Dynamic Contrast Enhanced MRI of Prostate Cancer: Correlation with Morphology and Tumour Stage, Histological Grade and PSA

Clinical Radiology (2000) 55, 99–109 doi:10.1053/crad.1999.0327, available online at http://www.idealibrary.com on

Dynamic Contrast Enhanced MRI of Prostate Cancer: Correlation with Morphology and Tumour Stage, Histological Grade and PSA ANW AR R. PADHA NI* †, C ONNIE J . GA PI NSKI*, DAV ID A. MACVI C AR*† , GE OFFRE Y J. PARK ER† ‡, J OHN SUCKL ING* ¶, PA T R I C K B . R E V E L L † , MART IN O. L E ACH†, DAVI D P. DE ARNA LE Y§ , JANE T E . HU SBAND *† *Academic Department of Radiology, †CRC Clinical Magnetic Resonance Research Group and §Academic Department of Radiotherapy, Institute of Cancer Research, The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT, U.K. Received: 5 February 1999 Revised: 30 June 1999

Accepted: 9 July 1999

AIM: To quantify MRI enhancement characteristics of normal and abnormal prostatic tissues and to correlate these with tumour stage, histological grade and tumour markers. MATERIALS AND METHODS: Quantitative gradient recalled echo MR images were obtained following bolus injection of gadopentetate dimeglumine in 48 patients with prostate cancer. Turbo spin-echo T2-weighted images at the same anatomical position were reviewed for the presence of tumours (45 regions), normal peripheral zone (33 regions), and normal appearing central gland (30 regions). Time-signal intensity parameters (onset time, mean gradient and maximal amplitude of enhancement and wash-out score) and modelling parameters (permeability surface area product, lesion leakage space and maximum gadolinium concentration) were correlated with tumour stage, histological grade (Gleason score) and serum prostatic specific antigen (PSA) levels. RESULTS: Significant differences were noted between peripheral zone and tumour with respect to signal intensity and modelling parameters (P ¼ 0.0001), except onset time. No differences between central gland and tumour enhancement values were seen. There was weak correlation between MRI tumour stage and tumour vascular permeability (r2 ¼ 12%; P ¼ 0.02) and maximum tumour gadolinium concentration (r2 ¼ 14%; P ¼ 0.015). However, no significant correlations were seen with Gleason score or PSA levels. CONCLUSION: Quantification of MR contrast enhancement characteristics allows tissue discrimination in prostate cancer consistent with known variations in microvessel density estimates. Padhani, A. R. et al. (2000). Clinical Radiology 55, 99–109. q 2000 The Royal College of Radiologists Key words: magnetic resonance (MR), contrast enhancement, tissue characterization, prostate, neoplasms, hyperplasia.

Magnetic resonance imaging (MRI) is a valuable technique for staging patients with prostate cancer and is helpful for selecting patients with surgically resectable disease [1,2]. The MRI assessment of prostate cancer has a number of important limitations, including a restricted ability to demonstrate microscopic and early macroscopic capsular penetration. Furthermore, it is not possible using conventional imaging criteria to reliably distinguish tumours from other causes of reduced signal in the peripheral zone such as scars or areas of prostatitis

Correspondence to: Dr A. R. Padhani, Academic Department of Diagnostic Radiology, The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT, U.K. ‡ Now at: NMR Research Unit, Institute of Neurology, Queen Square, London WC1N 3BG, U.K. and ¶ Clinical Age Research Unit, King’s College Hospital, School of Medicine and Dentistry, Bessemer Road, Denmark Hill, London SE5 9RS, U.K. 0009-9260/00/020099+11 $35.00/0

[3]. Thirty per cent of prostate tumours occur within the central gland (25% from the transitional zone and 5% from the central zone) and these are not well delineated on T2-weighted images [4]. In addition, tumour volume is often under- or overestimated when compared with pathological specimens [5–10]. Lencioni et al. showed that volume measurements were only accurate to within 50% of pathological volume, in 92% of patients examined [11]. The inability of MRI to identify consistently and localize accurately tumours within the gland may result in unrecognized proximity to the prostatic capsule, a feature important to prediction of transcapsular tumour spread and tumour staging. Other limitations of conventional MRI include the lack of information on tumour grade or vascularity, both of which are known to be useful predictors of patient prognosis [12,13]. On MRI, after the administration of intravenous contrast medium, the normal central zone (CZ) enhances more than the q 2000 The Royal College of Radiologists

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peripheral zone (PZ); both enhancing homogeneously. In the presence of benign prostatic hyperplasia (BPH), enhancement of the central gland (CG) becomes heterogeneous [14,15]. Prostate cancer also enhances following contrast medium administration [14,16]. The role of contrast enhancement for evaluating patients with prostate cancer has not been completely defined. An early study suggested no additional role of contrast enhancement compared to conventional T2-weighted imaging [15]. However, recently Brown et al. showed improved depiction of the tumour when MR images are obtained early after contrast enhancement [14], and it has been reported that contrast enhancement can improve the detection of minimal seminal vesicle invasion [15,17]. Furthermore, it now appears that dynamic contrast enhancement MRI (dMRI) can improve accuracy of tumour staging when used in conjunction with T2weighted images in patients with equivocal capsular penetration [16]. It is generally recognized that dMRI examinations can be used to characterize different tumours and that the onset and rate of enhancement are valuable parameters for differentiating malignant from normal tissues. Such studies have been undertaken to evaluate tumours in the breast, bladder, bone and prostate cancer [16,18–21]. In prostate cancer there are conflicting views as to whether these parameters correlate with histological grade and tumour stage [16,22]. The purpose of our study therefore was to elucidate the dynamics of contrast enhanced MRI in patients with prostate cancer, by quantifying enhancement patterns of normal and abnormal prostatic tissues and to correlate these with morphological, biological and histological features. MATERIALS AND METHODS

Patients The study was conducted between July 1995 and June 1997. Sixty-nine consecutive patients with untreated biopsy proven prostate cancer were entered into the study prospectively. Our Institutional Committees on Clinical Research and Ethics approved the study. Twenty-one patients were excluded from

analysis (seven patients because of voluntary or significant prostate movement due to rectal distension, six patients because of a poor bolus injection of contrast medium, seven patients did not complete the imaging protocol and in one the dynamic MRI data was not analysable). Thus, 48 patients were included in the final analysis. The median age of the 48 patients was 67 years (range 51–80 years). Histological proof of invasive prostate adenocarcinoma was obtained by ultrasound guided core biopsy in 36 patients and from transurethral resection of the prostate (TURP) in 12. The median time interval between prostate biopsy and MR imaging was 25 days (range 10–51 days) in 45 patients. Three patients were examined 126, 276 and 521 days after biopsy. The median Gleason score was 6 (range 2–9). The PSA value was a median of 13.5 ng/ml (range 2–90 ng/ml). The patients’ MR stages and histological grades are further defined in Table 1. Eleven of these patients were treated by androgen deprivation alone, one had radiotherapy alone, 33 had neoadjuvant androgen deprivation followed by radiotherapy, none had prostatectomies and three patients received no active treatment.

Imaging Technique All examinations were performed on a 1.5 T superconductive magnet (Vision; Siemens Medical Systems, Erlangen, Germany) using a circularly polarized pelvic phased array coil. All patients received a bowel relaxant before imaging; hyoscinbutylbromide 20 mg or glucagon 1 mg. The imaging protocol comprised routine T1 and T2-weighted images through the whole pelvis for the purposes of evaluation of pelvic lymph nodes. Thereafter, small field-of-view T2-weighted turbo spin-echo (TSE) sequences were performed in the axial and coronal planes for local tumour staging [repetition time (TR) ¼ 3.5–4.1 s, echo time (TE) ¼ 120 ms, echo train length ¼ 15, 4–5 mm thick contiguous slices, four signal averages, matrix size 256 × 150 and field of view of 18 cm (axial plane) or 16 cm (coronal plane)]. These images were inspected for the presence of a peripheral zone abnormality consistent with cancer. At this position, a series of transaxial

Table 1 – Patient MRI stage and histological grade MRI tumour stage*

Number of patients

Nodal disease

T1 T2 T3 T4

1 18 22 7

0 0 4 2

Total

48

6

Distant metastases†

Gleason Score‡ Not scored No.

2–4 No.

5–7 No.

8–10 No.

0 2 2 3

0 0 0 1§

1 5 1 0

0 13 20 5

0 0 1 1

7

1

7

38

2

* T1 – tumour not visible by MRI; T2 – tumour confined to the prostate; T3 – tumour extends through the capsule (includes seminal vesicle invasion); T4 – tumour invades adjacent structures other than seminal vesicles. † Includes nodal disease outside true pelvis. ‡ Score is the sum of two dominant grade numbers. § Moderately differentiated adenocarcinoma.

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dynamic contrast enhanced images were obtained. In one patient, no tumour was visible and a level that demonstrated normal anatomic detail was chosen. The dynamic enhanced protocol used either a single slice spoiled gradient-echo FLASH (fast low-angle shot, 39 patients) or five slice saturation recovery Turbo-FLASH (nine patients) sequences [23,24]. Proton density weighted images were acquired first followed by a series of T1-weighted images. Sequential T1-weighted images were obtained every 9–10 s for 6.3–7 min. The parameters for the T1-weighted FLASH were: TR – 35 ms, TE – 5 ms, flip angle – 708, 1 acquisition, matrix size 256 × 192, field of view 25 cm, 10 mm slice thickness, acquisition time – 10 s, single axial slice, 42 repetitions, total imaging time – 7 min. For the T1-weighted Turbo-FLASH sequence, the parameters were: recovery time 150 ms, TR – 11.7 ms, TE – 4.4 ms, flip angle 208, one acquisition, matrix size 128 × 128, field of view 20 cm, 8 mm slice thickness, acquisition time – 9 s, five slices, 42 repetitions, total imaging time – 6.3 min. For proton density weighted FLASH and Turbo-FLASH the parameters were altered (FLASH: TR – 350 ms, TE – 5 ms, flip angle 208, acquisition time 1.5 min, otherwise as above and Turbo-FLASH: recovery time 10 s, TR 11.7 ms, TE 4.4 ms, acquisition time 58 s, otherwise as above). Gadopentetate dimeglumine (Magnevist, Schering Health Care Ltd., Burgess Hill, Sussex) was injected intravenously as a bolus through a peripherally placed cannula after the third baseline data point (dose 0.1 mmol/kg bodyweight, injected within 10 s followed by a 20-ml flush of normal saline).

Image Review and Analysis Hard copy TSE T2-weighted images were assessed using standardized forms and diagrams. Two radiologists worked in consensus. These radiologists were not involved in making the decision on the location of the dynamic slice plane. The reviewers were aware that the patients were being evaluated for prostate cancer but were not informed of the histological grade, serum prostatic specific antigen (PSA) levels or the results of the dynamic enhancement studies. The reviewers were asked to identify and stage the tumour using standard TNM definitions (1997). At the slice positions corresponding to the dynamic enhanced sequence, they were also asked to diagrammatically indicate (i) the site of tumour and its outline, and (ii) identify areas of normal appearing peripheral zone (PZ) and central gland (CG). On the T2-weighted images, an irregular area of low signal in the PZ was considered to represent tumour. Low signal intensity in the central gland was not interpreted as being due to malignancy; however, when an obvious malignant peripheral zone tumour extended into the central gland then this was interpreted as probable central gland involvement. The criteria for extra-prostatic spread required one of the following features: disruption of the prostatic capsule by low signal tumour, extension of tumour in the periprostatic fat contiguous with low signal tumour in the gland and obliteration of the neurovascular bundle [25]. A bulge in the contour of the gland large enough to reach the puborectalis muscle was interpreted as probable capsular invasion by tumour. A homogeneous high signal peripheral zone was considered to be normal. Benign prostatic

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hyperplasia (BPH) which arises from the transitional zone was considered as part of the central gland of the prostate (central and transitional zones). The MRI features of BPH were uniform low signal intensity (glandular BPH), or areas of nodular whorls of low signal. When the diagnosis of prostate cancer had been made from transurethral resection of the prostate (TURP), the central gland was classified as involved by tumour by default. The FLASH and Turbo-FLASH images (dynamic enhanced images) were analysed on an independent workstation (Ultrasparc 2, Sun Microsystems, Mountain View, California) by a radiologist not involved in the hard copy evaluation of the T2-weighted images. Specialist software designed to qualitatively analyse and display contrast enhanced dynamic MR datasets was used [26]. Each dynamic dataset took approximately 20 minutes to analyse. Up to four regions of interest (ROIs) were placed on one slice for each set of time course images (when five slice Turbo-FLASH images had been obtained (nine patients), a single slice that passed through the centre of the tumour was analysed). Using the information on the diagrammatic review of the TSE images, small circular regions of interest were placed on normal peripheral zone and on the most enhancing part of central gland (Fig. 1). The enhancing whole tumour outline was traced on an early subtraction image obtained by subtracting a pre-injection image from one obtained 90 s after injection. Care was taken when tracing the outline of the tumour to carefully avoid areas of non-enhancing tissues and areas of necrosis. Using the mean gradient mapping facility, a circular region of interest was also placed on the fastest enhancing area within the tumour outline. For each ROI, time signal intensity curves normalized to baseline were generated and signal intensity and modelling parameters were derived. We used four time-signal intensity parameters to help describe the important features of the tissue enhancement curve (Fig. 2) [23]. (i) Onset time: defined as the time period between the bolus injection of contrast agent (taken as the middle of the 4th data point on the dynamic enhanced study) and the point on the enhancement curve at which the signal is 10% of its maximum. (ii) Mean gradient: defined as the average rate of change of the relative signal intensity between the 10% and 90% points of maximum enhancement. (iii) Maximum signal intensity: defined as the peak level of signal intensity during the dynamic measurement period. (iv) Wash-out score: this was scored as ‘benign’ when a slow monotonic increase in signal intensity was seen through the observation period; as ‘suspicious’ if the peak signal intensity was achieved within the first 2 min and was sustained or if there was late decrease in signal intensity (wash-out); and as ‘malignant’ when an early peak of enhancement was seen followed immediately by a decrease in signal intensity [27]. Quantitative modelling parameters including capillary permeability-surface area product (k), tissue leakage space (v1) and maximum tissue gadolinium concentration were then calculated by applying a multi-compartment model analysis to the tissue time-contrast agent concentration curve. The images from the dynamic enhancement protocol were used to derive measurements of contrast agent concentration in vivo. Firstly, the longitudinal relaxation rate, T1, of the water protons at each time point in the dynamic enhanced sequence was obtained from the ratio of each T1-weighted image to the

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(a)

(b)

(c) (d)

(e)

(f)

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(g)

(h)

Fig. 1 – Typical dynamic contrast enhanced MRI study. 62-year-old man with prostate cancer biopsied 31 days before MR imaging (Gleason grade 2+2 and PSA 11.5 ng/ml). (a) T2-weighted turbo spin-echo image showing a low signal intensity mass in the left peripheral zone (arrow) compatible with tumour. The peripheral zone shows homogeneous intermediate to high signal. The central gland is morphologically normal. (b) T1-weighted gradient-echo FLASH image at the same slice position as (a) above showing a focal wedge area of high signal in the right peripheral zone compatible with haemorrhage. The tumour is not visible. (c) Early (30 s) T1-weighted gradient-echo FLASH image after injection of contrast medium shows enhancement of the tumour and the central gland. The peripheral zone shows minimal enhancement. The area of haemorrhage in the right peripheral zone is still visible. (d ) Ninety-second subtraction image shows the enhancing tumour (arrow). (e) Five-minute image shows washout of contrast in the tumour and central gland. (f ) Time relative signal intensity curves for the regions of interest placed in the peripheral zone (diamonds), tumour (squares) and the central gland (circles). The peripheral zone shows a slow rising curve compared to the tumour or central gland. The tumour curve shows a faster rise and a higher maximum enhancement compared to the peripheral zone. The central gland shows the steepest rise and highest peak in enhancement; some washout is seen in the tumour and the central gland. (g) Permeability map (maximum permeability depicted equals 1 per minute) and (h) tissue leakage space map (maximum leakage space depicted equals 100%). High levels of capillary permeability and leakage space are seen in the tumour (0.66 per minute and 45%) and central gland (1.14 per minute and 51%) compared to the peripheral zone (0.11 per minute and 17%). Note that some pixels do not display a colour because there was a poor fit of the multi-compartment model to the data observed.

baseline proton density image. Once the T1 relaxation time of each pixel within each image has been obtained, the concentration of contrast agent can be calculated [28]. The model we used assumes four compartments within the body to which the contrast agent has access [29,30]. These are the whole-body vasculature, the whole-body extracellular space, the kidneys (the ultimate washout pathway) and the lesion ‘leakage space’ (effectively the lesion extracellular space). For further information on these modelling techniques the readers are referred to articles by Parker et al. [23,24,26]. The enhancement parameters of the different tissue types were compared using descriptive statistics and non-parametric methods (Kruskal–Wallis test and the Mann–Whitney U-test). These were correlated with MRI tumour stage, histological grade (Gleason score) and serum prostatic specific antigen (PSA) using Spearman’s correlation. A probability value of less than 5% was considered statistically significant.

RESULTS Fig. 2 – Typical malignant time signal intensity curve. The relative signal change with time in a prostate tumour after bolus injection of gadopentetate dimeglumine. Relative signal intensity is normalized to baseline.

The reviewers identified 45 tumours at the level of the dynamic enhancement sequence. In one patient, no tumour was visible and in another two, tumours were visible on T2-weighted

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(b) (a)

(c)

(d)

Fig. 3 – Malignant washout pattern in a normal appearing peripheral zone. Fifty-five-year-old man with prostate cancer (Gleason 1þ1, PSA 11 ng/ml); core biopsy 17 days before MR imaging. A single focus of well-differentiated invasive carcinoma was see on six biopsy specimens. (a) T2-weighted turbo spin-echo image showing homogeneous intermediate to high signal intensity in the peripheral zone with no evidence of a discrete tumour. The central gland is morphologically normal. (b) T1-weighted gradient-echo FLASH image at the same slice position as (a) above showing a homogenous gland with no appreciable zonal anatomy. (c) Early (30 s) T1-weighted gradient-echo FLASH image after contrast injection shows enhancement of the peripheral zone bilaterally and the central gland. (d ) Time relative signal intensity curves for the regions of interest placed in the left peripheral zone (squares) and the central gland (circles). Both curves show a fast rising curve with high maximum enhancement and washout is evident.

images but the wrong slice was chosen. Thirty-three regions of normal appearing peripheral zone were seen at the level of the dynamic enhanced sequence. In 15 patients no normal PZ was seen. Thirty regions of normal appearing central gland were noted. In six patients, the entire outline of the tumour could not be visualized because it invaded the central gland and became indistinct. In the remaining 12, the diagnosis of prostate cancer had been made by TURP and the central gland of such patients was classified as being involved by tumour by default. Our 33 measurements on normal PZ showed that in the majority the onset of enhancement occurred after the onset in tumour (28 of 33; 85%) and in BPH (26 of 33; 79%) in the same patients. The gradient of enhancement of normal PZ showed a

slow rise throughout the observation period in 23 (70%) (Fig. 1). The maximum enhancement was in general less than the CG or tumours (Table 2). In 10 patients (30%) normal appearing PZ showed a pattern different to that above. In nine patients the peak signal intensity was achieved within 2 min and was sustained or there was late decrease in signal intensity, and in one patient an early peak of enhancement was followed immediately by a decrease in signal intensity (‘malignant’ washout pattern; Fig. 3). Differences noted between the peripheral zone and central gland and tumours were statistically significant with respect to all time signal intensity parameters and in modelling parameters (P ¼ 0.0001) except onset time (Table 2, Figs 4, 5 and 6).

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Table 2 – Tissue characterization using enhancement parameters Enhancement parameters

Time signal intensity parameters Number of observations Onset time (min) Mean gradient Maximum enhancement (% from baseline) Wash-out patterns (benign: suspicious: malignant) Modelling parameters Number of observations Permeability surface area product (per min) Tissue leakage space (%) Maximum gadolinium concentration (mmol/kg)

Tissue regions of interest Peripheral zone*

Central gland

Whole tumour outline

Tumour: – fastest enhancing area

33 1.02† (0.93–1.11) 66 (43–89) 88 (76–99) 23 : 9 : 1

30 0.92 (0.86–0.97) 260 (164–357) 145 (120–170) 5 : 8 : 17

39 0.94 (0.88–1.01) 164 (118–209) 125 (111–139) 2 : 18 : 19

45 0.93 (0.87–1.00) 332 (231–433) 142 (126–157) 3 : 10 : 32

32 0.22 (0.15–0.29) 26 (22–31) 0.20 (0.17–0.24)

29 1.08 (0.68–1.48) 51 (45–56) 0.38 (0.34–0.42)

38 0.79 (0.62–0.96) 45 (42–48) 0.33 (0.31–0.35)

43 1.10 (0.78–1.41) 49 (46–53) 0.38 (0.36–0.40)

Values are mean and 95% confidence intervals in parentheses except for washout patterns where the number of patients in each category is indicated. * Kruskal–Wallis test, P ¼ 0.0001 for all parameters except for onset time (†) where P ¼ not significant.

There was complete overlap of the enhancement patterns of the central gland and tumour with respect to time signal intensity and modelling parameters (Table 2, Figs 4, 5 and 6). When enhancement parameters of the tumours were correlated with serum PSA levels, no significant correlations were seen (even after exclusion of non-prostatic sources of PSA production; that is, nodal and metastatic disease). Enhancement parameters of the peripheral zone and central gland also did not correlate with serum PSA levels. Patients with extra-prostatic disease (11 patients) had higher serum PSA levels (P ¼ 0.003) and Gleason scores (P ¼ 0.019) but no differences were seen in enhancement parameters except onset time (Table 3).

Fig. 4 – Permeability in different tissue types.

Fig. 5 – Tissue leakage space in different tissue types.

Fig. 6 – Summary of washout patterns observed for peripheral zone (PZ), central gland (CG) and fastest enhancing area within the tumour. For definitions of terms please see text.

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Table 3 – Comparison of patients without and with extra-prostatic metastatic disease

Prostatic specific antigen (ng/ml) Gleason score Time signal intensity parameters Number of observations Onset time (min) Mean gradient Maximum enhancement (% from baseline) Wash-out patterns [benign: suspicious: malignant] Modelling parameters Number of observations Permeability surface area product (per min) Tissue leakage space (%) Maximum gadolinium concentration (mmol/kg)

No metastatic disease (37)

Metastatic disease present (11)

Mann–Whitney U-test

12.4 (2–46) 6 (2–9)

29.1 (8–90) 7 (5–9)

P ¼ 0.003 P ¼ 0.019

34 0.95 (0.47–1.74) 197 (45–1188) 121 (83–293) 3 : 9 : 22

11 0.78 (0.57–1.34) 167 (117–1500) 155 (67–310) 0 : 1 : 10

P ¼ 0.014 P ¼ NS P ¼ NS P ¼ NS

33 0.78 (0.17–2.23) 47 (30–77) 0.38 (0.24–0.5)

10 1.02 (0.45–5.0) 54 (35–88) 0.39 (0.3–0.5)

P ¼ NS P ¼ NS P ¼ NS

Values refer to the most enhancing region of the tumours; Median and range in parentheses except for washout patterns where the number of patients in each category is indicated. NS, not significant.

There was no significant correlation between any tumour enhancement parameter and histological Gleason scores (Fig. 7). There was, however, a weak correlation between local tumour stage and tumour vascular permeability (r2 ¼ 12%; P ¼ 0.02) and maximum tumour gadolinium concentration (r2 ¼ 14%; P ¼ 0.015) (Fig. 8).

and machine gain settings and scaling factors. Important physiological factors include tissue microvessel density, capillary permeability and interstitial leakage space. There has been limited experience in the use of contrast enhancement in

DISCUSSION

After intravenous injection of contrast medium, T1-weighted images can demonstrate prostatic zonal anatomy but in general, T2-weighted images are better in this regard [15]. On postcontrast T1 weighted images, the normal peripheral zone (PZ) enhances homogeneously although some heterogeneity may be seen in up to 62% [15]. Prostate cancer also enhances following the administration of contrast media [14,16]. Generally, tissue enhancement following contrast medium administration is dependent on physical and physiological factors. Physical factors include sequence and parameter choice, contrast medium dose (a)

(b) Fig. 7 – Scatter plot of Gleason score with tumour vascular permeability (maximum enhancing tumour ROI).

Fig. 8 – Correlation of MRI tumour stage with (a) tumour vascular permeability and (b) maximum gadolinium concentration.

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staging patients with prostate cancer [14–17,31–35]. Some studies have found no additional benefit in evaluating tumour extension through the capsule compared to T2-weighted images [15,17,32,34], whereas others have found that improved staging results. One study showed improved depiction of extracapsular extension of tumour when images were obtained immediately after contrast medium injection [14]. Huch-Boni et al. reported that contrast enhancement improved the detection of minimal seminal vesicle invasion [17] and recently, dMRI was shown to improve the accuracy of staging when used in addition to T2-weighted images in patients with equivocal capsular penetration [16]. However, these studies did not set out to characterize prostate cancer using quantitative dMRI techniques. Quantification of the vascularity of tissues can be assessed using immuno-histochemical techniques (microvessel density estimations). Microvessel density is a quantitative measurement of the number of small blood vessels within a given area on a histological slide. In general, microvessel density counts of the peripheral zone and prostatic intra-epithelial neoplasia are similar (mean 8.6, range, 2.5–14.6 and mean 11.6, range, 6.0– 17.8 respectively). An overlap of the microvessel density counts between benign prostatic hyperplasia (BPH) and prostate cancer has also been observed (BPH: mean 70.2, range, 10–253.0; organ-confined cancer: mean 81.2, range, 45.7– 116.9; metastatic cancer: mean 154.6, range, 122.3–240.9) [12,36]. Microvessel density is a recognized prognostic factor for prostate cancer and an association between microvessel density and stage of disease, histological grade and the development of metastases has been noted [12,13]. Dynamic contrast-enhanced MRI can also be used to assess non-invasively the functional aspects of microcirculation of tissues [37,38]. Our measurements show characteristic differences in the enhancement patterns of PZ compared to the central gland and/or tumour thus allowing successful tissue discrimination based on enhancement alone. The enhancement characteristics of chronic prostatitis and scar tissue in the PZ, which are common causes of low signal PZ abnormalities [4], could not be documented by our study as no direct histological confirmation could be obtained (vide infra). In nine (27%) patients with normal appearing PZ early enhancement with a sustained plateau phase was seen and one patient showed early washout (Fig. 3), a pattern most frequently observed in malignant tumours (Fig. 6). These variations may have occurred due to the presence of undetected malignancy within the PZ. It is recognized that microscopic tumour in the peripheral zone is not always visible on T2-weighted images and this is a recognized cause for underestimation of tumour volume [11,39,40]. This also occurs because poorly differentiated prostate cancer can grow by infiltration, thus causing little architectural distortion or alteration in signal intensity [41]. The presence of inflammation in the peripheral zone would be an alternative explanation. In the presence of BPH the enhancement of the central gland becomes markedly heterogeneous in most cases [14,15]. We observed a complete overlap in the enhancement characteristics of tumour and BPH and this explains why we could not outline the entire tumour in six patients. The similarity of enhancement is not surprising because BPH is a benign proliferative process characterized by increased microvessel density comparable to cancers [36]. Our signal intensity parameter measurements are

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similar to Jager et al., who also observed that there was overlap in onset time and gradient of enhancement between tumours and the central gland [16]. They, however, did not specifically quantify these parameters. We have explored the possibility that obtaining physiologically relevant enhancement parameters that are largely free of variations between MR systems, and sequence parameters may allow improved tissue characterization. These modelling parameters (permeability surface area product and the tissue leakage space) were successful in differentiating tumour and peripheral zone but were unable to make the distinction between tumour and BPH. Recently, however, Turnbull et al. reported on a small histological study that quantitative analysis of dynamic MRI studies can distinguish tumour from fibrogladular and fibromuscular BPH [21]. The ability to estimate tumour volume accurately and delineate its intraprostatic extent has several clinical implications. Tumour volume is an important prognostic indicator; a volume larger than 0.3 cm3 is at high risk of extracapsular extension and micrometastases [42]. Accurate delineation of tumour is important in estimating proximity to the prostatic capsule, a feature important for predicting transcspsular tumour spread and tumour staging. Minimal extracapsular extension of tumour may not adversely affect the surgical relapse rate provided that an adequate margin on the side of the tumour is present at prostatectomy [43,44]. Similarly, depiction of a tumour at the prostatic apex can alter the surgical approach. For example, many surgeons will not operate on patients with prostate apex tumours because the prosatatic capsule is thin and resection margins may be positive. The presence of an apical tumour will also mitigate against a limited surgical dissection at the apex with attendant higher complication rate (incontinence and impotence) [45,46]. In addition, the presence of tumour at the apex of the gland requires an extra margin when planning radiotherapy. Jager et al., in their study, noted that poorly differentiated prostate cancer showed earlier onset and a faster rate of enhancement compared to other histological grades in five patients but made no formal correlation with histological grade or tumour stage [16]. Yoshizako et al., however, reported that poorly differentiated tumours demonstrated less overall enhancement compared to moderately differentiated tumours, possibly due to differences in washout patterns [22]. We, however, found no correlation between any enhancement parameters and histological grade. The Gleason score reflects the degree of architectural glandular differentiation and is a strong predictor of outcome in patients with prostate cancer. A correlation may have been expected because the Gleason score has been shown to correlate with microvessel density measurement [12]. The lack of correlation seen may be explained by histological sampling errors inherent in any needle biopsy technique [47–50]. Furthermore, the majority of patients had Gleason scores of 5–7 (38 patients) and few patients had well or poorly differentiated cancers. This may also have contributed to the lack of correlation. Weak correlation of MRI tumour stage with capillary permeability and maximum gadolinium concentration was observed (Fig. 8). This may in part be explained by the fact that there were relatively few patients with stage 1 or stage 4 disease (eight in total). When enhancement parameters of the tumours were correlated with serum PSA levels (after exclusion of nonprostatic sources of PSA production; that is, nodal and metastatic

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disease), no significant correlations were seen. It should be noted that PSA is not cancer specific, rather it is only prostate specific. BPH can also cause elevations of PSA levels so the volume of the prostate is important for PSA estimations. In this study we did not normalize the individual PSA levels with volume estimations because this would have been inappropriate for patients with lymph nodal disease and in those with metastases (13 patients). Single slice evaluation may also have contributed to the lack of correlation seen and it is possible that whole tumour evaluation (using multi-slice or volumetric acquisitions) may yield a more definite association. The multislice saturation recovery Turbo-FLASH techniques used in nine of our patients is one such technique. We did not evaluate all slices in these patients because of the difficulties of combined analysis of single slice with multi-slice measurements. The limitation of our study is that no such direct histological confirmation was obtained. This is because androgen deprivation and radiotherapy are routinely used to treat localized prostatic carcinoma at our institution and still considered the standard against which other treatments are measured. A surgical treatment option would not have been feasible in 31 of our patients who had either T2 disease with metastases, or T3 or T4 disease. Histological correlation for MRI studies is also recognized to be an imperfect gold standard for a number of reasons. These include errors in registering the location of the imaging sections with histological slice specimens, inaccuracies resulting from tissue shrinkage secondary to fixation and due to partial volume averaging effects [51–53]. MR imaging studies with histological correlation have shown that T2-weighted imaging is able to depict the position carcinoma within the peripheral zone of the prostate gland [4,5]. These studies have also shown that infiltrating adenocarcinomas and mucin producing (so-called signet ring) tumours can be difficult to detect [40,54]. They have also that noted that benign conditions such as scarring, prostatitis and haemorrhage may mimic the signal intensity changes of cancer [3,39]. Given these limitations and the subjective nature of MR image assessment, we chose to minimize interobserver effects by consensus reading of the hard copy images, thus allowing averaging of the interpretations. In this study, we did not use a balloon inflated endorectal coil for MRI staging of patients. Husband et al. have recently shown that prostate cancer patients may not be suited to examination by this method when potential treatment includes external beam radiotherapy [55]. This is because endorectal MR examinations are more likely to produce artefacts compared to pelvic phased array coil examinations; these include near field flare and coil related artefacts. Rectal movements are also common and can be observed in most patients on careful review. Furthermore, prostate gland distortion commonly occurs and the outline of the gland, particularly the anterior margin is poorly depicted when endorectal examinations are performed. These features taken together argue against routine use of endorectal MR examination for staging patients with prostate cancer who are to undergo radiotherapy. We therefore conclude that tissue discrimination is possible between peripheral zone and tumour/central gland using signal intensity (except onset time) and modelling parameters but is not reliable between central gland and tumour. These observations are consistent with known differences in

immuno-histochemical microvessel density measurements. Enhancement characteristics do not correlate well with local tumour stage, tumour grade or serum PSA levels. Dynamic contrast enhancement may therefore have application in distinguishing peripheral zone abnormalities. In particular, it may be possible to discriminate between areas of peripheral zone scarring and/or chronic prostatitis from tumour. A further role includes tumour localization and delineation within the gland as an aid for the selection of optimal treatment. Acknowledgements. The support of the Cancer Research Campaign (CRC] [Grant No: SP 1780/0103] and the Bob Champion Cancer Trust are gratefully acknowledged. This work was undertaken by The Royal Marsden NHS Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive.

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