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© 2003 American Society for Clinical Oncology Prognostic Significance of Visible Lesions on Transrectal Ultrasound in Impalpable Prostate Cancers: Implications for StagingFrom the Department of Urology, University Hospital Hamburg-Eppendorf, University of Hamburg, Germany; Department of Urology, Karl-Franzens-University Graz, Austria; Institute of Pathology, University Hospital Hamburg-Eppendorf, University of Hamburg, Germany; Department of Pediatrics, Karl-Franzens-University, Graz, Austria. Address reprint requests to Peter G. Hammerer, MD, Department of Urology, University of Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany; email: hammerer{at}uke.uni-hamburg.de.
Purpose: The current tumor-node metastasis (TNM) staging system classifies impalpable prostate cancers identified by needle biopsy and invisible by imaging as T1c and those visible as T2. Palpable cancers are classified as at least T2. However, most urologists consider impalpable prostate cancers T1c tumors, irrespective of findings on transrectal ultrasound (TRUS). The aim of this article is to provide a differentiated view of the significance of TRUS findings for staging purposes in impalpable prostate cancers. Patients and Methods: A consecutive series of 1,670 patients with impalpable tumors and palpable T2 cancers after radical prostatectomy were evaluated. Tumor characteristics and 5-year biochemical cure rates of cancers invisible and visible on TRUS were compared, as well as the rates of impalpable but visible and palpable T2 cancers. Results: Impalpable cancers invisible on TRUS presented significantly more favorable pathologic stages and lower cancer volumes than those visible on TRUS (P = .002, P = .010). In the latter, these clinical features were more favorable compared with T2 cancers (P < .001, P < .001). Progression-free probability of impalpable cancers invisible on TRUS was 86.8%; progression-free probability for impalpable cancers visible on TRUS was 85.4% (log-rank test P = .2060). The corresponding rate for T2 tumors was 73.9%, significantly lower when compared to those of visible and impalpable cancers (log-rank test P = .0001). Conclusion: Impalpable prostate cancers invisible on TRUS present more favorable cancer features than those that are visible on TRUS. However, these differences are not as pronounced as those between impalpable but visible cancers and palpable T2 tumors. Thus, based on our data, it seems inappropriate to classify impalpable prostate cancers visible on TRUS as T2 cancers.
THE PROSTATE gland is the most common cancer site in men. In 2002, prostate cancer (PC) is expected to account for 30% (189,000) of all new cancer cases among men in the United States.1 Fortunately, more than 80% of these estimated newly diagnosed patients will show local or regional disease.1 Among the various PC therapies, radical prostatectomy (RP) has been established in the overwhelming majority of institutions as the preferred treatment for localized prostate cancer. This procedure provides a 10-year progression-free probability in more than 90% of men with organ-confined disease.2–4 At present, in about two thirds of men undergoing RP, PC was impalpable at diagnosis and detected solely because of an elevated serum prostate-specific antigen (PSA) level.5–8 It is notable that approximately 25% of these men already showed non–organ-confined disease at the time a prostatectomy specimen was first analyzed.9,10 Impalpable PC is a heterogeneous disease that exhibits considerable histologic and anatomic variability.9–12 On transrectal ultrasound (TRUS), these cancers may present as invisible or visible. In particular, this distinctive feature has become important for clinical staging. Since 1992, T1c prostate cancers have been classified as tumors identified by needle biopsy (ie, because of elevated PSA) but not palpable or visible by imaging, whereas impalpable but visible tumors are defined as stage T2.13–15 Considerable uncertainty exists about the ability of TRUS to identify impalpable PC.12,16–18 Hence, most urologists will, regardless of their findings on TRUS, consider all impalpable PCs to be T1c tumors.8,11,12,19–21 This discrepancy between the theoretical demand of the current staging system and that of the newly implemented (as of 2003)TNM staging system, as well as that of common clinical practice, poses the question of whether the proposed classification of impalpable PC as either T1c or T2 on the basis of visibility by imaging is justified. However, an accurate prediction of final pathologic stage or an individual’s probability of disease recurrence is essential to determine which patients will experience maximum benefit from RP. Therefore, a detailed preoperative characterization of PC may lead to a more accurate prediction. Most additional parameters are cumbersome to assess and not commonly practiced by urologists or pathologists.22 In contrast, TRUS is performed routinely, and information about its findings is easily obtainable. We analyzed the significance of TRUS in the staging of impalpable PC, with emphasis on the current staging system, by comparing the tumor characteristics and 5-year progression-free probabilities of impalpable PC visible on TRUS with those of palpable T2 cancers. We also assessed the differences between impalpable, TRUS-invisible PC and impalpable PC visible on TRUS. Finally, we focused on the ability of TRUS to provide additional information about impalpable PC as a means of predicting organ-confined disease.
Patient Inclusion Criteria A consecutive series of 2,392 patients underwent radical retropubic prostatectomy for localized prostate cancer between January 1992 and June 2002. Men with complete data on clinical and pathologic stage, preoperative serum PSA level, Gleason score on biopsy, and prostatectomy specimen were enrolled. Patients with prior transurethral resection, as well as patients with any kind of neoadjuvant hormonal therapy, were not considered for this analysis. Furthermore, in cases of impalpable PC, only patients with detailed information about findings on TRUS were included. Overall, 942 patients with impalpable PC identified by needle biopsy exclusively, due to an elevated PSA, and 728 patients with palpable stage T2a/b cancer were eligible for evaluation.
TRUS
Assessment of Clinical and Pathologic Features
Up until June 2000, staging lymphadenectomy of the obturator lymph nodes was routinely performed in a total of 911 enrolled patients. From that point on, this procedure was not carried out when our clinical algorithm assessed a low risk (
Patients were examined routinely with PSA determination and digital rectal examination 3 months after radical prostatectomy and then yearly. A serum PSA level
Statistical Analysis The probability of biochemical cure after 5 years was calculated using the Kaplan-Meier method. Differences in biochemical cure rates between the groups were compared using the log-rank test.
Exclusively in impalpable cancers, we performed a multivariate analysis of prognostic factors for organ-confined disease. In short, a logistic regression analysis was done, with organ-confined disease as the dependent variable and preoperative serum PSA level, Gleason score on needle biopsy, and abnormal findings on TRUS as predictor variables. Deviation contrast coefficients with the first level as reference were used for the variable "Gleason score on biopsy." The relative importance of prognostic variables was measured by the
Effect of TRUS Findings on Impalpable PC Of 942 eligible patients with impalpable PC, TRUS-visible lesions were detected in 500 (53.1%) men. More specifically, of those 500 patients with TRUS-visible lesion, the PC featured a hypoechoic area in 496 men (99.2%). Furthermore, it showed either an irregularity of the prostatic capsule (7.4%) or a loss of the normal anatomy at the junction of the seminal vesicles (6.8%) as well. Overall, 442 (46.9%) of the 942 eligible patients presented without any suspicious lesion on TRUS.
Table 1
Table 2  compares the postoperative parameters. The pathologic stage and Gleason score were significantly (P = .002 and P < .001) different and in favor of impalpable PC with invisible lesions on TRUS. Of these tumors, as compared with the visible ones, 81.2% versus 70.6% were organ-confined, and 64.2% versus 50.8% showed a Gleason score  6, respectively. Metastases of the obturator lymph nodes were found in only 0.9% of men with invisible and impalpable PC. In men with TRUS-visible lesions, this rate was significantly (P = .033) higher, with 4.2% of affected patients. In addition, invisible, impalpable PC showed a significantly lower mean cancer volume than those cancers with visible lesions on TRUS (3.7 cm3 v 4.6 cm3; P = .010).
The mean follow-up of patients with impalpable PC, invisible as well as visible on TRUS, was 28.7 ± 21.7 months and 31.2 ± 23.9 months, respectively. Kaplan-Meier curves at 5 years of follow-up estimated an 86.8% progression-free probability in patients with an invisible lesion, versus 85.4% in those men with a TRUS-visible lesion (log-rank test P = .2060) (Fig 1 ).
Effect of TRUS Findings on the Prediction of Organ-Confined Disease in Impalpable PC For the whole group of 942 patients with impalpable PC, multivariate regression analysis of preoperative parameters found PSA level (P < .0001), biopsy Gleason score (P < .0001), and findings on TRUS (P = .005) to be independent predictors of organ-confined disease (Table 3 ). However, biopsy Gleason score was the most significant predictor, whereas findings on TRUS showed the lowest  2 value.
Effect of TRUS Findings on Clinical Staging of Impalpable PC Table 4 lists the comparison of preoperative parameters between impalpable PC visible on TRUS and clinical stage T2a/b PC. The latter showed a significantly higher preoperative PSA level than impalpable PC with visible lesions on TRUS (11.8 ng/mL v 9.3 ng/mL; P < .001). In addition, biopsy Gleason score of impalpable but visible PC was significantly (P < .001) more favorable than that of T2a/b cancers. Palpable T2a/b cancers were also associated with a significantly higher percentage of PC per biopsy set (22.4% v 14.3%; P < .001).
Table 5 presents the differences of postoperative cancer characteristics. Mean cancer volume was significantly lower in impalpable PC with TRUS-visible lesions (4.6 mL v 7.4 mL; P < .001). In these cancers, more favorable pathologic stages and more favorable Gleason scores were significantly (P < .001) more frequently assessed. Overall, 70.6% of these cancers were organ-confined, and 50.8% showed a Gleason score 6 in the prostatectomy specimen. In contrast, only 44.3% of clinical stage T2a/b cancers presented with organ-confined disease, and a Gleason score 6 was determined in 29.4%.
Patients with clinical T2a/b PC were followed by a mean of 39.6 ± 31.8 months. At 5 years of follow-up, the probability of nonprogression was 73.9%. This was significantly lower compared with the biochemical cure rate of patients with impalpable TRUS-visible PC (log-rank test P = .0001) (Fig 2 ).
In 422 (84.4%) of 500 patients with impalpable PC showing visible lesions, abnormal findings were detected in one single lobe; in 78 men (15.6%), lesions were seen in both lobes. Of 728 patients with clinical stage T2a/b cancer, a suspicious digital rectal examination of one single lobe (T2a) was assessed in 630 (86.5%) patients. Additionally, a total of 98 (13,5%) men were presented with an abnormal finding in both lobes (T2b). The separate comparisons between impalpable PC with visible lesions in one single lobe and T2a tumors, as well as between impalpable PC with visible abnormalities affecting both lobes and T2b, showed significantly more favorable cancer characteristics for each subgroup of visible, impalpable PC (Tables 6 and 7). Patients with impalpable PC and visible lesions in one single lobe were presented with an 87.9% biochemical cure rate at 5 years, compared to 76.5% of patients with PC at clinical stage T2a (log-rank test P = .0001) (Fig 3). The corresponding progression-free probabilities at 5 years were 67.2% in patients with impalpable PC harboring visible lesions in both lobes and 59.6% in patients with clinical stage T2b PC (log-rank test P = .1621) (Fig 4).
Staging of cancer is a cornerstone of oncology. In terms of PC, all statistical models use the clinical stage as an essential parameter to predict final pathologic stage or an individual’s probability of cancer recurrence.30–32 Remarkably, clinical staging of impalpable PC, which represents the most frequent condition for contemporary RP,5–8 is afflicted by some uncertainty in clinical practice. In particular, the definition of impalpable PC visible on imaging as stage T2 is not well accepted, although it has already been proposed by the TNM staging system since 1992.13 Conventional gray-scale TRUS is the imaging tool most frequently performed in diagnosing prostatic diseases and in guiding transrectal prostate biopsies. Nevertheless, perhaps resulting from a disappointingly low sensitivity and specificity for detection33 as well as a low rate of prediction of final pathologic stage in PC,34–36 the use of findings on TRUS for staging purposes is controversial. Furthermore, this attitude may be enhanced by discrepant reports in recent literature on this topic.12,16,37,38 In several of these studies, data were based only on small series. This fact may render the detection of probable differences between groups more difficult.
In this study, we analyzed a large consecutive series to determine the significance of TRUS for staging of impalpable PC and for predicting organ-confined disease in these cancers. Impalpable PC with visible lesions on TRUS showed significantly more favorable preoperative and postoperative parameters than palpable T2 cancers (Tables 4
We noted in our study that TRUS was able to separate impalpable PCs into two groups by their visibility. Those cancers that were invisible on imaging differed significantly in several preoperative and postoperative prognostic tumor characteristics (Tables 1
At 5 years, the progression-free probability of impalpable TRUS-invisible PC was nearly similar to that of impalpable but visible tumors (Fig 1
There are few studies12,16–18,37,38 attempting to provide insight into the significance of TRUS findings for the staging of impalpable PC. There is much debate regarding this issue. Ohori et al38 found that impalpable but visible PCs (n = 42) were similar in biopsy Gleason sum and cancer volume to impalpable and invisible PCs (n = 33), but the latter showed significantly less extracapsular extension (47% v 18%). On the other hand, Ferguson et al16 reported that invisible (n = 97) and visible (n = 97) impalpable PCs did not differ in common preoperative and postoperative prognostic parameters or in DNA ploidy. For example, cancer volumes of invisible, impalpable PCs were similar to those of visible PCs (6.1 cm3 v 6.8 cm3; P = .89). Moreover, they did not find the rates of PCs with < 0.5 mL cancer volume to differ statistically between both groups. This seems to be consistent with our observation on clinically insignificant PC (Table 2
Nonetheless, the differences between impalpable, TRUS-visible PC and clinical T2 cancers were more distinct than those between the two groups of impalpable PC stratified by the visibility of lesions on TRUS (Tables 1 In contrast, Tiguert et al37 found that impalpable, TRUS-invisible PCs (n = 138) differed significantly in common prognostic parameters TRUS-visible PCs (n = 366). For example, invisible and impalpable PCs presented more organ-confined disease (61% v 42%) and were superior in disease-free survival. On the other hand, cancers seen by TRUS were similar to palpable T2 cancers (n = 234) with regard to these characteristics and to progression-free probabilities. However, in our series, both groups of impalpable PCs were assessed with more favorable prognostic parameters, whereas palpable T2 cancers were similar. This may be due to the fact that contemporary T1c cancers are diagnosed earlier as a result of widespread PSA testing and thus may show more favorable tumor characteristics than in previous series.19 It is notable that in our present series, 66% of all impalpable PC had undergone RP in the prior 3 years. Another possible explanation for the similarities between impalpable but visible and T2 cancers reported by Tiguert et al37 might be that the earlier the examiner is able to identify a lesion on TRUS, the smaller the differences might be between invisible and visible impalpable PC. The ability to visualize PC on TRUS may be influenced by the examiner’s subjective interpretation of the imaging.44 Furthermore, the quality of imaging may also differ between ultrasonographic devices. However, invisibility of PC on TRUS may mean that these PCs are still too small for visualization, or that they are isoechoic. The prevalence of isoechoic lesions is reported between 35% and 42%.45,46 New developments in ultrasound techniques may improve the identification rate of such lesions in impalpable PC.47–50 In view of this, when used for staging purposes, it also would be necessary to standardize the technical criteria of TRUS. A limitation exists in the present study, because the mean follow-up times of the different groups were short. Nevertheless, our detailed analysis presents by far the largest series on this topic and thus provides valuable information for differentiated consideration. In conclusion, our study revealed that TRUS is able to separate impalpable PC by its visibility. Impalpable, invisible prostate cancers showed improved preoperative and postoperative cancer characteristics. Furthermore, impalpable but visible PC differed significantly, and to its advantage in most common prognostic cancer characteristics, from palpable T2 tumors. These differences were more pronounced than those within both groups of impalpable PCs. Patients with impalpable but TRUS-visible PC had a distinctly better prognosis after RP than did patients with palpable T2 tumors. In view of these data, impalpable but visible PCs should not be classified as clinical stage T2 tumors. By eliminating the distinction between impalpable cancers according to their visibility on imaging, staging systems would be simplified and would finally correspond to common clinical practice.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.1 ng/mL was considered biochemical failure. Postoperative information was available in 1,569 (93.9%) of 1,670 patients. 
