Prostate cancer is the most common invasive cancer diagnosed in men in the United States, affecting approximately one in six men [1
]. It is often not deadly because it grows so slowly that it does not escape the prostate. Identifying which prostate cancers will metastasize, leading to increased morbidity and loss of life, is currently a difficult clinical management problem. Current diagnostic methods cannot always discriminate among the different tissues of the prostate, nor can they fully assess a cancer’s aggressiveness.
The prostate contains glands and ducts that change dramatically with cancer. Prostate cancer is diagnosed based on histopathological assessment of biopsy tissue. The Gleason Grading system is commonly used to assess the aggressiveness of the prostate cancer. With this system, the tissue is graded from 1 to 5, with 5 representing the most aggressive cancer, which has been correlated with higher metastatic potential [2
]. The Gleason grading system relies on changes in the architectural patterns of the glands and the growth pattern of the tumors. In cancer, the basal cell layer and the basement membrane surrounding the glands and ducts are disrupted. With increasing Gleason grade, the ducts generally become smaller, sparser, and more irregularly shaped. In Gleason grade 5 cancer, the highest and most aggressive grade, there may be no discernable glands. Overall, ductal space is decreased in higher grade cancers [2
]. Consequently, providing a noninvasive (or minimally invasive, due to the contrast agent injection and the endorectal probe) measure of the healthy ductal volume or glandular versus stromal nature of the tissue may be very important in characterizing prostate cancer aggressiveness.
MR diffusion imaging and dynamic contrast-enhanced MR imaging (DCE MRI) have each shown an ability to differentiate cancer from normal prostatic tissues [4
]. In particular, DCE MRI has shown higher enhancement and greater washout in prostate cancer versus normal tissues [4
]. Current understanding of the MR contrast agent, Gadolinium-DTPA (Gd-DTPA) (generic name: gadopentetate dimeglumine), is that it does not penetrate cells but can collect in the extracellular space [25
]. The rate of enhancement can be attributed to the amount and permeability of the blood vessels bringing the contrast agent to the tissue. Once the contrast agent is mixed in the vasculature, the peak enhancement in the tissue is due to the size of the extracellular space in which the Gd-DTPA can accumulate (both the interstitium and vascular volume) [26
]. Thus, the persistent, greater enhancement found in prostate cancer with DCE MRI can be attributed to a larger
extracellular space. In contrast, the MR apparent diffusion coefficient and the MR directionally-averaged apparent diffusion coefficient (<D>) have been shown to be lower in prostate cancer than in normal [12
]. This has been postulated to be due to increased cellularity of cancer, resulting in a smaller
extracellular space [28
]. A better understanding of the underlying mechanisms of these MR measures will improve their interpretation and increase their value.
A hypothesis that could explain the seemingly conflicting interpretations of these MR measures is that Gd-DTPA cannot reach healthy prostatic ducts. This would imply that DCE MRI would not reflect glandular-ductal volume and would only reflect a subset of the extracellular space. However, diffusion weighted imaging would reflect the glandular-ductal volume in addition to the extracellular space visible to DCE MRI. Additionally, diffusion weighted imaging may be able to reflect some of the intracellular space, which DCE MRI would also not be able to assess. However, at lower b-values (an MR diffusion parameter indicating the strength of the diffusion gradient), such as b=600, the measured diffusion appears to be dominated by the extracellular water [29
It is difficult to prove whether this hypothesis that Gd-DTPA cannot reach healthy prostatic ducts is true. There is no simple way to measure if Gd-DTPA is indeed in the healthy ducts, even by step-section histopathology. Ejaculate could potentially be tested for Gd-DTPA, but such samples were not available from the subjects in this study to perform this type of analysis. Step section histopathological analysis with MR image correlation could help assess the MR measures in cancer, but is limited by the sampling of the tissue slides (generally less than 1 slide per 3 mm) and the correlation to the images.
It is, however, possible to investigate whether this hypothesis is plausible by using the MR data that has already been acquired. Pathology demonstrates that different noncancerous prostatic tissues have different amounts of glands and ducts [2
]. Healthy peripheral zone tissue and glandular benign prostatic hyperphasia (BPH) are highly glandular-ductal tissues whereas stromal BPH and central gland tissue, with its commonly found BPH, are more stromal and less ductal [30
]. MR imaging, MR spectroscopic imaging and biopsy, when available, can be used to identify these different tissues [31
]. Then, the DCE MRI peak enhancement and the MR diffusion behavior (MR <D>) in these tissues can be evaluated to infer if the hypothesis that Gd-DTPA does not enter the glands or ducts is plausible.
In this study, citrate, as measured by MRSI, will be used as an additional indicator of healthy prostatic glands and ducts [32
]. It is high, on the order of twice as large, compared to creatine, in the highly glandular-ductal prostatic tissues ( healthy peripheral zone tissue and glandular benign prostatic hyperplasia (BPH)). It is low, less than or similar to creatine, in the stromal-low ductal prostatic tissues ( stromal BPH and central gland / mixed BPH tissue). It is also decreased in peripheral zone cancer as compared to healthy peripheral zone tissue [32
]. This decrease may reflect a decrease in healthy glands and ducts but may also reflect changes in citrate metabolism.
If the evaluation of DCE MRI and diffusion in the glandular-ductal tissues versus the stromal-low ductal tissues supports the hypothesis that Gd-DTPA does not reach prostatic ducts, it will help the interpretation of DCE MRI and diffusion MR in the prostate and may lead to a better evaluation of prostate cancer. In future work, the combination of the DCE MRI pharmacokinetically modeled estimate of extracellular extravascular space in the prostate and the MR directionally-averaged apparent diffusion coefficient (<D>) in the prostate will need to be further evaluated. This combination will need to be compared to step section histopathology of the prostate and assessments made in different Gleason grades of cancer to determine if it can provide an assessment of the cancer’s aggressiveness, as higher Gleason grade cancers have less ductal space [2
The aims of this study are to compare peak enhancement, determined from dynamic contrast-enhanced (DCE MRI), with MR directionally-averaged apparent diffusion coefficient measures in glandular versus stromal prostatic tissues and, with this comparison, to infer if the hypothesis that Gd-DTPA does not enter healthy glands or ducts is plausible..