Combined MRI: improved tumor diagnostics

Joep kraeima1, Razmara Nizak1 and Hugo Hulshof1

1

Department of Technical Medicine, University of Twente, The Netherlands

27 January, 2011

Abstract: The diagnosis of prostate cancer is not an easy process. Currently the tumor is diagnosed with several techniques: microscopy, biopsy, the Gleason-score (used to determine whether surgical intervention is needed) and a few diagnostic modalities. Different MRI procedures could be helpful during this process, but the sensitivity and specificity are poor. Research has been done to determine whether a combination of these forms of MRI could improve the diagnostics, quantified by the most relevant parameters. The possibility to combine T2-weigthed MRI with diffusion weighted MRI and ADC-mapping shows a significant improvement in the sensitivity and specificity of the detection of prostate cancers with a high Gleason-score. This method could possibly improve the detection of prostate cancer and shorten the time between detection and surgical intervention or new techniques like Image Guided Photo thermal Focal Therapy. Keywords: Gleason Score, Sensitivity, Specificity, MRI and ADC-map Introduction Prostate tumors are not always easy to detect. In some cases the patient remarks no symptoms while he has quite a large tumor inside. Different minimal invasive methods can treat prostate cancer without a total prostatectomy. For a proper treatment, first the tumor has to be detected and graded. Currently, there are different diagnostic methods which are clinically applied to detect a tumor. MRI is a highly relevant and non invasive technique for the localization of tumorous tissue. The main question is: How can the tumor localization information be used to provide the best diagnostical data to start a treatment? This study will first describe how a tumor is diagnosed and which parameters of the tumor are used to determine the malignancy of the tumor. Then a review is made to determine which combination of MRI diagnostic methods delivers the most relevant information about the index lesion and gradation of the tumor. Accomplishing better diagnostics of a tumor will reduce affecting healthy tissue during treatment. Indexation and Gleason-score To decide which forms of MRI are best applicable in case of detecting a (possible) prostate tumor, it must be determined when a treatment is necessary. Not every case of detected prostate tumor can and will be followed by a treatment (cure). Several pathological and clinical factors like tumor volume, differentiation, EPE (extra capsular extension), ingrowth in vesicula seminalis, PSA, age, symptoms etc. are included when making such a decision. Some of these factors are easily obtained but others are more complex and only visible after making several scans. Here the main purpose of this study shows its relevance again.

The visualization of the tumor helps in decision making as well as in providing a proper view for laser-ablation therapy (which is of later concern). To guide a physician making the right choice, there are classifications or The widely used grading score for this index-lesion is the Gleason-score. One must notice there is an important difference between Gleason-score and the Gleason-grade. [3] The grade is a number represented by 15 and the score is represented by the sum of primary grade and the secondary grade (minority of the tumor) represented by 2-10. This score is a classification of the whole tumorous area and therefore most useful. It can be explained roughly by the following four groups. Scores from 2 to 4 are very low on the cancer aggression scale. Scores from 5 to 6 are mildly aggressive. A score of 7 indicates that the cancer is moderately aggressive. Scores from 8 to 10 indicate that the cancer is highly aggressive.[4] The Gleason-score is highly correlated with the previously named pathologicaland clinical factors and therefore most applicable and used as a standard in almost every clinical study. Clinical relevance After grading the lesion, it must be determined whether a treatment is started. More specific in this case, which tumors need to be sufficiently detected with a combination of MRI techniques? If the score is too high the tumor will and cannot be removed because it is highly metastasized. If the score is too low the risk of a surgical intervention does not outweigh the risks of leaving the tumor inside.

indices for tumors and prostate tumors specifically. The part of the tumorous tissue used to grade or stage is called the index-lesion.

The tumor is said to be significant (and thus treatable) when the Gleason-score is 6, so a tumor with score 6 is the smallest, least aggressive tumor that has to be proper visible on the selected imaging techniques. Some studies state that a Gleason-score of 7 is the important prognostic border value (especially in case of possible migration of the tumor outside the prostate, 3040% chance.)[5-7] Despite this, a score of 6 is maintained so no cases are excluded, because different studies have a different outcome in determining the significance of the tumor. The highest Gleason-score means that the tumor is highly metastasized, the patient will receive only palliative therapy in most cases. This could include a surgery to remove tumorous tissue, but it cannot cure the patient in this case. A note here is that the Gleason-score is determined by the normal, conventional, method. So a biopsy is taken and the pathologist determines the grade of the tumorous tissue. It is not part of this study to improve or digitalize the determination of the Gleason-score. The Gleason-Score is solely used to determine the clinical relevance of a lesion and to create a focus area in which the combination of chosen techniques can visualize the tumor as good as possible. Thereby, providing the best visual information about the tumor for the therapy.

Parameters To determine which combination of techniques will result in the best visualization of the tumor one must choose several parameters to compare techniques. The parameters must be selected in such a way that they are applicable on every possible form of MRI, otherwise a sufficient comparison cannot be made. When using MRI as an imaging technique, commonly used and reliable parameters are: sensitivity, specificity and accuracy. In almost every study where the characteristics of the MRI variant is mentioned or compared, these three parameters are used to express this. [1, 5, 8] Diagnostic procedure The following MRI techniques are sufficient and relevant for tumor detection: T2-weigthed imaging (T2WI), Diffusion-weighted imaging (DWI), 3D-

MR spectroscopic imaging (MRSI) and Dynamic contrast enhanced MR imaging (DCE-MRI). [1] As seen in table1, none of the described techniques has a high sensitivity for detecting prostate cancer. Because it is preferable to detect the tumor with a high sensitivity and a high specificity, a combination of different techniques could be used. Another reason to combine techniques, is the detection of a tumor in the central gland. Using only T2-weigthed MRI, it is difficult to differentiate them from the benign nodules of prostatic hyperplasia. [9] The low sensitivity rates are concerning, but when the priory selected border value is taken into account the sensitivity shows improvement. Table 2 shows the sensitivity of tumor detection with different Gleason-scores. As shown in this table the sensitivity raises along with the Gleason-score.

Table 1: The different relevant parameters of the researched techniques.[1]

Table 2: The sensitivity of prostate cancer detection by different Gleason-scores.[8]

To determine which possible combination of techniques should be used, different studies have been evaluated. Table 3 shows that the probability of detecting prostate cancer is the highest when a combination of T2w-MRI and DWI are used. Also, the usage of a combination with another MRI technique could reach a slightly higher probability when the another MRI technique is unsuspicious for prostate cancer. However when a functional technique shows a suspicious lesion the probability of prostate cancer is nearly twice as high when DWI is used.

ADC-map In addition to the results of this combination, it is possible to generate a ADC-map. The usage of ADC is helpful by solving the problem of benign nodules in the central gland. The ADC-map generates a sensitivity of 60% en specificity of 76% for detecting tumors in this zone. [9] The production of the apparent diffusion coefficient (ADC) acquires two or more images with a different gradient duration and amplitude. This apparent diffusion coefficient enables the production of an ADC-map. The contrast in this map depends on the spatially

Table 3: Probability of prostate cancer detection with T2w-Mri alone or T2w-MRI combined with other techniques[1]

Several other researches also showed that a combination of T2-weigthed MRI and DWI is a possible solution. The combination of these two techniques gives improved values for the ROC curve, sensitivity, negative predictive value and accuracy (table 4). [5, 9]

distributed diffusion coefficient of the acquired tissues and does not contain any of the T1 or T2 values. This ADC map increases the specificity of the diagnostic procedure because ADCs are significantly lower in malignant compared with non-malignant prostate

Table 4: Increase of the mentioned parameters when T2w-MRI and DWI are used combined[5]

tissue (see figure 1). This can be explained by the difference between the extensive branching ductal structure of the normal prostate.

When compared with the restricted intracellular and interstitial spaces in prostate cancers they produce a highly different ADC. The ADC quantifies the combined effects of both diffusion and capillary perfusion. Random motion in the field gradients produces incoherent phase shifts resulting in signal attenuation. When the intracellular and interstitial spaces are restricted, the diffusion of water decreases. This produces a lower ADC as seen in malignant prostate tissue. This difference between non-malignant tissue and malignant tissue makes ADCmapping usable for a image with high contrast. Therefore, different tissue types are properly distinguishable. Another advantage of the usage of a ADC-map is the possibility to differentiate shine through effects or artifact from real ischemic lesions.[2, 911] Parameter Reader 1
Sensitivity Specificity Accuracy 74 (167/227) [68, 79] 79 (312/397) [75, 83] 77 (479/624) [73, 80]

Figure 1: The difference between the apparent diffusion coefficient of non-malignant and malignant tissue [2]

As seen in the table below (table 5), ADC-mapping is useful to raise the sensitivity of the detection of prostate cancer. A combination of T2w-imaging and ADC-map shows an increasing value in each of the used readers.

T2-weighted Images ADC Map

T2-weighted Images and P Value* ADC Map

88 (199/227) [83, 93] 88 (348/397) [84, 91] 88 (547/624) [85, 90] .01 .03 <.001

75 (171/227) [69, 82] 86 (340/397) [82, 89] 82 (511/624) [79, 85]

Reader 2
Sensitivity Specificity Accuracy 67 (152/227) [60, 74] 77 (307/397) [73, 81] 77 (479/624) [73, 80] 75 (171/227) [68, 82] 78 (310/397) [74, 82] 77 (481/624) [74, 80] 81 (185/227) [76, 87] 89 (354/397) [86, 92] 86 (539/624) [84, 89] .02 <.001 <.001

Reader 3
Sensitivity Specificity Accuracy 67 (152/227) [60, 74] 57 (226/397) [52, 62] 61 (378/624) [57, 64] 74 (168/227) [66, 80] 68 (270/397) [63, 73] 70 (436/624) [66, 73] 78 (177/227) [71, 85] 68 (270/397) [63, 73] 68 (426/624) [65, 72] .02 .07 .04

Note.Data are percentages, with numbers used to calculate percentages in parentheses and 95% confidence intervals in brackets. * Indicates difference between T2-weighted images and ADC map and T2-weighted images alone.

Table 5 Comparison between the sensitivity of T2w-MRI and ADC-map or the combination of the both.[11]

Conclusion Prostate tumor detection without the help of multiple MRI techniques is not very accurate. A combination of T2wMRI and DWI increases the sensitivity and other important parameters for the detection of prostate cancer. Combined with an ADC-map the possible rate of detection raises. All together, to obtain the most reliable diagnostic information with the highest accuracy, the combination of these three MRI-techniques is advised. Future developments of each techniques separately will contribute to an even better visualization and diagnostic information in case of prostate cancer with a Gleason-score of 6 and higher. References 1. Portalez, D., et al., Prospective comparison of T2w-MRI and dynamiccontrast-enhanced MRI, 3D-MR spectroscopic imaging or diffusionweighted MRI in repeat TRUS-guided biopsies. Eur Radiol, 2010. 20(12): p. 2781-90. Hosseinzadeh, K. and S.D. Schwarz, Endorectal diffusion-weighted imaging in prostate cancer to differentiate malignant and benign peripheral zone tissue. J Magn Reson Imaging, 2004. 20(4): p. 654-61.

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