section show a circumferentially invasive tumor. On the MR images, extensive extramural venous invasion also is visible as characteristic nodular infiltration (arrows) of an intermediate-signal-intensity tumor into perirectal vessels. The maximal extramural depth of spread measured on both the images and the histopathologic section is 7 mm.

 

Figure 4A
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  		Figure 4a: Tumors in lower rectal region. (a) On oblique axial thin-section T2-weighted fast spin-echo MR image (4080/85), angulation of imaging plane perpendicular to tumor ensures that images through the true transverse plane of the tumor are obtained. (b) Oblique axial thin-section T2-weighted fast spin-echo MR image (4000/101) shows the primary tumor (curved arrow) as an intermediate-signal-intensity mass with a central ulcer, arising from the anterolateral aspect of the lower rectal region on the left side. The muscularis propria (long black arrow) is well seen on the right side of the rectum as a low-signal-intensity area, but anteriorly on the left the tumor has replaced the muscularis propria (open arrow) and there is nodular infiltrating spread (short black arrow) beyond the muscularis propria over a distance of 4 mm. (c) Findings on corresponding gross pathologic section (scale in millimeters) confirm the presence of a pT3 tumor with a maximal extramural spread (arrowhead) of 4 mm. Curved arrow points to the luminal component of the mass, which corresponds to the raised, rolled, nonadvancing edge of the tumor. Open arrow points to the infiltrating edge of the tumor, which is the site of maximal depth of tumor penetration.

 

Figure 4B
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  		Figure 4b: Tumors in lower rectal region. (a) On oblique axial thin-section T2-weighted fast spin-echo MR image (4080/85), angulation of imaging plane perpendicular to tumor ensures that images through the true transverse plane of the tumor are obtained. (b) Oblique axial thin-section T2-weighted fast spin-echo MR image (4000/101) shows the primary tumor (curved arrow) as an intermediate-signal-intensity mass with a central ulcer, arising from the anterolateral aspect of the lower rectal region on the left side. The muscularis propria (long black arrow) is well seen on the right side of the rectum as a low-signal-intensity area, but anteriorly on the left the tumor has replaced the muscularis propria (open arrow) and there is nodular infiltrating spread (short black arrow) beyond the muscularis propria over a distance of 4 mm. (c) Findings on corresponding gross pathologic section (scale in millimeters) confirm the presence of a pT3 tumor with a maximal extramural spread (arrowhead) of 4 mm. Curved arrow points to the luminal component of the mass, which corresponds to the raised, rolled, nonadvancing edge of the tumor. Open arrow points to the infiltrating edge of the tumor, which is the site of maximal depth of tumor penetration.

 

Figure 4C
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  		Figure 4c: Tumors in lower rectal region. (a) On oblique axial thin-section T2-weighted fast spin-echo MR image (4080/85), angulation of imaging plane perpendicular to tumor ensures that images through the true transverse plane of the tumor are obtained. (b) Oblique axial thin-section T2-weighted fast spin-echo MR image (4000/101) shows the primary tumor (curved arrow) as an intermediate-signal-intensity mass with a central ulcer, arising from the anterolateral aspect of the lower rectal region on the left side. The muscularis propria (long black arrow) is well seen on the right side of the rectum as a low-signal-intensity area, but anteriorly on the left the tumor has replaced the muscularis propria (open arrow) and there is nodular infiltrating spread (short black arrow) beyond the muscularis propria over a distance of 4 mm. (c) Findings on corresponding gross pathologic section (scale in millimeters) confirm the presence of a pT3 tumor with a maximal extramural spread (arrowhead) of 4 mm. Curved arrow points to the luminal component of the mass, which corresponds to the raised, rolled, nonadvancing edge of the tumor. Open arrow points to the infiltrating edge of the tumor, which is the site of maximal depth of tumor penetration.

 
In 13 (4.4%) of 295 patients, use of MR imaging led to underestimation of tumor depth, which resulted in a discrepancy of more than 5 mm. At review of these patients' images, eight patients had tumor growth along a vein, with the growth extending in continuity from the invasive tumor margin, which had been overlooked by the reporting radiologist. There were five interpretation errors due to movement artifact, which resulted in blurring of the outer muscularis propria and thus the inability to accurately measure tumor depth. There was no relationship between these interpretation errors and the experience of the reporting radiologist.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Preoperative downstaging of cancers formerly regarded as inoperable is now a frequent practice in modern clinical settings (21,22). However, the routine nonselective use of preoperative therapy has major financial implications for health care providers and poses a risk of impaired quality of life for some patients (23). In a relatively recent multicenter trial (8), the use of staging at endoluminal US resulted in substantial preoperative overstaging and consequent overtreatment. Therefore, it is important that a robust and accurate preoperative staging system is developed.

The two major advantages of thin-section MR imaging are the ability to differentiate malignant tissue from the muscularis propria (15,24) and clear delineation of the mesorectal fascia (16,25), which forms the circumferential resection margin at total mesorectal excision. To validate the staging accuracy of thin-section MR imaging by means of comparison with histopathologic staging results, we chose an objective primary end point: demonstrated equivalence of measurements of the extramural depth of tumor invasion.

Although tumor staging with use of the T component of the TNM classification is the traditional method of prognostically stratifying patients, this approach has limitations (26). The main limitation of T staging is that T3 tumors comprise the majority of rectal cancers seen at presentation, and the outcome of patients with these tumors depends on the depth of extramural spread. We measured the depth of extramural spread and used a modification of the T3 classification system proposed by Hermanek et al (27) to better assess the prognoses. From existing pathologic studies (2,3,28–30), it is clear that patients with more than 5 mm of extramural spread should be identified because they have a markedly worse prognosis than do patients who have T3 tumors with 5 mm or less of spread. Thus, the distinction between T2 stage and T3 stage is not relevant when the T3 tumor has less than 2 mm spread.

The demonstration of equivalence based on a mean difference of less than 0.5 mm means that highly accurate preoperative measurements of extramural depth of tumor invasion can be achieved and confirms that the tumor extent determined by using MR imaging correlates well with the tumor extent determined histopathologically. Our study was based on multidisciplinary data form–based data capture, so ensuring quality control was of paramount importance (31). Therefore, the gastrointestinal radiologists used standardized imaging criteria and definitions after participating in intensive training workshops in which correlated histopathologic and MR archives were used.

Total mesorectal excision surgery was performed by all surgeons in our study, and a measure of surgical quality was the number of specimens graded as complete by the histopathologist. Only 5% of the 428 specimens graded in this study were incomplete. This compares favorably with the 24% of 180 specimens graded as incomplete in another large study involving the same quality assessment protocol (19). In the MERCURY Study, the quality of the pathologic analysis, with multiple blocks, whole-mount sections, and a median lymph node harvest of 12, ensured true sampling and measurement of all specimens (32,33). This quality control was achieved owing to initial dedicated workshops in which pathologists were trained to standardize detailed assessments of the specimens.

Our imaging technique differs from conventional MR imaging in that the tumor is imaged in its true transverse plane. This prevents overestimation of tumor invasion with use of thin (3-mm) sections and a small field of view. Therefore, the tumor is accurately depicted in the plane of the corresponding histopathologic section. Work on the detailed reporting of the other known prognostic factors visible on thin-section MR images continues. For example, extramural vascular invasion is particularly amenable to diagnosis (13), and the accuracy of node assessment is improving rapidly (34,35).

A limitation of this study was the potential to overestimate and underestimate tumor depth unless meticulous care was taken to ensure that the imaging plane was orthogonal to the rectal wall and that the images were subsequently carefully interpreted. National programs to train radiologists in this technique that are based on the MERCURY model of workshops and data form–based reporting are now underway (36).

The results of this study demonstrate that MR imaging is feasible and reproducible in a multicenter setting and yields data equivalent to histopathologic results regarding the preoperative prediction of tumor spread. Demonstration of accurate measurement of the depth of extramural tumor spread in the MERCURY Study enabled accurate preoperative prognostication. Therefore, we now have a robust preoperative staging method that can be used for individualized treatment planning.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The study was initiated with the formation of a multicenter multidisciplinary study group and was coordinated by the Pelican Cancer Foundation. The study was governed by a steering committee comprising multidisciplinary representatives from the MERCURY Study Group (Appendix E1; http://radiology.rsnajnls.org/cgi/content/full/2431051825/DC1). Data from each center were collected and collated by the research fellow (I. R. Daniels, FRCS) and research nurse (S. E. Fisher), who are based at the Pelican Cancer Foundation. Data analysis was performed at the Royal Marsden Hospital by an independent statistician (A. R. Norman, PhD). The study was performed in collaboration with 12 hospitals in the United Kingdom, Norway, Sweden, and Germany. The principal investigators were I. R. Daniels, FRCS, and G. Brown, MD. I. R. Daniels, FRCS, and S. E. Fisher coordinated the study.

Members of the study steering committee, which contributed to the concept, design, and conduct of the study, were J. M. Fowler, MD (chairperson), C. E. Beagley (Chief Executive Officer, Pelican Cancer Foundation), L. Blomqvist, MD, PhD, G. Brown, MD, I. R. Daniels, FRCS, R. J. Heald, MChir, B. J. Moran, MChir, A. R. Norman, PhD, P. D. Peppercorn, FRCR, P. Quirke, PhD, and D. Sebag-Montefiore, FRCR.


   FOOTNOTES
 

Abbreviations: MERCURY = Magnetic Resonance Imaging and Rectal Cancer European Equivalence

See Materials and Methods for pertinent disclosures.


   References
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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