Transrectal Ultrasound for Prostate Cancer: Perspectives from National Cheng Kung University Hospital

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1 R E V I E W A R T I C L E Transrectal Ultrasound for Prostate Cancer: Perspectives from National Cheng Kung University Hospital Yuh-Shyan Tsai 1,2, Chia-Horng Chen 3, Yi-Hsiang Lin 4, Tzong-Shin Tzai 1 * Following a recent increase in the incidence and cancer deaths of prostate cancer, transrectal ultrasound (TRUS) has become an important tool that enables accurate sampling of prostate tissue for histologic examination in patients with a high risk of harboring cancer (patients with elevated prostate-specific antigen and abnormal digital rectal examination). The biopsy protocol continues to evolve with progress in ultrasound technology. In countries with a rising incidence of prostate cancer, it is important to determine an optimal biopsy strategy. In this article, we briefly summarize our experience and the problems we encountered when using TRUS in diagnosing prostate cancer at National Cheng Kung University Hospital. We also review progress in biopsy protocols according to the targeted lesion or systematic random biopsy protocols. We consider promising predictive models regarding the optimal number of biopsy cores and the probability of being diagnosed with prostate cancer. This information will enable biopsy strategies to be better applied according to the requirements of individual institutions. KEY WORDS biopsy, prostate, prostate cancer, ultrasound J Med Ultrasound 2007;15(3): Introduction Prostate cancer has been the sixth most common malignancy and the seventh leading cause of cancer deaths in Taiwanese males for more than 5 years. More than 2,000 men are diagnosed annually with prostate cancer, of which approximately 750 die [1]. There has been an obvious increase in the annual detection rate in Taiwan since the late 1990s, as well as in other Asian countries [2,3]. Despite the increase in detection rates, tumors have not been detected at an earlier stage [4]. In contrast, prostate cancer remains the most common malignancy in Western males and second leading cause of cancer deaths [5]. Given that the majority of biopsy protocols are reported and conducted in countries with a high incidence of prostate cancer, it is worth discussing the optimal strategy for those countries with a rising incidence of the disease [6]. As in general medical ultrasound, transrectal ultrasound (TRUS) is a continuously developing field; Watanabe et al [7] first introduced TRUS as a clinical 1 Department of Urology, College of Medicine, National Cheng Kung University Hospital and 2 Douliou Branch, Tainan, and Departments of 3 Urology and 4 Medical Imaging, Buddhist Tzu-Chi Dalin General Hospital, Chia-Yi, Taiwan. *Address correspondence to: Professor Tzong-Shin Tzai, Department of Urology, College of Medicine, National Cheng Kung University, 138, Sheng Li Road, Tainan 70428, Taiwan. tts777@mail.ncku.edu.tw Elsevier & CTSUM. All rights reserved. J Med Ultrasound 2007 Vol 15 No 3 183

2 Y.S. Tsai, C.H. Chen, Y.H. Lin, et al application for evaluating the prostate [8 10]. Fewer prostate cancers can be detected by lesiondirected biopsy using two-dimensional (2-D) grayscale imaging compared with systematic random biopsy [8]; therefore, the strategy of systematic random biopsy with reasonable biopsy cores has replaced the protocol of targeting hypoechoic lesions and has become the mainstay in prostate-specific antigen (PSA) screening [9]. Nevertheless, following advances in ultrasound technology machines, particularly the progress in computing and Doppler techniques, sonomorphologic lesions and/or associated increased vascularity are still worthy of attention [6,10,11]. In this article, we briefly summarize our experience and the problems we have encountered using TRUS in diagnosing prostate cancer at National Cheng Kung University Hospital (NCKUH). We review the progress in biopsy protocols for both targeted lesion and systematic random biopsy protocols. The NCKUH Experience TRUS has been applied at NCKUH for the detection of prostate cancer since the 1990s using the following biopsy strategy: three to five lesion-targeted biopsy cores are taken in the case of any sonomorphologically suspicious lesion over the peripheral zone; otherwise, 3 to 5 biopsy cores are obtained randomly on the basis of transverse examination of prostate halves [6]. The role of TRUS is to ensure accurate sampling of prostate tissue for histologic examination in men at higher risk of harboring cancer, particularly those with an elevated PSA level and abnormal digital rectal examination (DRE). Both PSA and DRE aid in the detection of prostate cancer [6,12,13]. Data from a small cohort of 90 patients who received prostate biopsy revealed that among 59 patients with abnormal DRE prostate cancer was detected not only in hypoechoic lesions (n = 10; 17.8%), but also in an isoechoic lesion (n = 1; 1.8%) and in diffusely heterogeneous lesions (n = 7; 12.5%). In contrast, only two prostate cancers were detected in hypoechoic lesions (n = 2; 5.9%) among 34 patients with normal DRE [12]. The results of a 5-year cohort study of 518 patients conducted between 1998 and 2002 showed that the cancer detection rate was superior for lesion-directed biopsy when compared with that for random biopsy, regardless of PSA levels. Nevertheless, approximately 40 patients would have been missed if lesiondirected biopsy alone had been performed [6]. Only 25 of 207 prostate cancers (12%) were detected for cases with a PSA level of less than 10.0 ng/ml. These results served as a warning that some prostate cancers would be missed using such a biopsy strategy, particularly for those with PSA of less than 10.0 ng/ml. Therefore, we were prompted to consider the most effective strategy for enhancing the detection of early prostate cancer in patients with PSA of less than 10.0 ng/ml. Biopsy Protocols Targeted hypoechoic or sonomorphologic lesions Grayscale 2-D imaging in the axial and longitudinal planes remains the main method of obtaining the best view of the anatomic delineation of structures around or within the prostate gland, such as the surrounding fat tissue, rectum, neurovascular bundles, seminal vesicles, and venous plexus, as well as the transition, central and peripheral zones [14]. Even so, it is only possible to obtain partial visualization of prostate cancer, meaning that limitations are encountered in obtaining accurate staging status [15], hypoechoic lesions are traditionally thought to be the main presentation of prostate cancer (Fig. 1); over the past two decades, these lesions have been targeted at biopsy [16]. The hypoechoic appearance is thought to reflect increased microvascularity density [17]. In the PSA era, the likelihood of a hypoechoic lesion being diagnosed as prostate cancer declined from 17 57% to 9% following the increased use of random biopsy cores [15,18,19]. Schroder et al reported a positive predictive value of DRE and TRUS of only 9.7% in a 184 J Med Ultrasound 2007 Vol 15 No 3

3 TRUS for Prostate Cancer A B C D Fig. 1. Lesions sonomorphologically suspicious for cancer, confirmed by histologic examination. (A) A 72-year-old man received bilateral sextant biopsies because of an elevated prostate-specific antigen (PSA) level (7.19 ng/ml). Pathologic examination revealed prostatic adenocarcinoma in all 6 cores (Gleason score, 3 + 3; right-sided cores, 50% of area; left-sided cores, 30% of area). (B) A 73-year-old man had lesion-directed prostate biopsy in the left peripheral zone and random biopsy on the right side because of an elevated PSA level (11.29 ng/ml). Pathologic examination revealed prostatic adenocarcinoma solely from the left isoechoic lesion (Gleason score, 4 + 4; 40% of area). (C) A 69-year-old man underwent 10-core prostate biopsy (including one core from a hypoechoic lesion) because of an elevated PSA level (10.21 ng/ml). Pathologic examination of the targeted hypoechoic lesion showed prostatic adenocarcinoma (Gleason score, 4 + 3; 80% of area), and one core from the other side showed microfocal prostate cancer (Gleason score, 2 + 2; 5% of area). (D) A 53-year-old man had bilateral sextant biopsy because of an elevated PSA level (11.36 ng/ml). Transrectal ultrasound found only one suspicious hypoechoic lesion in the right peripheral zone. Pathologic examination revealed prostatic adenocarcinoma on the right side (Gleason score, 3 + 2; 20% of area) and prostatitis on the left side. large cohort of 9,211 patients with PSA of less than 4.0 ng/ml [20]. It is, therefore, difficult to visualize prostate cancer from grayscale 2-D images solely by hypoechoic lesion. In general, the accuracy rate in cancer detection ranges from 41 to 74% [21]. Targeted Doppler-enhanced lesions Over the past two decades, Doppler techniques have been applied in perfusion studies of the prostate gland [22,23]. Until recently, three Dopplerassociated techniques were available for prostate ultrasound: color Doppler, power Doppler, and contrast-enhanced techniques [24 26]. In simple terms, the prostaticovesical arteries, arising from the internal iliac arteries, provide the blood supply to the human prostate. The prostaticovesical arteries divide into two branches: the prostatic artery and the inferior vesical artery. The prostatic artery, which is either single or composed of four to five branches, reaches the prostate gland on its anterolateral surface and gives rise to two groups of intraprostatic arteries: the urethral arteries and the J Med Ultrasound 2007 Vol 15 No 3 185

4 Y.S. Tsai, C.H. Chen, Y.H. Lin, et al capsular arteries. These arteries are distributed in a moderately regular manner throughout the prostate [27]. Because prostate cancer tends to have an increased density of capillaries compared with healthy prostatic tissue due to neovascularization [28], several phenomena are viewed as significant, including the presence of hypervascularity, a high degree of flow, left right asymmetry, and mass effect changes (a gap in perfusion around the lesion due to compression of the vessels by the pressure of the tumor mass) on the vessel structure [24 26,29]. Although some technical differences exist among these three Doppler-related perfusion imaging techniques, the accuracy rates in cancer detection are reported to be similar (color Doppler, 53 84%; power Doppler, 40 83%; contrast-enhancing Doppler, 40 91%) [21]. Color Doppler imaging measures blood flow velocity and direction, while power Doppler uses the Doppler signal amplitude rather than velocity or flow direction. Power Doppler shows greater sensitivity in depicting blood flow and the number, course, and continuity of vessels, and is more able to visualize smaller vessels and vessels with lower flow velocity than is the case with color Doppler [30]. The vascular anatomy of the normal prostate, as displayed by power Doppler, demonstrates a reproducible and symmetric flow pattern [30]. Three flow patterns are recognized as signs of prostate cancer: increased flow within a lesion, increased flow surrounding a lesion, and asymmetric flow in comparison to adjacent tissue or contralateral areas (Fig. 2) [31]. In a cohort of 579 patients with PSA of more than 3.5 ng/ml, 20 of 39 patients had T1c cancer that was invisible with power Doppler sonography [32]. These data reflect limited performance in the detection of early prostate cancer. In fact, power A B C D E F Fig. 2. Doppler-enhanced lesions confirmed by histologic examination. (A, B, C) Case 1: a 57-year-old man received bilateral biopsies (right side, targeted biopsy [3 cores]; left side, random biopsy [5 cores]) because of an elevated prostate-specific antigen (PSA) level of ng/ml. Pathologic examination revealed prostatic adenocarcinoma solely from the targeted hypoechoic lesion that had Doppler enhancement (Gleason score, 4 + 3; 80% of area). (D, E, F) Case 2: a 67-year-old man received bilateral biopsies (right side, targeted biopsy [2 cores]; left side, random biopsy [4 cores]) because of an elevated PSA level of 27.1 ng/ml. Pathologic examination revealed prostatic adenocarcinoma on both sides (Gleason score, 4 + 3, bilateral; right, 80% of area; left, 15% of area). In both of these cases, three flow patterns categorized as a sign of prostate cancer were visible. These signs include increased flow within a lesion, increased flow surrounding a lesion, and asymmetric flow relative to adjacent tissue or contralateral areas (A, D: 2-D grayscale; B, E: color Doppler; C, F: power Doppler). 186 J Med Ultrasound 2007 Vol 15 No 3

5 TRUS for Prostate Cancer Doppler ultrasound plays the dominant role in optimizing the number of useful biopsy cores and avoiding unnecessary cores in advanced disease [32,33]. Because the contrast agents (microbubbles) remain within the vessels, the difference in acoustic impedance between microbubbles and adjacent tissue results in higher reflective interfaces. Therefore, these microbubbles are optimal for real-time visualization of the vasculature [34]. Contrastenhanced Doppler techniques have become increasingly sensitive in perfusion imaging [26,35]. In a cohort of 85 patients, Roy et al compared the diagnostic performance of color Doppler images with and without contrast enhancement [26], reporting that contrast-enhanced color Doppler had higher sensitivity (93%) than unenhanced color Doppler (54%), while specificity increased from 79 to 87% for enhanced imaging [26]. Nevertheless, it is worthwhile to explore the diagnostic value of contrastenhanced Doppler techniques in early prostate cancer. Three-dimensional (3-D) images 3-D technique has been applied to ultrasound of the prostate [36,37]. Theoretically, in comparison with 2-D TRUS, which is a projection of a single image, 3-D TRUS produces a series of sequentially overlaid images, with the final result being an image of greater resolution and quality. Despite this benefit, the image acquired using a standard 3-D endorectal transducer uses the same gray scale as conventional 2-D TRUS. The diagnosis of prostate cancer is the same as for conventional 2-D TRUS [38], relying entirely on the visibility of prostate cancer lesions. Nevertheless, 3-D reconstructions in conventional TRUS imaging are superior to 2-D imaging in staging localized prostate cancer. Garg et al, in a small cohort of 36 cases of newly diagnosed localized prostate cancer, first reported that 3-D TRUS had an overall staging accuracy comparable to 2-D TRUS (94% vs. 72%; p < 0.05) [36]. Recently, Mitterberger et al reported in a larger cohort of 180 patients that 3D-TRUS identified extracapsular extension with an overall accuracy of 92% and seminal vesicle invasion with an overall accuracy of 91% [39]. Similarly, other modalities, such as power Doppler with or without contrast-enhanced images, might serve to augment the cancer detection rate of 3-D TRUS [40]. Systematic biopsy protocols Following the introduction of the systematic sextant biopsy method by Hodge et al in the detection of prostate cancer [8], systematic random biopsy became a mainstream technique following several modifications, including the optimal number of biopsy cores and the location [9,41]. The systematic random biopsy method differs from imaging-based techniques that target hypoechoic or Doppler-enhancing lesions, because it does not target any sonomorphologically suspicious lesions from TRUS; instead, it uses standard locations from which biopsies are taken. As reported by Hodge et al, the prostate is bilaterally divided into three regions (apex, mid-gland, and base), all of which are systematically biopsied once [8]. However, numerous studies demonstrated that further biopsy cores from additional bilateral transition zone, apex, or lateral regions result in higher detection rates, and data from the early 1990s demonstrated that a significant number of cancers were being missed using the six-core approach, particularly in larger glands [41 43]. For example, Eskicorapci et al reported in a cohort of 303 patients that the cancer detection rate of the 10-core biopsy strategy was 31% (94/303), compared with 23.1% (70/303) for the sextant biopsy strategy, in which there were 3 (0.9%) serious complications requiring hospitalization because of infections [42]. Thus, one particular question was frequently asked: how many biopsy cores are sufficient for cancer detection when the systematic random biopsy strategy is selected [44]? Currently, a systematic standard biopsy session may encompass any number of biopsy cores, with being used most frequently [42,43], detecting 31% more cancers (95% confidence interval, 25 37%) than sextant biopsy when taking additional laterally directed cores [9,45]. The severity of biopsy-related pain and the number of J Med Ultrasound 2007 Vol 15 No 3 187

6 Y.S. Tsai, C.H. Chen, Y.H. Lin, et al post-biopsy complications are possibly the same for both systematic sextant and 12-core extended biopsy [9,46,47], and increased sampling of the prostate does not increase the detection of potentially insignificant tumors [42,48]. Therefore, TRUS has become important in obtaining the accurate location of prostate tissue sampling in a systematic random method. Despite that taking more than 12 cores adds no significant benefit [9], a 24-core saturation prostate biopsy protocol was conducted and investigated under local anesthesia [49]; however, the role of this technique remains to be defined. Sampling location is also a key point in maximizing the cancer detection rate, particularly in the peripheral zone [50]. Philip et al, in a cohort of 241 patients with persistent elevated agespecific PSA and initial negative biopsy, reported that the maximum cancer detection rates were obtained from the peripheral apices, followed by basal biopsies and parasagittal biopsies in repeat 12-core biopsy protocols [50]. Predictive models to provide optimal cores or the probability of prostate cancer Many factors potentially influence the cancer detection rate during prostate biopsy, including PSA level, DRE findings, age, race, prostate volume, number of biopsy cores, location, and the selected biopsy strategy [6,8,9,12,51]. Conventionally, patients with either an elevated PSA level or abnormal DRE have a higher probability and a greater extent of prostate cancer [6]. Because TRUS is not accurate in staging prostate cancer [15], a standard sextant biopsy or a lesser number of biopsy cores might be sufficient for pathologic proof of malignancy in advanced or even metastatic prostate cancer patients with a strongly elevated level of PSA or hard prostate, rather than an extended 12-core biopsy strategy. To reduce unnecessary biopsy cores, previous authors have investigated and reported a predictive model for prostate biopsy concerned with the minimum number of cores required to detect cancers with a high degree of certainty [41,52]. Two determining variables, age and prostate volume, can be used to create a nomogram for determining the number of biopsy cores necessary to ensure a 90% certainty of cancer detection (e.g. the Vienna nomogram) [41, 53]. In a cohort of 834 Japanese patients, Suzuki et al incorporated several clinical and laboratory factors, including PSA, percentage of free PSA, prostate volume, and DRE findings, into a pre-biopsy nomogram that can significantly improve the prediction of the existence of prostate cancer compared with predictions based solely on these factors individually [52]. Despite this advance, it is important to ask whether such a nomogram would be effective in countries with a low incidence, rising incidence, or high incidence of prostate cancer [4,51]. Summary The incidence and cancer deaths of prostate cancer have been increasing over the past decade. Our experience in using our own biopsy strategy indicates that most patients have a PSA level of greater than 10.0 ng/ml when diagnosed with prostate cancer. The data also reveal that many patients are diagnosed with prostate cancer mainly from random biopsy cores, rather than from sonomorphologic lesions. Because ultrasound technology continues to progress, the introduction of methods, such as color Doppler, power Doppler, and contrast-enhanced techniques, means that Doppler-enhanced lesions enable more information to be provided in targeting. Moreover, 3-D TRUS appears to be superior to conventional 2-D TRUS in staging of prostate cancer, although further investigation is required to verify this observation. The 10- to 12-core systematic random biopsy remains the mainstream strategy in prostate biopsy. With the aid of a nomogram, it is possible to obtain the optimal number of biopsy cores while ensuring a 90% certainty of cancer detection. Acknowledgments The authors wish to thank Professor Cheng-Keng Chuang for inviting us to submit this paper. This review was partly supported by a collaboration between National Cheng 188 J Med Ultrasound 2007 Vol 15 No 3

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