Clinical staging of prostate cancer: Reproducibility and clarification of issues

Authors


  • The opinions expressed herein are those of the authors and do not necessarily reflect those of the United States Army or Department of Defense.

Abstract

The American Joint Committee on Cancer (AJCC) staging system for prostate cancer adopted in 1992 is based on tumor-node-metastasis (TNM) designations. It has been widely accepted for use in local and advanced disease. The purpose of this study was to assess reproducibility of staging among observers and to help clarify staging issues. Twelve prostate cancer cases were sent to 20 physicians with special expertise in prostate cancer including eight urologists, eight radiation oncologists, and four medical oncologists. Physicians were asked to assign a stage based on the 1992 AJCC clinical staging. The most frequently reported stage assigned to each case was taken to be the consensus. Agreement was the percentage of physicians who reported that particular stage. Seventy-five percent of the physicians responded. The overall agreement for assignment of T stage was 63.9%. Differences were found by specialty for inclusion of available information in designating a T stage. The overall agreement for N stage was 73.8%. The most common designation was Nx regardless of availability of a computed tomography scan. The overall agreement for M stage was 76.6%. Without a bone scan the most common designation was Mx regardless of Gleason grade or prostate-specific antigen (PSA). A frequent comment was that PSA was more indicative of disease extent than current clinical staging. The reproducibility of the 1992 clinical AJCC staging is poor even among experts in the field. This problem arises primarily from disagreement regarding which studies are included in assigning a stage. Some of these difficulties are addressed in the 1997 revision. However, the clinical staging does not address the true biological significance of disease in many instances. © 2001 Wiley-Liss, Inc.

INTRODUCTION

The purpose of staging is five-fold: (1) to aid in the selection of therapy, (2) to determine prognosis, (3) to aid in evaluating and comparing results, (4) to allow effective communication between physicians and centers, and (5) to assist in investigation [1]. With this perspective it is obvious why staging systems need to be accurate in terms of grouping diseases with similar biology appropriately and classifications must be readily reproducible between observers.

The tumor-node-metastasis (TNM) system was described in the 1940s in France [2]. The logic of this system follows from the prevailing view of the natural history of cancer in the earlier parts of this century. The view was surgically based and held that cancer grows in an orderly, centrifugal fashion, progressing from tumor to nodes to distant sites. If the anatomic extent can be defined, then the cancer can be excised. In 1959, the American Joint Committee on Cancer (AJCC) was organized to develop an appropriate clinical classification based on simplicity, practicability, and credibility [3]. AJCC staging since that time has been driven primarily by the same anatomically based concepts.

The AJCC staging for prostate cancer adopted in 1992 was used for the present study. The goals were to provide a readily usable classification, preserve the logic of the Whitmore system, and allow flexibility to incorporate new information [4]. This system is dictated primarily by the extent of local tumor on digital rectal examination (DRE) and imaging, although there is considerable disagreement concerning the latter. During the past decade other important strides in defining prostate cancer have been made, most notably prostate-specific antigen (PSA), transrectal ultrasound (TRUS), and sextant biopsy. The work of Partin et al. [5] has led to nomograms and formulas to help predict pathologic stage and influence management decisions based on clinical T stage, PSA, and Gleason score. A widely used nomogram based on The Johns Hopkins experience was recently evaluated on a large patient data set at the Baylor College of Medicine [6]. The predicted probability of organ-confined disease was different from the actual pathologic assessment; in particular, the prediction of nodal status and seminal vesicle invasion was inadequate. A possible explanation may be discrepancy in the assignment of clinical stage between the two institutions.

Although PSA, TRUS, and sextant biopsy are significant advances, no agreement has been reached regarding their application to staging. Other means that may become more widely available to determine or predict the extent of disease may include molecular staging by detection of mRNA-encoding PSA or prostate-specific membrane antigen detected by reverse transcriptase-polymerase chain reaction, quantitation of microvessel density, other biomarkers such as p53, magnetic resonance imaging (MRI) with endorectal coil, immunoscintigraphy, and laparoscopic pelvic lymphadenectomy [7].

Clinical staging will assume greater importance in the future as advances in non-surgical therapies improve outcome in appropriately selected patients. In an effort to clarify issues in clinical staging and assess reproducibility, expert opinion regarding specific cases was sought from specialists with significant interest and experience in the treatment of prostate cancer.

MATERIALS AND METHODS

Twelve prostate cancer cases described in detail were mailed to 20 physicians with expertise in prostate cancer therapy, demonstrated by publication or clinical experience, together with a cover letter explaining the purpose of the study. The group of 20 physicians included eight urologists, eight radiation oncologists, and four medical oncologists. After approximately 6 weeks, a reminder letter and a second copy of the cases were mailed to non-responding physicians. They were asked to review and stage each case by clinical AJCC criteria. Space was provided for comments regarding the rationale for stage assignment, the need for further work-up, and suggestions for improvements in the precision of staging.

The 12 cases are presented in Figures 1 to 12. The actual figures and descriptions were sent to the surveyed physicians. These cases, although not actual patients, were designed to be representative of cases seen at the University of Chicago in which staging dilemmas and concerns had been noted. Many of the difficulties presented have been encountered commonly in clinical practice by one author (S.V.) and each case presents at least one specific issue.

Figure 1.

Findings for case #1. Digital rectal examination (DRE): no palpable nodules; symptoms: obstructive symptoms; prostate-specific antigen: 28 ng/ml; sextant biopsy: all six cores positive; Gleason score: 3 + 4 = 7 in all cores; transrectal ultrasound: seminal vesicle negative consistent with DRE; bone scan: increase uptake at L3-L4, x-rays negative for metastases; computed tomography of the pelvis: slightly enlarged, no nodes; chest x-ray: not done.

Figure 2.

Findings for case #2. Digital rectal examination (DRE): 1.5 × 1.5-cm right lobe nodule; symptoms: nocturia; prostate-specific antigen: 18 ng/ml; sextant biopsy: positive in left and right mid-gland; Gleason score: left and right mid-gland cores 3 + 3 = 6; transrectal ultrasound: hypoechoic area, right mid-gland 1.5 × 1.5 cm, confirming DRE; bone scan: negative for metastases; computed tomography of the pelvis: not done; chest x-ray: negative.

Figure 3.

Findings for case #3. Digital rectal examination (DRE): 1.0 × 1.0-cm left lobe nodule; symptoms: none; prostate-specific antigen: 20.0 ng/ml; sextant biopsy: positive in left base and left seminal vesicle; Gleason score: 3 + 2 = 5; transrectal ultrasound: hypoechoic area left base and left mid-gland 1.0 × 1.0 cm, confirming DRE; bone scan: negative for metastases; computed tomography of the pelvis: not done; chest x-ray: not done.

Figure 4.

Findings for case #4. Digital rectal examination: 1.0 × 1.0-cm right lobe nodule; symptoms: none; prostate-specific antigen: 7.5 ng/ml; sextant biopsy: positive left mid-gland, all other cores negative; Gleason score: 3 + 4 = 7; transrectal ultrasound: normal; bone scan: not done; computed tomography of the pelvis: not done; chest x-ray: not done.

Figure 5.

Findings for case #5. Digital rectal examination: 3.0 × 3.0-cm left lobe nodule with involvement of the seminal vesicle; symptoms: obstructive symptoms; prostate-specific antigen: 28.0 ng/ml; sextant biopsy: left apex, mid-gland, and base positive, biopsy not obtained from seminal vesicle; Gleason score: 4 + 4 = 8; transrectal ultrasound: multiple hypoechoic lesions in right and left lobes, normal seminal vesicles; bone scan: negative for metastases; computed tomography of the pelvis: not done; chest x-ray: negative.

Figure 6.

Findings for case #6. Digital rectal examination: no palpable nodules; symptoms: none; prostate-specific antigen: 18.9 ng/ml; sextant biopsy: positive in al six cores, seminal vesicles positive bilaterally; Gleason score: 3 + 4 = 7 in left base and left mid-gland, rest all 3 + 3 = 6; transrectal ultrasound: normal; bone scan: negative for metastases; computed tomography of the pelvis: not done; chest x-ray: not done.

Figure 7.

Findings for case #7. Digital rectal examination: two nodules—1.5 × 1.5-cm left lobe and 1.0 × 1.0-cm right lobe; symptoms: obstructive symptoms; prostate-specific antigen: 12.3 ng/ml; sextant biopsy: bilaterally positive mid-gland; Gleason score: 3 + 3 = 6 for both mid-glands; transrectal ultrasound: hypoechoic 1.0 × 1.0-cm area left mid-gland; bone scan: negative for metastases; computed tomography of the pelvis: periprostatic involvement on the left, multiple small (≈1 cm) nodes in plevis; chest x-ray: negative.

Figure 8.

Findings for case #8. Digital rectal examination (DRE): both nodes involved, sulci obliterated bilaterally, seminal vesicle not involved; symptoms: obstructive symptoms; prostate-specific antigen: 33.8 ng/ml; sextant biopsy: all six cores positive; Gleason score: 5 + 4 = 9 in four of six specimens, 4 + 4 = 8 in rest, seminal vesicles negative; transrectal ultrasound: consistent with DRE, seminal vesicles normal; bone scan: negative for metastases; computed tomography of the pelvis: not done, Prostascint scan positive in prostate area and left pelvis; chest x-ray: negative.

Figure 9.

Findings for case #9. Digital rectal examination: 0.5 × 1.0-cm palpable left nodule with invasion into prostate apex; symptoms: none; prostate-specific antigen: 8.3 ng/ml; sextant biopsy: positive in left apex; Gleason score: 3 + 2 = 5 in left apex; transrectal ultrasound: hypoechoic area, 0.25 cm, in left apex; bone scan: not done; computed tomography of the pelvis: not done; chest x-ray: not done.

Figure 10.

Findings for case #10. Digital rectal examination: large prostate in obese patient, no nodules, seminal vesicles could not be palpated, examination considered suboptimal due to patient's obesity; symptoms: obstructive symptoms; prostate-specific antigen: 8.3 ng/ml; sextant biopsy: positive bilaterally at base; Gleason score: 2 + 2 = 4; transrectal ultrasound: hypoechoic area measuring 1.5 × 1.5 cm in both bases; bone scan: not done; computed tomography of the pelvis: not done; chest x-ray: negative.

Figure 11.

Findings for case #11. Digital rectal examination: 1.5-cm palpable nodule left mid-gland; symptoms: obstructive symptoms; prostate-specific antigen: 11.5 ng/ml; sextant biopsy: positive in left mid-gland; Gleason score: 4 + 3 = 7 in one of six cores; transrectal ultrasound: 1.5-cm hypoechoic area left mid-gland; bone scan: not done; computed tomography of the pelvis: enlarged prostate, MRI with endorectal coil showed capsular invasion; chest x-ray: negative.

Figure 12.

Findings for case #12. Digital rectal examination: no palpable nodules; symptoms: none; prostate-specific antigen: 17.0 ng/ml; sextant biopsy: positive in right base; Gleason score: 3 + 3 = 6; transrectal ultrasound: 1.0-cm hypoechoic area in right base; bone scan: negative; computed tomography of the pelvis: slightly enlarged prostate, multiple enlarged periaortic nodes; chest x-ray: negative.

Many respondents did not fill in the stage grouping. In this case, stage grouping was assigned based on T, N, and M classifications assigned by the respondent. For each case, the most frequently reported T, N, or M stage was assumed to be the consensus and “agreement” was the percentage of physicians who reported that particular stage. Comments are reported with reference to specialty. Additionally, comparisons of stage assignments were made by specialty.

RESULTS

Response from Experts

The response rate (i.e., the percentage of the physicians returning the cases) was 75% (15 of 20). For the urologists, six physicians responded, one passed the cases to an associate who subsequently responded, and one declined for a total response rate of 87.5% (7 of 8). Seventy-five percent (6 of 8) of the radiation oncologists returned the cases and two declined. Two of the four medical oncologists responded; the other two did not respond after two mailings. The responding physicians are listed as co-authors.

T Stage

Overall agreement for T stage in these 12 cases was 63.9%. Agreement rates ranged from 93.3% for case #1 to 46.7% for cases #2 and #6.

Case #1 (Fig. 1 and Table 1).

11This case addresses the issue of a patient with a negative DRE and TRUS who has extensive disease noted in biopsy results. The extensive nature of the disease is supported by the PSA and grade. In general, there was agreement in assigning this case as T1c. However, there was clear discomfort with the adequacy of this classification. The patient “likely has extracapsular disease” (urologist) and with the elevated PSA is a “probable pathologic T3” (urologist). Two of the radiation oncologists made specific comments to the effect that “current clinical stage does not adequately represent the biological significance of the disease.” It was suggested that “this patient be staged with a new clinical/serological” staging system similar to that proposed for testis cancer (medical oncologist).

Table 1. Stage Assignments for Case #1
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T1c66214
 T2c11
N
 Nx3519
 N0415
M
 Mx1113
 M064111
 M1b11

Case #2 (Fig. 2 and Table 2).

22This case addresses two issues: palpable disease in one lobe with bilateral disease by biopsy and a palpable nodule at or near the limit of ½ of the lobe to assess the subjective nature of this finding by different examiners. There was no clear consensus in staging this case.

Table 2. Stage Assignments for Case #2
StageU (n = 7)RO (n = 6)MO (n = 2)Total (n = 15)
  1. a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

T
 T2a2215
 T3a4217
 T3c123
N
 Nx63110
 N01315
M
 Mx112
 M065213

Case #3 (Fig. 3 and Table 3).

33The primary issue in this case is the significance of a seminal vesicle biopsy. Five of six radiation oncologists assigned T2a, but four of seven urologists assigned T3c, presumably because of the positive seminal vesicle biopsy.

Table 3. Stage Assignments for Case #3
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T2a3519
 T3a11
 T3c415
N
 Nx74112
 N022
M
 Mx112
 M07512

Case #4 (Fig. 4 and Table 4).

44This case involves a positive biopsy contralateral to a palpable nodule. Twelve of 15 physicians called this a T2a lesion. One urologist commented that this case would be called T2b in his institution's data base.

Table 4. Stage Assignments for Case #4
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T1c112
 T2a65112
 T2b11
N
 Nx74112
 N02
M
 Mx3418
 M0426

Case #5 (Fig. 5 and Table 5).

55In this case the seminal vesicle was involved by DRE but not by TRUS; additionally, no seminal vesicle biopsy was performed. There was good agreement in classifying this case as T3c (13 of 15).

Table 5. Stage Assignments for Case #5
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T2b11
 T3b11
 T3c66113
N
 Nx74112
 N011
M
 Mx11
 M074112

Case #6 (Fig. 6 and Table 6).

66The primary issue in this case is extensive disease noted in the biopsy results, including positive seminal vesicles in a patient with a normal DRE and TRUS. There was considerable disagreement in this case. Four of six radiation oncologists called this case T1c, but five of seven urologists classified it as T3c. The medical oncologists were split. A concern that this is advanced-stage disease was expressed by the statement that “although we would stage the patient as T1c, we would likely treat the patient as if [he had] locally advanced disease” (radiation oncologist).

Table 6. Stage Assignments for Case #6
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T1c2417
 T3b11
 T3c527
N
 Nx75113
 N011
M
 Mx112
 M07512

Case #7 (Fig. 7 and Table 7).

77This case shows extraprostatic disease by computed tomography (CT) scan with no other clinical evidence for extension. Most staged this case as T2c consistent with the clinical examination and biopsy (11 of 15).

Table 7. Stage Assignments for Case #7
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T2b22
 T2c6511
 T3a112
N
 Nx358
 N04116
 N111
M
 Mx11
 M075113

Case #8 (Fig. 8 and Table 8).

88This case demonstrates extensive disease in the prostate by DRE with bilateral obliteration of the sulci. Eight of 15 classified this case as T2c; however, five classified this case as T3b, presumably because of the obliteration of the sulci.

Table 8. Stage Assignments for Case #8
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T2b11
 T2c448
 T3b2215
 T4a11
N
 Nx3418
 N011
 N1314
 N211
M
 Mx11
 M075113

Case #9 (Fig. 9 and Table 9).

99This case shows a nodule invading the prostatic apex. The extent of disease on the diagram was purposely made difficult to interpret, as is palpable disease in this area. There was no clear consensus for this case.

Table 9. Stage Assignments for Case #9
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T2a3328
 T3a437
N
 Nx74112
 N022
M
 Mx4419
 M0325

Case #10 (Fig. 10 and Table 10).

1010This example represents a case without palpable disease; however, the examination is not optimal. Bilateral findings are present on both TRUS and biopsy. There was a difference between urologists and radiation oncologists. Four of seven urologists assigned this case as T1c and four of six radiation oncologists classified it as T2c.

Table 10. Stage Assignments for Case #10
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 Tx112
 T1c415
 T2a11
 T2b11
 T2c246
N
 Nx74213
 N022
M
 Mx44210
 M0325

Case #11 (Fig. 11 and Table 11).

1111In this case the DRE, TRUS, and biopsy were all positive in the left mid-gland; however, MRI with endorectal coil showed capsular invasion. This case presents two difficulties: one being the specificity of MRI findings and the other differentiating between invasion into and through the capsule. Twelve of 15 physicians called this T2a disease, including both medical oncologists.

Table 11. Stage Assignments for Case #11
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T2a65212
 T3a123
N
 Nx3519
 N0415
M
 Mx45110
 M0314

Case #12 (Fig. 12 and Table 12).

1212This case demonstrates disagreement between DRE and TRUS. Six of seven urologists classified this as T1c but five of six radiation oncologists classified this case as T2a.

Table 12. Stage Assignments for Case #12
StageU (n = 7)RO (n = 6)MO (n = 2)aTotal (n = 15)a
  • a

    MO = medical oncologists; RO = radiation oncologists; U = urologists.

  • a

    Not included if no classification given.

T
 T1b11
 T1c6118
 T2a156
N
 Nx3418
 N022
 N22215
M
 Mx112
 M04318
 M1a11
 M1123

N Stage

The overall level of agreement in N stage designation was 73.8% (127 of 172); however, the most common designation in every case was Nx regardless of whether or not CT scan or Prostascint scan was obtained. For the seven cases in which no CT or Prostascint scan was obtained 84.8% (84 of 99) were designated Nx. This percentage was not greatly different for PSA > 10 ng/ml (83.9%) or PSA < 10 ng/ml (86.0%). The percentage of designation as Nx was lower for the two cases with a negative CT scan (65.5%); however, Nx was still the most common assignment. For the case with ≈1-cm nodes observed in the pelvis on CT, the predominant designation was still Nx, but it is interesting to note that this case also had the highest number of observers reporting N0 (6 of 15). Several comments to the effect that CT scan has no relevance were made in the cases with a negative CT. A frequent suggestion was to consider lymph node dissection, particularly by laparoscopic approach. Another suggested approach was to perform a seminal vesicle biopsy and proceed to laparoscopic lymph node dissection if positive.

Case #12 showing enlarged periaortic nodes was still most commonly called Nx (8 of 15). Five individuals commented that this finding required biopsy confirmation. Two individuals commented that this was M1 disease because of enlarged periaortic nodes (both radiation oncologists).

Case #8 with a positive Prostascint scan in the pelvis with no CT obtained also was most commonly called Nx (8 of 14). Five physicians, however, called the patient node positive: four of seven urologists, but only one of six radiation oncologists.

M Stage

The overall agreement in assignment of M stage was 76.6% (131 of 171). Considering just the six cases where negative bone scans were obtained, the agreement level rose to 89.2% (75 of 84), with the most common assignment being M0. There were four cases in which the PSA was < 12 ng/ml and no bone scan was obtained. The agreement in these cases was lower (64.9%) and the predominant designation was Mx. This level of agreement was not affected if the Gleason grade was ≤ 6 (65.5%) versus > 6 (64.3%). For case #1, in which the bone scan showed uptake in the lumbar spine but x-rays were negative, 73.3% (11 of 15) called this case M0. One individual asked for clarification of “x-rays” to indicate whether this designation included MRI (radiation oncologist). The other case with variance in assignment was case #12. Although no bone scan was obtained, the most common classification was M0 (8 of 16). The four individuals calling this case positive for metastases presumably made this choice because of the finding of positive periaortic nodes on CT.

DISCUSSION

As stated at the onset, the purpose of staging is to aid in selection of therapy and to determine prognoses. Staging, as defined by the AJCC system, attempts to define the anatomic extent of disease, which is a predominant prognostic variable in prostate cancer. However, clinically assessable anatomic extent is not the only prognostic variable currently available. The goal of pretreatment assessment of a patient is to determine the biological significance of malignancy in an individual patient. This task requires the use of all available data, including clinical anatomic extent in a uniform and reliable manner. The comment that the 1992 AJCC staging system “is totally inadequate” (radiation oncologist) likely reflects the frustration inherent in accomplishing this goal.

T Stage

In assessing primary tumor extent, the relatively low level of consensus (63.9%) in assigning a T stage even among experts in the field is remarkable. Although it is true that these 12 cases were designed to present dilemmas in staging, these cases are not uncommon. It may be reasonable to expect that even with difficult cases the considerable expertise of the individuals to whom the cases were submitted would result in more consistent staging than would be seen in a general population of physicians treating prostate cancer in the community. Explanations of the high level of inconsistency include errors in assigning T stage categories according to the staging manual instructions and considerable bias and disagreement in the application of imaging studies to staging. As written, the 1992 AJCC staging protocol was not sufficiently reproducible between observers. Factors affecting the level of uncertainty are related to physical examination, imaging, and biopsy information.

Physical Examination

Understaging of patients with clinical stage B disease (which corresponds to stage II) is reported in multiple large surgical series. Zincke et al. [8] reported that only 47% of patients had pathologically organ-confined disease in a series of more than 3,100 clinical stage B patients. Likewise, Catalona and Smith [9] reported organ-confined disease in 64% of 925 clinical stage B patients. It is probable that much of this understaging is due to inaccuracies inherent in DRE. In 97 patients staged as clinical stage A or B by DRE only, 48% were found to have extracapsular extension (ECE) and 14% to have seminal vesicle involvement in the pathologic specimen [10]. It is true, however, that DRE would not be expected to detect microscopic extension. Another concern is that objective findings such as obliteration of the lateral sulci have different interpretations between physicians. This lack of agreement is indicated by the difference in assignment of T stage in case #8. We conclude that although physical examination will continue to play a role in staging, it is inadequate by itself.

Imaging Studies

The 1992 staging system does not address which imaging studies can be used. The AJCC states in reference to clinical staging, “clinical examination, acid phosphatase determination, PSA serum level, and imaging techniques (including transrectal ultrasound) are suggested” [3]. The fact that TRUS is the only specific study mentioned is interesting, because many urologists disregard TRUS in assigning clinical stage [11]. It has been reported that imaging may make staging less effective [12]. This hypothesis is consistent with our findings that in general the urologists did not include TRUS findings in reporting T stage for these cases, as compared with the radiation oncologists. The reported range of sensitivity for TRUS in screening studies is 36% to 85% and the specificity is 41% to 79% [13]. As with DRE, information is not currently available regarding the inter- and intraobserver variability of TRUS; however, a multi-institutional study is currently being conducted by the National Cancer Institute. Although neither DRE nor TRUS reliably predict ECE, the combined use of DRE and TRUS may be superior. One study found that if either TRUS or DRE were positive for ECE, the combined results had a sensitivity of 91% and a positive predictive value of 79% [14]. CT scan has not been shown to provide significant and reliable help in staging. Engeler et al. [15] reported only a 24% accuracy for identifying capsular extension and 69% accuracy for determining seminal vesicle invasion by CT. MRI with body coil is not better than TRUS for local staging of prostate cancer [16]; however, endorectal coil may have a role as it is reported to be more sensitive and specific than other imaging modalities in assessing local prostatic disease [17,18]. Fast spin-echo MRI may also be of value [19]. The role of newer imaging techniques has not been defined. The responses in our study indicate disagreement regarding the value and application of imaging in assigning T stage.

Biopsy Data

There is controversy regarding whether or not histologic information may be used as part of clinical staging. The 1992 system states, “Primary tumor assessment includes digital rectal examination of the prostate and histologic or cytologic confirmation of prostatic carcinoma” [3]. Some individuals have taken this statement to mean that all histologic information is to be used in staging, whereas others use only the histologic information that confirms palpable findings. Contralateral biopsies have been found to be positive in 42% of patients with unilaterally palpable disease in one study [20] and to be predictive of pathologic features including extraprostatic disease [21,22]. Additionally, positive seminal vesicle biopsy results have been found to predict seminal vesicle invasion in the pathologic specimen in all cases if normal seminal vesicle epithelium is noted in the biopsy specimen adjacent to tumor [23]. Specific indications have been proposed for the use of seminal vesicle biopsies [24]. Our study indicates that histologic information is not being uniformly applied to staging.

PSA

Several respondents to this series of cases indicated that PSA should be incorporated into staging. One medical oncologist suggested a clinical/serological staging system. It is true that PSA rises with advancing disease for both clinical and pathologic stage [25,26]. However, in both situations there is considerable overlap of serum PSA values comparing stage to stage. Another difficulty arises in using PSA to predict ECE, perhaps the most important factor in determining therapy. Using a cut-off of 10 ng/ml, Oesterling et al. [27] found a false-positive rate of 65%. Preoperative serum PSA has been found unreliable for predicting final pathologic stage, but the predictive power was significantly enhanced by combination with grade and clinical stage [28]. It is likely that the most effective use of pre-treatment serum PSA will be in combination with other prognostic factors [5]. It is also clear that incorporation of prognostic factors, such as PSA, into staging would require a considerable effort to reach a consensus.

N Stage

The most predominant N stage assigned in all cases was Nx regardless of whether or not CT was obtained. The frequency of the designation of Nx for cases in which no CT results were given was not affected by serum PSA. CT staging of pelvic nodes is not reliable compared with surgical staging [29]. Although CT can identify grossly enlarged lymph nodes, it is clear that the respondents in this study did not consider CT sufficient to define lymph node status. If surgical biopsy is necessary, depending on factors such as serum PSA and Gleason score, laparoscopic lymph node dissection has been found to be as accurate as open biopsy and to have lower morbidity [30]. Another possible approach is the combined use of CT and fine needle aspiration [31]. The appropriate indications for lymph node sampling by any approach should be driven by defined prognostic factors such as PSA and Gleason score [24,32].

Nuclear Imaging

Although it is very rare (< 0.5%) for a bone scan to be positive without the presence of symptoms in prostate cancer patients with a PSA concentration less than 10 ng/ml, most of the respondents classified the case stage Mx if no bone scan was obtained regardless of PSA [27,33–35]. Additionally, there was disagreement about the work-up and meaning of a positive bone scan as exhibited by the responses in regard to case #1. In case #8, although several respondents commented that the use of Prostascint scan [36] information may be premature, five individuals staged this patient as having nodal disease presumably on the basis of having a positive Prostascint scan in the pelvis.

CONCLUSION

It is evident that AJCC staging could be made more reproducible and accurate by specifying the inclusion or exclusion of particular imaging and histologic studies from the staging system. Some of these issues are addressed in the newest revision [37]. Many of our experts agree that the incorporation of serologic information would be valuable, although it may be difficult to reach a consensus on specifics. “Prognostic and staging equations incorporating factors such as pretreatment PSA value, grade, race, and well-defined stage parameters such as biopsy positivity number may be a future alternative . . . Early equations are already available [38,39], but consensus equations will require multicenter collaboration” (urologist). One suggested approach is the creation of “a data base of approximately 10,000 patients” (urologist). Presumably information regarding prognostic information to include in staging could be based on analysis of outcome within this data base. Although this task is by no means simple, a population of this magnitude is clearly possible to define in a disease with a high yearly incidence. By this means, understanding of the disease process as well as staging could be advanced well beyond the purely anatomic definitions of the past. The goal is a method of incorporating all relevant and useful findings, both anatomic and biological, into a clinically usable format for prognostic and investigative purposes.

Ancillary