Is it necessary to separate clinical stage T1c from T2 prostate adenocarcinoma?

Authors


Liang Cheng, Department of Pathology and Laboratory Medicine, Indiana University Medical Center, University Hospital 3465, 550 North University Blvd., Indianapolis, IN 46202, USA.
e-mail: lcheng@iupui.edu

Abstract

OBJECTIVE

To test the hypothesis that prostate cancer patients with clinical stage cT1c and cT2 have similar outcomes and clinicopathological features, and should be grouped together.

PATIENTS AND METHODS

From a series of men with prostate cancer who had a radical retropubic prostatectomy (RP), we assessed those with cT1c (223) and cT2 (65) adenocarcinoma. All RP specimens were totally embedded and whole-mounted; tumour volume was measured using the grid method. Clinical and pathological characteristics were analysed.

RESULTS

Patients with cT2 tumours were more likely to have a higher Gleason score (P = 0.04) and final pathological stage (P = 0.05) than those with cT1c tumours. There was no significant difference in age (P = 0.92), preoperative PSA level (P = 0.17), prostate weight (P = 0.34), tumour volume (P = 0.16), surgical margin status (P = 0.86), multifocality (P = 0.92), the presence of perineural invasion (P = 0.09), or high-grade prostatic intraepithelial neoplasia (P = 0.99) between patients with clinical stage cT1c and those with cT2 tumours. There was no difference in PSA recurrence between patients with clinical stage T1c and those with cT2 tumours (P = 0.27).

CONCLUSIONS

Patients with clinical stage cT2 tumours have a higher Gleason score and advanced pathological stage than tumours detected because of a high serum PSA level (cT1c). These results suggest that clinical stage cT1c tumours should be separated from clinical stage cT2 disease, but the PSA recurrence rate for both tumour stages is similar, indicating a need for further evaluation and refinement of the current clinical staging system.

Abbreviations
(R)RP

(retropubic) radical prostatectomy.

INTRODUCTION

The use of PSA screening has significantly increased the number of patients with prostate cancer who are detected at an earlier stage, but the data to suggest whether there is a survival advantage over the use of a DRE alone is not conclusive. The current TNM staging system, which aids in determining the prognosis, suggests that there is a survival advantage in patients with prostate cancer detected by PSA screening. Recent studies suggest that the clinical outcome between prostate adenocarcinoma detected by PSA screening (cT1c) or disease detected on a DRE (cT2) may have the same prognosis after treatment [1]. In the present study, we compared the clinicopathological characteristics of a contemporary series of patients who had a radical retropubic prostatectomy (RRP) and subsequent whole-mount specimen processing for cT1c and cT2 adenocarcinoma of the prostate.

PATIENTS AND METHODS

The study population comprised 288 men who had a RRP between 1999 and 2003 at Indiana University Medical Center. Patients who received preoperative adjuvant therapy were excluded. Patients had a preoperative abdominal CT, a bone scan and a chest X-ray, based on clinical circumstance and preoperative PSA level. No patients with evidence of metastatic disease had a RRP. The patients were clinically staged using the 2002 TNM system [2]. Serum PSA concentration was measured using the Immulite® PSA assay (Diagnostics Products Corporation, Los Angeles, CA). PSA recurrence was defined as a serum PSA level of ≥0.1 ng/mL after surgery [3–5]. The patients were followed at 1, 3, 6, 12, 18 and 24 months during the first 2 years; thereafter the follow-up was adjusted according to the clinical situation, but was at least annual.

The RP specimens were examined as previously described [6–9]; the prostates were weighed, measured, inked and fixed in 10% neutral formalin. After fixation the apex and base were amputated and serially sectioned at 3–5 mm intervals in the vertical, parasagittal plane. The seminal vesicles were sectioned parallel to their junction with the prostate and entirely submitted for examination. The remaining prostate was serially sectioned perpendicular to the long axis from the apex of the prostate to the base, and whole-mount sections prepared. The volume of carcinoma in the entire prostate was determined by the grid method, and was the sum of the volumes of individual foci of tumour [10–13]. Perineural invasion was assessed using the established criteria [14]; it typically occurred in the peripheral zone of the prostate and can be located within the prostatic parenchyma, at both the capsular and extracapsular levels. Pathological stage was assessed according to the 2002 TNM criteria [2], and tumours were classified as either T2 or T3 for the purposes of statistical analysis. In our previous study, we found that a true pT2b tumour probably does not exist [15]. Gleason score was determined according to the Gleason grading system [16–18]. All pathological data were collected prospectively by one genitourinary pathologist (L.C.).

The Spearman coefficient of rank correlation was calculated for variables including age, preoperative PSA level, prostate weight, tumour volume, the largest tumour size, Gleason score, surgical margin status, the presence of perineural invasion, and high-grade prostatic intraepithelial neoplasia, between patients with clinical stage cT1c and those with cT2 tumours. Because of the low frequencies, stages cT2a and cT2b were combined into cT2. In all, tests, P < 0.05 was considered to indicate statistical significance.

RESULTS

In all, 288 patients who had RRP for presumed organ-confined disease (cT1c and cT2) were included (mean age 60 years, range 41–77). After final pathological evaluation, 215 patients had pT2 and 73 had pT3 disease. The mean preoperative PSA level was 5.75 ng/mL for pT2 disease and 7.50 ng/mL for pT3 disease.

Patients with cT2 tumours were more likely to have a higher Gleason score (P = 0.04) and final pathological stage (P = 0.05) than those with cT1c tumours (Fig. 1a,b, Table 1). There was no significant difference in age, preoperative PSA level, prostate weight, tumour volume, surgical margin status, multifocality, the presence of perineural invasion, or high-grade prostatic intraepithelial neoplasia between patients with clinical stage cT1c and those with cT2c tumours (Table 1).

Figure 1.

Comparison ofa, final Gleason score, andb, final pathological stage in RP specimens between clinical stage T1c and T2.

Table 1.  Comparison of clinical T1c and T2 prostate cancer
CharacteristicscT1ccT2P*
  • *

    Wilcoxon rank sum test or N (%) and Fisher's exact test;

  • †2002 TNM staging system; PIN, prostatic intraepithelial neoplasia.

N22365 
Median (range):
age, years 60 (41–76)61 (44–77)0.92
preoperative PSA level, ng/mL  6.1 (0.1–58) 5.8 (1.2–48.7)0.17
prostate weight, g 39 (14–149)37 (21–140)0.34
Pathological stage, n (%)  0.05
 T2a 33 (15.8) 6 (9.2) 
 T2b  0 0 
 T2c140 (62.8)36 (55.4) 
 T3a 40 (17.9)21 (32.3) 
 T3b 10 (4.5) 2 (3.1) 
Median (range):
Tumour volume, mL  1.6 (0.02–12.5) 1.9 (0.1–13.6)0.16
Largest tumour dimension, cm  1.6 (0.04–4.1) 1.8 (0.1–3.8)0.12
Gleason score  6 (4–9) 7 (5–9)0.04
Surgical margin, n (%) 45 (20.2)14 (21.5)0.86
Multifocality193 (86.6)57 (87.7)0.92
Perineural invasion168 (75.3)56 (86.2)0.09
High-grade PIN220 (99.1)65 (100)0.99
PSA recurrence 23 (10.3)10 (15.4)0.27

Thirty-three patients had a PSA recurrence during a median (range) follow-up of 14 (1.5–48) months. There was no difference in PSA recurrence between patients with clinical stage T1c and those with cT2 tumours (P = 0.27).

DISCUSSION

In the present study, patients with clinical stage T2 tumours had a higher Gleason score and final pathological stage than those with tumours detected because of a high serum PSA level (cT1c). However, the PSA recurrence rate for cT1c and cT2 tumours was similar. There was no significant difference in the other variables assessed (Table 1) between cT1c and cT2 disease. These findings suggest a need for further evaluation and refinement of the current clinical staging system.

Many groups have shown that the pathological characteristics are nearly identical in cT1c and cT2 tumours [19–22]. Stamey et al.[23] reviewed 791 RRP specimens for final pathology of cT1c and cT2a disease for cancer volume (2.4 vs 1.8 mL), elements of Gleason 4 or 5 (10% vs 10%), capsular penetration (30% vs 30%), and biochemical cure rates (70% vs 72%) and found them to be statistically similar. Ramos et al.[24] reviewed 1620 patients who had a RRP, comparing cT1c to cT2a disease; positive surgical margins (20% vs 23%), seminal vesicle invasion (5% vs 5%), lymph node metastasis (0.8% vs 0.3%) and 5-year recurrence rate (85% vs 83%) were similar for cT1c and cT2a disease. Many studies have shown that cT1c disease also behaves similarly to cT2 disease after RRP. The Search Database Study Group [25] retrospectively reviewed the Gleason grade, age, preoperative PSA level, PSA-recurrence-free survival and biopsy laterality in 992 patients after RRP for cT1c and cT2 disease, finding similar rates of PSA recurrence. Lerner et al.[26] found there to be no statistically significant disease-free survival advantage in the cT1c vs cT2a group (84% vs 75%). A large series of 4453 patients who had RRP at the Mayo Clinic compared cT1c to cT2a, cT2b and cT2c prostate cancer. Overall, the 5- and 7-year survival free of PSA progression was 82.2% vs 82.5% and 72.9% vs 74.7% for cT1c and cT2a disease [27].

The continued separation of cT1c from cT2 tumours could be problematic for several reasons. The DRE has a low sensitivity for assessing the presence and extent of adenocarcinoma. This calls into question the current category of cT2 in the TNM staging system, which relies heavily on the subjective detection of cancer on a DRE. Obek et al.[28] reviewed 89 patients with clinically palpable tumours (cT2) to assess whether the clinicians’ characterization of the disease as unilateral or bilateral by DRE correlated with the final pathology specimen. In tumours characterized preoperatively as cT2a (unilateral) adenocarcinoma, 69% were pathologically cT2b/c (bilateral), and 4% had no cancer in the lobe described as having the palpable abnormality [28]. A DRE reported as clinically benign in a lobe failed to detect 36% of extraprostatic extension [28]. The current TNM staging of separate cT2a and cT2b disease may not hold true, as positive biopsy laterality has not been shown to correlate significantly with biochemical failure independent of PSA level, Gleason score and palpation T stage [29]. In a large series of whole-mount-processed RP specimens, Eichelberger and Cheng [15] found that a true pT2b prostate cancer (using the 2002 TNM classification) probably does not exist. Further refinement of the T1 and T2 clinical staging system is needed to stratify patients into different prognostic groups.

There are several limitations of the current study; the sample size was relatively small, which limits the statistical power. In addition, our method of whole-mount processing is not universally adopted, making it difficult to directly compare our data with other reported data. Whole-mount processing may give a better estimate of true tumour volume, laterality, presence of extraprostatic extension and positive surgical margin status than random sampling. Variability in clinical staging and surgical procedure cannot be eliminated, given that many urologists were involved in the study.

In summary, patients with clinical stage cT2 tumours have a higher Gleason score and final pathological stage than those with tumours detected because of elevated serum PSA levels (cT1c). The present data suggest that clinical stage cT1c tumours should be separated from clinical stage cT2 disease. We recommend that a DRE be routine as part of standard protocols for evaluating patients with prostate cancer.

ACKNOWLEDGEMENTS

Joanne Daggy assisted in statistical analysis.

CONFLICT OF INTEREST

None declared.

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