DOI: 10.1148/radiol.2462070042
(Radiology 2008;246:454-462.)
© RSNA, 2008
Mesorectal Fascia Invasion after Neoadjuvant Chemotherapy and Radiation Therapy for Locally Advanced Rectal Cancer: Accuracy of MR Imaging for Prediction1
Roy F. A. Vliegen, MD,
Geerard L. Beets, MD, PhD,
Guido Lammering, MD, PhD,
Raphaëla C. Dresen, MD,
Harm J. Rutten, MD, PhD,
Alfons G. Kessels, MSc,
Toen-Khiam Oei, MD,
Adriaan P. de Bruïne, MD, PhD,
Jos M. A. van Engelshoven, MD, PhD, and
Regina G. H. Beets-Tan, MD, PhD
1 From the Departments of Radiology (R.F.A.V., R.C.D., T.K.O., J.M.A.v.E., R.G.H.B.), Surgery (G.L.B.), Statistics (A.G.K.), and Pathology (A.P.d.B.), University Hospital Maastricht, P. Debyelaan 25, 6202 AZ, Maastricht, the Netherlands; Radiotherapeutical Institute Maastro Clinics, Maastricht, the Netherlands (G.L.); and Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands (H.J.R.). Received January 8, 2007; revision requested February 28; revision received May 8; accepted June 11; final version accepted August 10.
Address correspondence to R.F.A.V. (e-mail: rvli{at}rdia.azm.nl).
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ABSTRACT
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Purpose: To retrospectively assess sensitivity and specificity of magnetic resonance (MR) imaging after chemotherapy and radiation therapy for predicting tumor invasion of the mesorectal fascia (MRF) in locally advanced primary rectal cancer, by using results of histologic examination and surgery as the reference standard, and to determine morphologic MR imaging criteria for MRF invasion.
Materials and Methods: The Ethical Committee of University Hospital Maastricht approved this study and waived informed consent. Two observers independently scored postchemoradiation MR images in 64 patients with rectal cancer (38 male [mean age, 60 years] and 26 female [mean age, 64 years] patients) for MRF tumor invasion with a confidence level scoring system defined by subjective criteria. In a subsequent consensus reading session, morphologic MR criteria for invasion were defined by comparing morphologic changes with histologic findings. These criteria were evaluated and compared with the subjective criteria by comparing areas under the receiver operating characteristic curves (AUCs).
Results: AUCs of postchemoradiation MR imaging for predicting MRF tumor invasion were 0.81 and 0.82 for observers 1 and 2, respectively. The following four types of morphologic tissue patterns at MR imaging were associated with whether or not MRF invasion was present at histologic examination: (a) development of fat pad larger than 2 mm (seen in no quadrants with and in four quadrants without invasion), (b) development or persistence of spiculations (seen in no quadrants with and in 22 quadrants without invasion), (c) development of diffuse hypointense "fibrotic" tissue (seen in 21 quadrants with and in 32 quadrants without invasion), and (d) persistence of diffuse iso- or hyperintense tissue (seen in 19 quadrants with and in two quadrants without invasion). AUC of postchemoradiation MR imaging for predicting MRF invasion on the basis of morphologic criteria was 0.80. There was no significant difference between the performance of subjective and morphologic criteria (P = .73–.76).
Conclusion: Postchemoradiation MR imaging findings have moderate accuracy for predicting tumor invasion of the MRF related to the limitation in differentiating between diffuse "fibrotic" tissue with and that without small tumor foci. Specific other types of morphologic patterns at MR imaging can highly predict a tumor-free or invaded MRF.
© RSNA, 2008
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INTRODUCTION
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Locally advanced rectal cancer requires extensive surgical resection to remove the tumor with a clear margin (1,2). The rationale of neoadjuvant therapy is to downstage and downsize the tumor to improve resectability and obtain better local control (3,4). With a long course of radiation therapy (45–52 Gy) without chemotherapy, some tumor downsizing has been seen, but complete pathologic remissions are uncommon (<10%) (5,6). In patients who have responded, the initial tumor area was replaced by fibrotic scar tissue that often contained residual tumor nests (7). To achieve complete eradication of tumor, most surgeons have favored a resection of the complete area of initial tumor, more or less regardless of the amount of response. With more effective modern neoadjuvant chemotherapy and radiation therapy (hereafter, chemoradiation therapy) regimens, complete remission rates of up to 38% have resulted in questioning of the aggressive surgical approach of resecting the complete area of the initial tumor (8–10). An important issue of current surgical debate is whether or not it is safe to perform a less extensive resection in a patient with a locally advanced tumor that responded well to chemoradiation therapy (9,10).
Total mesorectal excision is now accepted as the standard surgical technique for treatment of the majority of rectal cancers (11). In this technique, a distinct anatomic compartment called the mesorectum, which contains the rectum and mesorectal fat, is removed by sharp dissection along the mesorectal fascia (MRF). Tumors that have invaded or come very close to the MRF have a higher risk for local recurrence after total mesorectal excision and should be considered as locally advanced (12). Magnetic resonance (MR) imaging has repeatedly been shown to be the most accurate modality for the prediction of MRF tumor invasion and could be an important tool in selecting patients for different types of neoadjuvant treatment regimens according to the risk of local recurrence (13–15). To our knowledge, the role of MR imaging after neoadjuvant treatment in defining the optimal surgical resection planes has not been well studied. Thus, the purpose of our study was to retrospectively assess the sensitivity and specificity of postchemoradiation MR imaging for predicting tumor invasion of the MRF in locally advanced primary rectal cancer, by using results of histologic examination and surgery as the reference standard, and to determine morphologic MR imaging criteria for invasion of the MRF.
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MATERIALS AND METHODS
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The Ethics Committee of the University Hospital Maastricht, Maastricht, the Netherlands, approved our retrospective study and waived the need to obtain informed consent.
Patients
The records of patients with locally advanced primary rectal cancer who were treated at the University Hospital Maastrich and at Catharina Hospital in Eindhoven, the Netherlands, between 1998 and 2006 were retrospectively studied. Locally advanced primary cancer was defined as invasion of surrounding organs or (near) invasion of the MRF at MR imaging. Only patients who received a long course of radiation therapy or chemoradiation therapy and who subsequently underwent surgical resection were included. Further requirements for inclusion were the availability of adequate pre- and postchemoradiation MR images and detailed surgical and histologic examination reports. Overall, of a total of 390 patients with locally advanced rectal cancer, 64 met these inclusion criteria and formed the population of this study. The main reason for exclusion was the absence or unavailability of both pre- and postchemoradiation MR images. MR imaging was not a routine investigation in the earlier time period (ie, 1998–2001). There were 38 male patients (mean age, 60 years; range, 15–82 years) and 26 women (mean age, 64 years; range, 45–81 years). According to results of the initial staging MR imaging examination, eight of the 64 patients had advanced T3 tumors with a tumor close to the MRF (defined as a tumor with a distance of 
2 mm from the MRF or with tissue strands into the MRF), 31 patients had T3 tumors with MRF invasion, and 25 patients had T4 tumors (organ invasion).
Neoadjuvant Therapy
Fifty of 64 patients received neoadjuvant radiation therapy (50.4 Gy given in 1.8-Gy fractions in 6 weeks) together with one of the following chemotherapy regimens: (a) continuous infusion of 5-fluorouracil (225 mg per square meter of body surface area per day) during the radiation course (n = 5); (b) a bolus of 5-fluorouracil (350 mg/m2) plus leucovorin (20 mg/m2) in irradiation weeks 1 and 5 (n = 14); (c) continuous capecitabine (two doses of 825 mg/m2/d) during the radiation course, with (n = 15) or without (n = 14) oxaliplatin (50 mg/m2) on the 1st day of each week; or (d) capecitabine on days 1–14 and 22–35 (two doses of 1000 mg/m2/d) combined with oxaliplatin (85 mg/m2) on days 1 and 22 (n = 2). The remaining 14 patients underwent a long course of radiation therapy only, receiving 50.4 Gy in 1.8-Gy fractions in 6 weeks.
Surgery
Six of 64 patients underwent standard total mesorectal excision, and four patients underwent standard abdominoperineal resection. Fifty-four of 64 patients underwent a more extensive resection outside the MRF, with or without sphincter preservation, which included complete or partial resection of pelvic organ(s) in 35 patients.
MR Imaging Technique
MR imaging was performed with a 1.5-T system (Gyroscan Powertrack 6000 NT; Philips Medical Systems, Best, the Netherlands) by using a phased-array coil (quadrature phased-array spine coil, cardiac or phased-array body coil). The standard protocol in both institutions consisted of the performance of T2-weighted sequences without the use of contrast material enhancement, fat suppression, rectal contrast material, or bowel relaxation. The following parameters were applied: fast spin-echo imaging; repetition time msec/echo time msec, 1288–3427/150; section thickness, 3–4-mm; intersection gap, 0.3–0.8 mm, number of signals acquired, three to eight; matrix, 168–175 x 240–256; and field of view, 20–32 cm. The images were obtained in three orientations: sagittal, coronal, and transverse. The latter two orientations were angled exactly perpendicular to the long axis of the tumor. All MR images were viewed at a workstation (Kodak, Rochester, NY).
The median time between the initial MR imaging examination and the start of chemoradiation therapy was 28 days (range, 1–93 days), the median time between the end of chemoradiation therapy and the second MR imaging examination was 34 days (range, 1–132 days), and the median time between the postchemoradiation MR imaging examination and surgery was 24 days (range, 1–72 days).
MR Image Evaluation
The MR images were read by two observers (R.G.H.B. and R.F.A.V.). Observer 1 (R.G.H.B.) was a dedicated pelvic MR radiologist with 12 years of experience in reading pelvic MR images. Observer 2 (R.F.A.V.) was a general radiologist with 8 years of experience in reading MR images.
Both observers, while blinded to each other's findings and to the histologic results, independently scored the postchemoradiation MR images for tumor invasion of the MRF by using a confidence level scoring system. The following confidence level scores were used: a score of 1 indicated that tumor invasion of the MRF was definitely absent; a score of 2, that invasion was probably absent; a score of 3, that invasion was possibly present; a score of 4, that invasion was probably present; and a score of 5, that invasion was definitely present. Prechemoradiation MR imaging studies were available during the assessment and were used for the interpretation of postchemoradiation MR images by both observers. For the definition of these confidence level scores, both observers were free to use subjective MR imaging criteria according to their individual experience with reading postchemoradiation MR images. We predefined only both ends of the confidence level spectrum. We considered the development of a fat pad larger than 2 mm between a residual (tumor) mass and the MRF a definitive sign of absence of tumor invasion at postchemoradiation MR imaging (16). At the other end, the presence of a mass infiltrating into or beyond the MRF was considered a definitive sign of tumor invasion. The MRF was defined as the fine linear structure enveloping the mesorectal compartment harboring the rectum and perirectal fat that appears hypointense on T2-weighted MR images.
In a subsequent consensus reading session, both observers described tumor morphologic changes on the combined pre- and postchemoradiation MR images to define morphologic postchemoradiation MR imaging criteria. This assessment was performed (with the previous reading results and surgical and histologic results at hand) in four individual quadrants of the MRF (the anterior, presacral, and left and right lateral quadrants) in each patient and only in quadrants that were initially threatened or invaded by the tumor.
Histologic Examination and Surgery Reference Standard
Histologic evaluation of the surgical specimens was performed according to the method of Quirke and Dixon (17) by two specialized pathologists with 17 years (A.P.d.B.) and 15 years of experience in gastroenterologic pathology. The pathologic reports stated the T stage and the shortest distance between tumor and the radial resection plane(s) and resected pelvic organ(s). In patients who underwent a multivisceral resection, the topographic orientation of the residual tumor relative to the MRF was reconstructed by means of the interpretation of pathologic reports in combination with detailed surgical reports and pre- and postchemoradiation MR imaging studies. In eight of 64 patients, the pathology report did not contain sufficiently detailed information to enable reconstruction of the relation of the tumor to the MRF. In these patients, histologic findings were reviewed (A.P.d.B., R.F.A.V.).
Statistical Analysis
The MR imaging findings were compared with findings of MRF tumor invasion at histologic examination and surgery, which served as the reference standard. We defined MRF invasion as a distance of 2 mm or less between tumor tissue and the MRF at histologic examination (16). Failures of MR imaging findings to predict MRF invasion were reviewed by one author (R.F.A.V., with 6 years of experience in reading rectal MR images) to determine the cause of the failure. Interobserver agreement was calculated by using linear-weighted 
statistics based on the scored confidence levels (18).
The morphologic tissue patterns identified at MR imaging on the quadrant level were ranked according to the rate of tumor invasion at histologic examination, and ranking categories for predicting MRF tumor invasion were assigned to these tissue changes. The value of these morphologic MR criteria for predicting MRF tumor invasion was analyzed on a per-patient level in the entire study population. When two or more patterns were visualized in one patient, the per-patient validation was based on the most aggressive pattern of invasiveness. Receiver operating characteristic curves and areas under the receiver operating characteristic curves (AUCs) were calculated with the confidence level scores and assigned ranking categories. The difference in performance was analyzed by comparing the corresponding AUC derived in the same set of patients and by calculating a critical ratio z according to the method of Hanley and McNeil (19). A P value of less than .05 was considered to indicate a statistically significant difference.
The confidence level scores were dichotomized for the calculation of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The cutoff level for the analysis of subjective criteria was set between confidence level scores 1 and 2 (considered to indicate no invasion) and confidence level scores 3–5 (considered to indicate tumor invasion of the MRF). For the analysis of morphologic MR criteria, different cutoff levels were set (as described in Results).
Statistical analysis was performed by using software (SPSS, release 11.5; SPSS, Chicago, Ill).
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RESULTS
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The results of the analysis of postchemoradiation MR imaging findings versus histologic findings showed substantial overstaging of tumor invasion of the MRF at MR imaging, which occurred in 23 (36%) of the 64 patients for observer 1 and in 14 (22%) patients for observer 2 (Table 1). In the majority of patients in whom disease was overstaged (20 of 23 patients for observer 1 and 11 of 14 patients for observer 2), diffuse hypointense tissue infiltration into the MRF was noticed at MR imaging that corresponded to sterilized areas of fibrosis at histologic examination. The sensitivity for the prediction of tumor invasion of the MRF was 100% for both observers, but the specificity was only 32% for observer 1 and 59% for observer 2 (Table 2). The interobserver agreement was = 0.38 (95% confidence interval: 0.14, 0.62).
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Table 1. Prediction of Invasion of MRF with Subjective Criteria at Postchemoradiation MR Imaging by Observers 1 and 2 Compared with Histologic Findings
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Table 2. AUC, Sensitivity, Specificity, PPV, and NPV of Postchemoradiation MR Imaging for Prediction of Tumor Invasion
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Initial tumor threatening or invasion of the MRF at MR imaging was observed in 112 of a total of 256 quadrants of the MRF in 64 patients. Reference-standard findings could not be determined on the basis of all available information (at histologic examination and surgery) in 12 of 112 quadrants, and these quadrants were therefore excluded from the analysis; a total of 100 quadrants remained for which surgical and histologic validation was possible. We identified the following four types of morphologic tissue patterns in the combined pre- and postchemoradiation MR imaging studies: Pattern A was characterized by development of a fat pad larger than 2 mm between the residual tumor mass and the MRF; pattern B, by development or persistence of spiculations invading the MRF (Figs 1, 2); pattern C, by development of diffuse hypointense "fibrotic" tissue infiltrating the MRF at the initial tumor site (Fig 3); and pattern D, by persistence of diffuse iso- or hyperintense tissue infiltrating the MRF (Fig 4).
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Figure 1a: Spiculations at pre- and postchemoradiation MR imaging correlated with tumor-free MRF. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows spiculations (arrow) that reach a minimally thickened and retracted MRF (arrowheads). T = tumor. (b) Postchemoradiation image shows that these spiculations (arrow) remain unchanged; some tumor shrinkage can be noticed. Arrowheads = MRF. (c) Corresponding histologic slice shows fibrotic spiculations (arrows) (without residual tumor tissue) in perirectal fat that project into the circumferential resection margin (arrowheads). (Hematoxylin-eosin stain; original magnification, x2.5.)
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Figure 1b: Spiculations at pre- and postchemoradiation MR imaging correlated with tumor-free MRF. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows spiculations (arrow) that reach a minimally thickened and retracted MRF (arrowheads). T = tumor. (b) Postchemoradiation image shows that these spiculations (arrow) remain unchanged; some tumor shrinkage can be noticed. Arrowheads = MRF. (c) Corresponding histologic slice shows fibrotic spiculations (arrows) (without residual tumor tissue) in perirectal fat that project into the circumferential resection margin (arrowheads). (Hematoxylin-eosin stain; original magnification, x2.5.)
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Figure 1c: Spiculations at pre- and postchemoradiation MR imaging correlated with tumor-free MRF. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows spiculations (arrow) that reach a minimally thickened and retracted MRF (arrowheads). T = tumor. (b) Postchemoradiation image shows that these spiculations (arrow) remain unchanged; some tumor shrinkage can be noticed. Arrowheads = MRF. (c) Corresponding histologic slice shows fibrotic spiculations (arrows) (without residual tumor tissue) in perirectal fat that project into the circumferential resection margin (arrowheads). (Hematoxylin-eosin stain; original magnification, x2.5.)
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Figure 2a: Spiculations at pre- and postchemoradiation MR imaging were associated with tumor-free MRF. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows spiculations (arrow) projecting into the MRF (arrowheads). (b) Postchemoradiation image shows that spiculations (arrow) remain unchanged. Arrowhead = MRF. (c) Corresponding histologic slice shows residual tumor (arrow) limited to the rectal wall and fibrotic spiculations (arrowheads) projecting into the circumferential resection margin. (Hematoxylin-eosin stain; original magnification, x5.)
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Figure 2b: Spiculations at pre- and postchemoradiation MR imaging were associated with tumor-free MRF. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows spiculations (arrow) projecting into the MRF (arrowheads). (b) Postchemoradiation image shows that spiculations (arrow) remain unchanged. Arrowhead = MRF. (c) Corresponding histologic slice shows residual tumor (arrow) limited to the rectal wall and fibrotic spiculations (arrowheads) projecting into the circumferential resection margin. (Hematoxylin-eosin stain; original magnification, x5.)
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Figure 2c: Spiculations at pre- and postchemoradiation MR imaging were associated with tumor-free MRF. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows spiculations (arrow) projecting into the MRF (arrowheads). (b) Postchemoradiation image shows that spiculations (arrow) remain unchanged. Arrowhead = MRF. (c) Corresponding histologic slice shows residual tumor (arrow) limited to the rectal wall and fibrotic spiculations (arrowheads) projecting into the circumferential resection margin. (Hematoxylin-eosin stain; original magnification, x5.)
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Figure 3a: Diffuse hypointense tissue infiltration at postchemoradiation MR imaging suggestive of fibrosis can be associated with MRF tumor invasion caused by residual tumor nests within fibrosis. V = seminal vesicle. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). B = bladder, T = tumor. (a) Prechemoradiation image shows diffuse isointense invasion of anterior MRF (arrows) and left seminal vesicle. (b) Postchemoradiation image shows that this type of invasion has changed into diffuse hypointense tissue infiltration (arrows), suggesting diffuse fibrosis. (c) Corresponding histologic slice shows a diffuse fibrotic reaction (arrows) that reaches the seminal vesicle and contains small residual tumor nests. These small tumor nests cannot be seen at MR imaging; therefore, it is impossible to differentiate fibrosis with from that without small tumor nests at MR imaging. (Hematoxylin-eosin stain; original magnification, x2.5.)
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Figure 3b: Diffuse hypointense tissue infiltration at postchemoradiation MR imaging suggestive of fibrosis can be associated with MRF tumor invasion caused by residual tumor nests within fibrosis. V = seminal vesicle. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). B = bladder, T = tumor. (a) Prechemoradiation image shows diffuse isointense invasion of anterior MRF (arrows) and left seminal vesicle. (b) Postchemoradiation image shows that this type of invasion has changed into diffuse hypointense tissue infiltration (arrows), suggesting diffuse fibrosis. (c) Corresponding histologic slice shows a diffuse fibrotic reaction (arrows) that reaches the seminal vesicle and contains small residual tumor nests. These small tumor nests cannot be seen at MR imaging; therefore, it is impossible to differentiate fibrosis with from that without small tumor nests at MR imaging. (Hematoxylin-eosin stain; original magnification, x2.5.)
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Figure 3c: Diffuse hypointense tissue infiltration at postchemoradiation MR imaging suggestive of fibrosis can be associated with MRF tumor invasion caused by residual tumor nests within fibrosis. V = seminal vesicle. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). B = bladder, T = tumor. (a) Prechemoradiation image shows diffuse isointense invasion of anterior MRF (arrows) and left seminal vesicle. (b) Postchemoradiation image shows that this type of invasion has changed into diffuse hypointense tissue infiltration (arrows), suggesting diffuse fibrosis. (c) Corresponding histologic slice shows a diffuse fibrotic reaction (arrows) that reaches the seminal vesicle and contains small residual tumor nests. These small tumor nests cannot be seen at MR imaging; therefore, it is impossible to differentiate fibrosis with from that without small tumor nests at MR imaging. (Hematoxylin-eosin stain; original magnification, x2.5.)
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Figure 4a: Diffuse hyperintense tissue infiltration (morphologic tissue pattern D) associated with tumoral invasion. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows hyperintense (compared with muscle) tissue invasion of presacral MRF (arrow). T = tumor. (b) Postchemoradiation image shows that diffuse hyperintense infiltration of the MRF (arrow) is still present. S = sacrum. (c) Corresponding histologic slice shows gross residual tumor (T) near the circumferential resection margin, with only a small tumor-free margin (between arrows). This was considered as proof of tumor invasion of the MRF because the surgeon performed a wide extramesorectal surgical excision posteriorly. (Hematoxylin-eosin stain; original magnification, x5.)
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Figure 4b: Diffuse hyperintense tissue infiltration (morphologic tissue pattern D) associated with tumoral invasion. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows hyperintense (compared with muscle) tissue invasion of presacral MRF (arrow). T = tumor. (b) Postchemoradiation image shows that diffuse hyperintense infiltration of the MRF (arrow) is still present. S = sacrum. (c) Corresponding histologic slice shows gross residual tumor (T) near the circumferential resection margin, with only a small tumor-free margin (between arrows). This was considered as proof of tumor invasion of the MRF because the surgeon performed a wide extramesorectal surgical excision posteriorly. (Hematoxylin-eosin stain; original magnification, x5.)
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Figure 4c: Diffuse hyperintense tissue infiltration (morphologic tissue pattern D) associated with tumoral invasion. (a, b) Transverse T2-weighted fast spin-echo MR images (3427/150). (a) Prechemoradiation image shows hyperintense (compared with muscle) tissue invasion of presacral MRF (arrow). T = tumor. (b) Postchemoradiation image shows that diffuse hyperintense infiltration of the MRF (arrow) is still present. S = sacrum. (c) Corresponding histologic slice shows gross residual tumor (T) near the circumferential resection margin, with only a small tumor-free margin (between arrows). This was considered as proof of tumor invasion of the MRF because the surgeon performed a wide extramesorectal surgical excision posteriorly. (Hematoxylin-eosin stain; original magnification, x5.)
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Comparison of these MR imaging patterns with the reference-standard histologic findings showed an increasing frequency of tumor invasion of the MRF from pattern A to pattern D (Table 3). Morphologic MR criteria for the prediction of MRF tumor invasion were defined on the basis of the analysis of tissue findings and were ranked as follows: A rank of 1 indicated definitely no MRF tumor invasion and included patterns A and B, a rank of 2 indicated possible invasion and included pattern C, and a rank of 3 indicated probable invasion and included pattern D.
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Table 3. Morphologic Tissue Patterns Identified in Combined Pre- and Postchemoradiation MR Imaging Studies versus Tumor Invasion of MRF at Histologic Examination
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Regarding the performance of these morphologic MR criteria (Table 4, Fig 5) for the prediction of MRF tumor invasion at a per-patient level in the entire study population, there was overstaging of disease in 34% (22 of 64) of patients and understaging of disease in 0% (zero of 64) of patients when a cutoff level was taken between ranking category 1 (as indicating no invasion) and categories 2 and 3 (as indicating MRF invasion). A cutoff level between ranking categories 1 and 2 (as indicating no invasion) and category 3 (as indicating MRF invasion) resulted in understaging of disease in 25% (16 of 64) of patients and overstaging of disease in 3% (two of 64) of patients.
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Table 4. Performance of Morphologic MR Imaging Criteria for Prediction of Tumor Invasion of MRF at Per-Patient Level with Different Cutoff Levels
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Figure 5: Flowchart of patient inclusion and results of postchemoradiation (PostCRT) MR imaging for prediction of tumor invasion of the MRF by application of MR imaging criteria. Note that prediction of invasion of the MRF at a per-patient level was determined by the most aggressive MR imaging pattern observed. * = See patient inclusion criteria in Materials and Methods section, ** = individual quadrants without reference-standard (ref.) findings in patients with histologically proved tumor invasion of the MRF at other quadrant(s). CRT = chemoradiation, Def. = definitely, PreCRT = prechemoradiation.
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There was no statistically significant difference between the performance of subjective criteria used by the observers and morphologic MR criteria for the prediction of MRF invasion at postchemoradiation MR imaging (P = .73–.76).
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DISCUSSION
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Our study evaluated the performance of postchemoradiation MR imaging for the prediction of MRF tumor invasion. We found a relatively high AUC (0.81 and 0.82) and a high sensitivity and NPV (both 100%) for both observers. However, our results showed only a moderate specificity (32% and 59%) and PPV (57% and 68%). The main difficulty of postchemoradiation MR imaging in the assessment of MRF tumor invasion is the assessment of diffuse hypointense "fibrotic" tissue in the initial tumor area, which is a feature seen in more than 50% of patients. In one of three quadrants, this fibrotic tissue at MR imaging showed tumor infiltration at histologic examination. Residual tumor within these fibrotic areas is often confined to small tumor nests that are beyond the depiction level of MR imaging (7,20). It is therefore virtually impossible to differentiate these from completely sterilized areas of fibrosis.
Although, to our knowledge, no other studies have addressed the question of the prediction of MRF tumor invasion with MR imaging after long courses of chemoradiation therapy, there are some reports on the prediction of T stage at MR imaging after chemoradiation therapy (21–23). These have reported accuracies of only 47%–53%, confirming the limited ability of postchemoradiation MR imaging to help differentiate between viable tumor, fibrotic tissue, and inflammatory reaction.
Our experienced observers were generally aware of the limitation of MR imaging in depicting residual tumor disease in diffuse hypointense "fibrotic" areas and set their cutoff levels so as to minimize the number of false-negative findings, at the expense of many false-positive findings. From a clinical point of view, overstaging of disease is much more acceptable than understaging, as understaging may lead to incomplete tumor resection and an unacceptably high risk of local tumor recurrence (1,2,24).
The moderate interobserver agreement ( = 0.38) between both experienced observers implies substantial difficulty in interpreting postchemoradiation MR images, and this may be a reflection of the lack of uniform postchemoradiation MR imaging criteria for tumor invasion of the MRF. The application of uniform MR imaging criteria on the basis of our analysis of morphologic tissue changes did not improve the staging results compared with the subjective assessment of both observers (P = .73–.76). We still encountered substantial overstaging in 34% (22 of 64) of patients when the cutoff level was set so as to accept no understaging. On the other hand, dramatic understaging occurred in 25% (16 of 64) of patients when a less conservative cutoff level was chosen by considering cases of diffuse "fibrotic" tissue infiltration as negative for MRF tumor invasion.
Despite the problems of MR imaging in the interpretation of postradiotherapy fibrosis, some potentially useful specific morphologic patterns were identified. The presence of diffuse iso- or hyperintense tissue infiltration of the MRF at MR imaging was associated with tumor invasion at histologic examination in 90% (19 of 21) of the quadrants in which this pattern was seen. On the other hand, when spiculations had developed at postchemoradiation MR imaging or were seen in the combined pre- and postchemoradiation MR imaging studies, this was always associated with a tumor-free MRF at histologic examination (22 of 22 quadrants). We are aware that in some of these patients, the initial tumor invasion of the MRF before chemoradiation therapy was debatable, as in some patients the tumor was close to the fascia rather than invading it (13,25).
When considering the results of our study, one must keep in mind that the design of the study had some limitations. First, although the reference standard of this study was based on results of the combined analysis of detailed standardized pathologic reports, detailed surgical reports, MR imaging studies, and, in some patients, histologic results, inaccuracies might have been introduced because of the retrospective nature of this study. Second, a selection bias might have been introduced because of the inclusion of nonconsecutive patients and the exclusion of MR imaging features seen in quadrants for which no reference-standard finding could be determined. This occurred, however, in only a minority of quadrants; therefore, we believe this does not substantially influence our main findings. The third limitation was the time span between the postchemoradiation MR imaging examination and the resection. In this period, with a median of 24 days, a further regression of the tumor is likely to occur, and theoretically, this could account for some of the overstaging errors that mainly occurred in the interpretation of areas of fibrosis (26). This should be kept in mind when interpreting the results.
Furthermore, the MR imaging protocol could have been a matter of debate. After it had been shown in a previous study (25) that static gadolinium-enhanced T1-weighted sequences had no additional value in the assessment of MRF invasion in nonirradiated rectal cancer, these sequences were omitted from the standard MR imaging protocol in our department. The use of dynamic contrast material–enhanced sequences has been reported to be useful in other applications such as differentiating tumor (recurrences) from benign (postoperative) tissue by enabling measurement of time–signal intensity curves or perfusion indexes (27,28). However, it remains questionable whether these techniques would offer any help for the main problem in our study: The detection of small areas of tumor within poorly vascularized fibrotic tissue. Positron emission tomography (PET) suffers from the same limitation, as illustrated in a publication (29) that reported no increased tracer uptake in the majority of responding tumors with small residual areas of disease. Additionally, the increased uptake of fluorine 18 fluorodeoxyglucose by nontumorous inflammatory tissue after neoadjuvant therapy could lead to interpretational errors.
If imaging of small amounts of viable tumor is ever to be successful, we believe it will be through advances in the field of molecular imaging with PET or MR imaging. When considering the above limitations of interpreting postchemoradiation MR imaging studies, one could question their usefulness. Many surgeons will choose to resect the complete initial tumor area, more or less irrespective of the amount of response. At present, it is unclear if and when it is safe to perform more conservative resections on the basis of imaging findings of the response, and so far the present standard of care does not take into consideration postchemoradiation MR findings. However, with higher response rates and better imaging methods, surgeons will be forced to rethink this strategy. At present, even with its limitations, we still perform postchemoradiation MR imaging. Its results help tell the surgeon what to expect, and occasionally—for example, in frail patients with a good response—a more conservative resection can be performed. A resection along the MRF (total mesorectal excision surgery) seems to be justified when "fibrotic" spiculations are identified at postchemoradiation MR imaging. It is clear that when diffuse iso- or hyperintense "tumor" infiltration is seen at MR imaging, whole-area resection is required. Maybe of even more importance is the fact that that MR imaging findings may alert the surgeon and change the resection plan in case of tumor progression after chemoradiation therapy. It is the most commonly seen pattern of diffuse hypointense "fibrotic" tissue infiltration that remains difficult to interpret. We inform the surgeon of the chances of an invaded MRF (one in three in our population), and it is up to the surgeon to weigh the benefit of a less aggressive surgical approach against a potentially positive resection margin.
In conclusion, postchemoradiation MR imaging has a moderate accuracy (sensitivity, 100%; specificity, 32%–59%) for predicting tumor invasion of the MRF that is related to the inherent limitation of differentiating between diffuse "fibrotic" tissue harboring small tumor foci and completely sterilized areas of fibrosis. "Fibrotic" areas should therefore be considered as potentially invaded. Specific other types of morphologic tissue changes at MR imaging can highly predict a tumor-free or invaded MRF.
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ADVANCES IN KNOWLEDGE
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- Postchemoradiation MR imaging has a moderate accuracy (sensitivity, 100%; specificity, 32%–59%) for the prediction of tumor invasion of the mesorectal fascia (MRF) because of its limitations for differentiating diffuse "fibrotic" tissue with or without small residual tumor foci.
- Specific morphologic tissue patterns identified at MR imaging highly correspond with a tumor-free or tumor-invaded MRF.
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IMPLICATION FOR PATIENT CARE
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- Certain morphologic tissue patterns identified at MR imaging may inform the surgeon of a high, intermediate, or low risk for tumor invasion of the MRF.
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FOOTNOTES
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Abbreviations: AUC = area under the receiver operating characteristic curve • MRF = mesorectal fascia • NPV = negative predictive value • PPV = positive predictive value
Author contributions: Guarantors of integrity of entire study, R.F.A.V., G.L.B., A.P.d.B., R.G.H.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, R.F.A.V., G.L.B., R.C.D., R.G.H.B.; clinical studies, R.F.A.V., G.L.B., G.L., R.C.D., H.J.R., A.P.d.B., R.G.H.B.; statistical analysis, R.F.A.V., G.L.B., A.G.K., R.G.H.B.; and manuscript editing, all authors
Authors stated no financial relationship to disclose.
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Radiology,
March 1, 2009;
250(3):
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ABSTRACT
INTRODUCTION
