Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎
Original article
Multiparametric magnetic resonance imaging localizes established extracapsular extension of prostate cancer Tom S. Feng, M.D.a, Ali Reza Sharif-Afshar, M.D.a, Steven C. Smith, M.D.b, Joseph Miller, M.D.c, Christopher Nguyend, Quanlin Li, M.S.d, Daniel Luthringer, M.D.b, Debiao Li, Ph.D.d, Rola Saouaf, M.D.c, Hyung L. Kim, M.D.a,* b
a Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA c Department of Radiology, Cedars-Sinai Medical Center, Los Angeles, CA d Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
Received 7 September 2014; received in revised form 10 November 2014; accepted 11 November 2014
Abstract Objective: To define the accuracy of multiparametric magnetic resonance imaging (MP-MRI) for identifying focal and established extracapsular extension (ECE) in various zones of the prostate. Methods: Between 2010 and 2013, 342 patients underwent MP-MRI of the prostate (3 T, no endorectal coil with axial perfusion and diffusion images). The findings of the images were reported as negative, suspicious, or positive for ECE by a single expert radiologist. Radical prostatectomy specimens were reviewed to confirm the size and the location of ECE and further defined as focal or established ECE. Established ECE included extension that was multifocal or involving more than 5 glands. The accuracy of MRI in localizing focal and established ECE to each zone of the prostate was determined. Regression analyses were performed to identify predictors of ECE. Results: We identified 112 patients who underwent prostate MP-MRI and radical prostatectomy. MRI findings considered suspicious or definite for ECE accurately predicted pathologic ECE (P o 0.001). MP-MRI identified established ECE but not focal ECE. Sensitivity, specificity, positive predictive value, and negative predictive value of MP-MRI for established ECE were 70.7%, 90.6%, 57.1%, and 95.1%, respectively. MRI identified ECE to the left vs. right side as well as each zone of the prostate; however, sensitivity was lowest at the apex. On multivariate analysis, MRI was a significant predictor of ECE that was independent of prostate-specific antigen level, Gleason score, and clinical stage. Conclusion: MP-MRI is useful for identifying established but not focal ECE in all zones of the prostate. MRI was a significant independent predictor of established ECE and may be a useful adjunct in staging prostate cancer. r 2014 Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Extracapsular extension; Magnetic resonance imaging; Cancer staging
1. Introduction Accurate clinical staging is important for managing prostate cancer. Compared with organ-confined disease, prostate cancer with extracapsular extension (ECE) is associated with decreased overall and cancer-specific survival following radical prostatectomy [1,2]. Moreover, even the extent of ECE predicts disease recurrence and survival [3,4]. When ECE is suspected, the cavernous nerves, which are responsible for erectile function, are often resected to Corresponding author. Tel.: þ1-310-423-4700; fax: þ1-310-423-4711. E-mail address:
[email protected] (H.L. Kim). *
http://dx.doi.org/10.1016/j.urolonc.2014.11.007 1078-1439/r 2014 Elsevier Inc. All rights reserved.
enhance the likelihood of achieving negative margins [5,6]. Therefore, preoperative identification of ECE may be beneficial for patient counseling, surgical planning, and even deciding between modes of therapy such as surgery and radiation therapy. Historically, the mainstay for clinical staging of prostate cancer has been the digital rectal examination and transrectal ultrasound (TRUS), which have low accuracy for identifying ECE. However, multiparametric magnetic resonance imaging (MP-MRI) promises to provide more accurate diagnosis and staging. The accuracy of MRI for detecting ECE has been estimated to be 62% to 76% [6–8]. However, none of these prior reports considered the extent
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or location of ECE that MRI can detect. We aim to show that MP-MRI can identify established ECE but not focal ECE, and we define the accuracy of MP-MRI for predicting established ECE in various zones of the prostate. 2. Methods
corresponds to PI-RAD 1–2, 3, or 4–5, respectively. For example, irregularity of the capsule (PI-RAD 3) was reported as “suspicious” for ECE. PI-RAD 4 and 5 findings such as bulge with loss of capsule, neurovascular bundle thickening, or measurable extracapsular disease were considered “definite” for ECE by the radiologist. 2.3. Pathology
2.1. Subjects Between January 2010 and July 2013, 342 patients underwent MP-MRI of the prostate gland. For all patients, prostate-specific antigen (PSA) level, clinical stage determined by digital rectal examination, Gleason score from TRUS biopsy, and findings from the radical prostatectomy specimen were recorded. Patients receiving preoperative androgen deprivation therapy or having MRIs before TRUS biopsy were excluded. 2.2. Imaging and interpretation All patients underwent imaging using a 3.0-T MRI system (Verio, Siemens) equipped with a 12-channel pelvic phased array coil. Anatomic images, including T1- (0.5 0.5 3.5 mm3, repetition time [TR]/echo time [TE] = 4,800/10 ms) and T2-weighted (T2W) (0.5 0.5 3.5 mm3, TR/TE = 4,800/ 125 ms) turbo spin echo, were acquired in the axial, sagittal, and coronal planes. Diffusion-weighted imaging was acquired using a standard single-shot echo-planar imaging sequence (2.1 1.7 3.5 mm3, TR/TE = 5,000/80 ms, iPat = 2, NEX = 3). Three orthogonal diffusion directions including a single b0 measurement were acquired at 2 nonzero b values (400 and 800 s/mm2), yielding 7 measurements to calculate trace apparent diffusion coefficient maps. Dynamic contrastenhanced MRI (1.3 1.3 3.5 mm3, TR/TE = 3.02/ 1.09 ms, temporal resolution = 40 s) was acquired and consisted of a prescan, a series of continuous acquisition of 12 volumes postcontrast delivery, and a final 9-minute delay postscan. All patients with glomerular filtration rate less than 30 mL/min/1.73 m2 were not administered a contrast agent. All cases were reviewed by a single radiologist with expertise in prostate MR images, who was blinded to the final pathology. Three techniques (T2W imaging, diffusionweighted imaging, and dynamic contrast-enhanced) were used for localization of tumor and ECE. All patients had previously undergone biopsy, and T1-weighted images were correlated with T2W images to evaluate for changes owing to postbiopsy hemorrhage. Most MRI studies were obtained 4 weeks after biopsy to reduce hemorrhage artifact. The radiologist evaluated suspicious lesions with apparent diffusion coefficient values as well. The level of suspicion for ECE was categorized as none, suspicious, or definitely positive. Our 3-point system is compatible with the 5-point prostate imaging and reporting data system (PIRAD) proposed by the European Society of Urogenital Radiology [9]. In our system, none, suspicious, and definite
Following radical prostatectomy, prostate specimens were fixed in 10% neutral buffered formalin and processed according to the standard prostatectomy gross protocol at our institution, which uses the International Society of Urological Pathology (ISUP) Consensus Guidelines on prostatectomy handling and processing [10]. Briefly, after fixation and surface capsular inking (multicolor for anatomic orientation), 5-mm bladder neck and apex shave sections were sampled as margins, as were longitudinal sections of both seminal vesicles. The remainder of the gland was sectioned in 3-mm increments perpendicular to the urethra. For prostates less than 30 g, all serial sections were submitted; for prostates more than 30 g, an ISUP Guideline–compliant partial submission protocol was used, which emphasizes submission of all grossly visible tumor and any areas suspicious for ECE [10]. In either case, the sections were submitted with ordered anatomic designations to enable 3-dimensional reconstruction of the gland from histologic sections. After histologic staining, all tumor foci were outlined on the microscopic slides. Primary and secondary Gleason grade patterns, as well as presence of ECE and seminal vesicle involvement, were documented in all cases for staging purposes. For this study, archival hematoxylin and eosin–stained slides were rereviewed by the blinded pathologist to confirm the diagnosis and the staging. ECE was defined as recommended by the ISUP as “presence of tumor beyond the confines of the prostate” [11]. Each case was reviewed to identify the specific location (laterality and zone: apex, mid, and base). In conformity with the current reporting guidelines recommending quantitation of ECE [12], the extent of ECE was further stratified as focal or established ECE. Consistent with the “Epstein criterion” [4], focal ECE was defined as ECE limited to a “few glands” (glands meaning invading acini of adenocarcinoma). A cutoff of 5 or less invading glands was defined as “few.” By contrast, established ECE was defined as either ECE involving more than 5 glands outside the prostate or ECE occurring at multiple distinct locations. These scenarios and their definitions are illustrated in Supplemental Figure S1. 2.4. Statistical analysis The diagnostic value of MP-MRI for ECE was summarized by sensitivity, specificity, positive predictive value (PPV), and negative predictive value. The descriptive statistics were calculated for focal and established ECE as
T.S. Feng et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–8 Table 1 Patient characteristics Mean age ⫾ SD Mean PSA level ⫾ SD
62.8 ⫾ 7.5 8.2 ⫾ 7.2
Clinical stage (%) cT1 cT2a cT2b cT2c
81 (72) 26 (23) 4 (3.5) 1 (0.9)
Gleason score on biopsy (%) 6 7 8 Or greater
47 (42) 47 (42) 18 (16)
Final Gleason score (%) 6 7 8 Or greater
27 (24) 73 (65) 12 (11)
SD ¼ standard deviation.
well for each zone of the prostate (apex, mid, and base). The Fisher exact test was used, and significance was set a priori at P o 0.05. Regression analyses were performed to identify predictors of ECE. Area under the curve was calculated for predictive models.
3. Results In total, 112 patients who underwent prostate MP-MRI before undergoing radical prostatectomy were identified. Table 1 shows the demographic characteristics of the study population. Mean age was 62.8 years and mean PSA level was 8.2. Most (95%) patients had clinical stage T1c or T2a cancer. In total, 33 patients (29%) had ECE based on the findings of on MP-MRI, whereas 29 patients (26%) had ECE on the final pathology. Of the 33 MRI findings suspicious for ECE, 61% were classified as “suspicious” and 39% as “definite.” The location of ECE was identified
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based on the findings of the MR image and on the pathology. Fig. 1A shows the number of cases with established ECE in each zone of the prostate based on the findings of the pathology test, and Fig. 1B shows the number of MR images with findings suspicious or definitive for ECE. Figs. 2 and 3 show examples of ECE. First, we determined whether different levels of suspicion for ECE on MRI affect the prediction of final pathology. MRI findings considered suspicious for ECE predicted pathologic established ECE in 50% of cases. By contrast, MRI findings considered definitive for ECE predicted pathologic established ECE in 92% of cases. In the course of patient care, MRI findings lead to binary clinical decisions (e.g., decision to save or sacrifice the cavernous nerve). Therefore, we considered 2 separate scenarios where suspicious MRI findings were considered positive or negative (Table 2). When suspicious MRI findings were considered negative, MRI as a predictor of ECE had a sensitivity, specificity, and receiver operating characteristic (ROC) area of 42.4%, 99%, and 0.72, respectively. However, when suspicious MRI findings were considered positive as well as the definite findings, MRI as a predictor of ECE had a sensitivity and an ROC area of 72.7% and 0.86, respectively. Given the higher ROC area, suspicious MRI findings were considered positive in all subsequent analyses. We considered whether MP-MRI can identify focal or established ECE seen on pathology (Table 3). For this analysis, each lobe (i.e., left and right, n ¼ 224) was considered a single entity. MP-MRI was significantly predictive of ECE (P o 0.001) with a sensitivity and a specificity of 62.5% and 90.8%, respectively. However when focal and established ECE were considered separately, MP-MRI only identified 1 of 7 focal ECE (P ¼ 0.506), resulting in a sensitivity of 14.3% and PPV of 5.6%. By contrast, MP-MRI was more accurate for predicting established ECE, with a sensitivity and a PPV of 73% and 57%, respectively. Finally, the locations of
Fig. 1. Location of extracapsular extension. (A) On pathology, the number of cases with established ECE in each zone was noted. (B) On MRI, the number of cases with findings suspicious or definitive for ECE in each zone was noted.
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Fig. 2. Example of right apical prostate cancer suspicious for extracapsular extension. (A–C) Axial, coronal, and sagittal T2-weighted MR images through the prostate demonstrate an ill-defined area of hypointensity within the right apical peripheral zone consistent with malignancy. Reduction in T2 signal is characteristic of increased cellularity. Irregularity of capsular margin (arrows) is seen, suspicious for extracapsular extension. (D and E) Axial diffusionweighted image (DWI) and apparent diffusion coefficient (ADC) image of the same lesion. Although difficult to differentiate on DWI, ADC demonstrates a clear focus of restricted diffusion seen as a relative dark spot (arrow). Diffusion restriction is seen with increasing cellularity and supports diagnosis of neoplasm. (F–H) T1-weighted dynamic contrast evaluation is performed by taking multiple images through the prostate at continuous intervals after contrast agent injection. Individual time points (F) are compared to generate a color map of vascularity (G) and a graph of enhancement over time (H). Neoplastic lesions typically reveal a characteristic rapid enhancement and subsequent washout, as seen here. Normal prostate tissue does not wash out, but instead demonstrates either a flat or a linearly increasing enhancement. (I) Representative photomicrograph (40, H&E) of a focus of ECE at the apex of the prostate. Several malignant glands show perineural invasion and bulge outside the contours of the prostate. Multiple foci of ECE were present; thus, extracapsular extension at the apex was considered established. H&E ¼ hematoxylin and eosin. (Color version of figure is available online.)
ECE determined on MRI and final pathology were correlated (Table 4). MP-MRI was more accurate for predicting established ECE at the midprostate and base (P o 0.001) than at the apex (P ¼ 0.003). Sensitivity of
the MP-MRI was greatest at the base of the prostate (70.4%) and least at the apex (30%). On univariate analysis, Gleason score, PSA level, clinical stage, and MP-MRI findings were significantly
T.S. Feng et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–8
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Fig. 3. Example of established extracapsular extension of prostate cancer at the midgland and base. (A–C) Axial, coronal, and sagittal T2-weighted MR images through the prostate demonstrate 2 distinct foci ECE at the left midgland (black arrows) and left base (white arrows). (D) Representative photomicrograph (40, H&E) of an area of ECE at the base of the prostate. High-grade, poorly differentiated adenocarcinoma is apparent, with desmoplastic stromal response to the sheetlike growth of invading tumor. ECE broadly involved the midgland and base of the organ. H&E ¼ hematoxylin and eosin. (Color version of figure is available online.)
Table 2 Predictive value of MP-MRI comparing definitions for ECE on MRI Criteria for positive MRI
Fisher exact, P value
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
AUC
Suspicious or definite Definite only
o0.001 o0.001
72.7 (54.5–86.7) 42.4 (25.5–60.8)
90.6 (85.5–94.3) 99.0 (96.3–99.9)
57.1 (41.0–72.3) 87.5 (61.7–98.4)
95.1 (90.8–97.7) 90.9 (86.1–94.4)
0.86 0.72
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Table 3 MP-MRI for identifying extent of histologic ECE in each side of the prostate ECE extent on pathology
Fisher exact, P value
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
All ECE Focal ECE Established ECE
o0.001 0.506 o0.001
62.5 (45.8–77.3) 14.3 (0.4–57.9) 72.7 (54.5–86.7)
90.8 (85.6–94.4) 90.8 (85.6–94.5) 90.6 (85.5–94.3)
59.5 (43.3–74.4) 5.6 (0.1–27.3) 57.1 (41.0–72.3)
91.8 (86.8–95.3) 96.5 (92.6–98.7) 95.1 (90.8–97.7)
associated with detection of ECE on final pathology (Table 5). On multivariate analysis, when controlling for Gleason score, PSA level, and clinical stage, MP-MRI remained significantly associated with the detection of ECE. In fact, MP-MRI had the highest odds ratio of 26.8 (P o 0.001) for predicting ECE as compared with Gleason score (odds ratio ¼ 2.63) and PSA level (odds ratio ¼ 2.9). By contrast, clinical stage was not an independent predictor of ECE (P ¼ 0.969). Area under the curve (AUC) for risk of ECE calculated from the Partin tables was 0.85 (Supplemental Figure S2). The AUC increased to 0.92 when MP-MRI was added and was statistically significant (P o 0.05).
4. Discussion ECE predicts survival and influences management of prostate cancer. In this study, ECE was noted in 26% of radical prostatectomy specimens, which is similar to prior reports [13]. Identifying these patients before surgery can influence the selection of definitive local therapy and decision to spare the neurovascular bundles during surgery. However, clinical staging based on physical examination has limited accuracy with 25% to 30% of patients with ECE being understaged preoperatively [14,15]. To improve preoperative risk assessment, numerous nomograms have been developed to predict ECE. Partin tables were constructed to assess the risk of ECE based on PSA level, biopsy Gleason score, and clinical stage [16]. Other models for predicting ECE include additional information from the findings of the prostate biopsy such as percentage of biopsy cores with cancer and presence of perineural invasion [17]. However, these well-established measures of disease aggressiveness correlate only roughly with final pathologic stage. MRI may be a better tool for preoperative staging because it has the potential to directly visualize the prostate cancer and its relationship to the prostate capsule. MP-MRI has been reported to have sensitivities of 35% to 58% and
specificities of 89% to 92% for predicting ECE [6–8]. Our study confirms that MP-MRI can be useful for predicting ECE. The overall sensitivity and specificity of 62.5% and 90.8%, respectively, reported by us are similar to those reported by others [8]. Furthermore, we assessed MP-MRI in a multivariate analysis with clinical factors used in the Partin tables [16] and showed that MP-MRI was a significant and strongest predictor of ECE among all the parameters tested. Our study confirmed the usefulness of MP-MRI as the AUC increased with the addition of MPMRI to readily available clinical parameters from the Partin tables. An important distinction of our study is that we considered ECE in specific areas of the prostate. For example, we considered ECE in each lobe (left/right) as well as in each zone (apex, mid, and base) of the prostate. When the entire gland is considered as a unit as done in prior studies, the performance of the MRI may be overestimated when the MRI and pathology identify ECE in different areas in the same patient. The current study correlates ECE in each specific zone of the prostate and yet provides similar performance characteristics of the MRI in predicting ECE. Furthermore, we address the possibility that performance of the MRI may differ in various parts of the prostate. Another important distinction of our study is that we assessed the predictive value of MRI on the extent of pathologic ECE. It is intuitive that MRI would be able to identify extensive or multifocal ECE. However, MRI is unlikely to identify focal ECE, which we defined as 5 or fewer glands outside the prostate. We show that established ECE was readily identifiable by MP-MRI with a sensitivity and a specificity of 72.7% and 90.6%, respectively, and that MP-MRI is unable to identify and localize focal ECE. However, this limitation may have minimal clinical impact, as focal ECE carries a relatively good prognosis [3,4]. With a 5-year follow-up, Epstein et al. [4] reported that 82% of patients with focal ECE remained disease free compared with 65% of patients with established ECE. When evaluating the accuracy of MP-MRI, it is important to consider the level of suspicion for ECE on imaging.
Table 4 MP-MRI for identifying established ECE in each zone of the prostate Zone
Fisher exact, P value
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
Apex Mid Base
0.003 o0.001 o0.001
30.0 (6.7–65.2) 61.9 (38.4–81.9) 70.4 (49.8–86.2)
97.7 (94.6–99.2) 96.1 (92.4–98.3) 93.4 (89.0–96.4)
37.5 (8.5–75.5) 61.9 (38.4–81.9) 59.4 (40.6–76.3)
96.8 (93.4–98.7) 96.1 (92.4–98.3) 95.8 (92.0–98.2)
T.S. Feng et al. / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–8 Table 5 Univariate and multivariate logistic analysis for the prediction of ECE. Univariate
Gleason scorea PSA levelb Clinical stage MRI a
Multivariate
Odds ratio (95% CI)
P value Odds ratio (95% CI)
2.71 (1.8–4)
o0.001 2.63 (1.4–5)
2.46 (1.4–4.4) 3.73 (1.7–8.1) 37.5 (11–129)
0.003 2.92 (1.2–6.8) 0.001 0.97 (1.24–3.9) o0.001 26.8 (5.5–132)
P value
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first to demonstrate that MP-MRI can predict established but not focal ECE. MP-MRI is able to identify ECE in each zone of the prostate but with less accuracy at the apex. MPMRI is the strongest independent predictor of pathologic ECE and thus be a useful adjunct to clinical parameters in staging prostate cancer.
0.003 0.014 0.969 o0.001
Gleason score (6, 3 þ 4, 4 þ 3, 8, and 9–10). PSA level (0–2.5, 2.6–4.0, 4.1–6.0, greater than 10.0 ng/mL).
b
The 3-point scale used in this study is compatible with the 5-point scale proposed in PI-RAD [9], and the translation between the 2 scales is reported in the methods section. We demonstrate that pathologic ECE can be predicted by MPMRI findings that are considered suspicious or definitive for ECE. In medicine, clinical decisions are often binary. For example, the surgeon needs to decide whether the neurovascular bundle should be spared or sacrificed. Therefore, in such settings, we recommend that MP-MRI findings that are suspicious for ECE be considered a positive predictor for pathologic extracapsular disease. In this study, we considered the possibility that MP-MRI has different accuracies for different zones of the prostate. The accuracy of MP-MRI for identifying established ECE was statistically significant in all zones of the prostate; however, the sensitivity and the PPV were only 30% and 37.5%, respectively, at the apex. By contrast, at the base the sensitivity and the PPV were 70% and 59%, respectively. The small number of cases with ECE at the apex precludes a definitive conclusion on accuracy of MRI in this region. However, this observation is consistent with the difficulty that radiologists acknowledge in recognizing ECE at the apex owing to lack of fatty planes. There are several limitations to our study. As with any retrospective study, there is a risk of selection bias. MP-MRI was ordered by the treating urologists when there was concern for ECE based on clinical parameters. However, not all patients receiving MP-MRI underwent prostatectomy, and only a fraction of patients having surgery at our institution underwent an MRI. Therefore, it is possible that MP-MRI performs differently in groups not included in this study. All MR images were assessed by a single radiologist with expertise in prostate MRI, and prostatectomy specimens were reviewed by a pathologist who did not have access to the MRI results. Therefore, we are not able to comment on interobserver variability. Furthermore, accuracy of MRI may depend on the skill of the reporting radiologist. 5. Conclusions Our study confirms the usefulness of MP-MRI for predicting ECE. To the best of our knowledge, we are the
Acknowledgment The authors would like to thank Dr. Mahul B. Amin, Chairman and Professor of Pathology and Laboratory Medicine of Cedars-Sinai Medical Center, for his invaluable consultation regarding the definitions and criteria for extracapsular extension of adenocarcinoma of the prostate. Appendix A. Supporting Information Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.urolonc.2014.11.007.
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