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Keywords:

  • prostate;
  • neoplasms;
  • staging;
  • radical prostatectomy;
  • extraprostatic extension;
  • periprostatic adipose tissue

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Because the prostatic capsule is often indistinct, recognition of extraprostatic extension by carcinoma depends heavily on the identification of carcinoma cells in the periprostatic adipose tissue. However, the distribution of adipose tissue along the prostatic surfaces has not been studied extensively.

METHODS

The authors analyzed the periprostatic adipose tissue in specimens from 100 patients treated with radical retropubic prostatectomy and bilateral pelvic lymphadenectomy for prostatecarcinoma. Each specimen was totally embedded and examined by the whole mount method. The presence or absence of adipose tissue on the anterior, posterior, right, and left surfaces of the prostate was determined and analyzed.

RESULTS

Periprostatic adipose tissue was present on 48% of all prostatic surfaces examined. The distribution of periprostatic adipose tissue varied among the different surfaces of the prostate, with the anterior, posterior, right, and left surfaces showing 44%, 36%, 59%, and 57% adipose tissue, respectively. The amount of periprostatic adipose tissue was similar among specimens from operations performed by different surgeons (P = 0.72). However, nerve-sparing procedures resulted in less adipose tissue (46%) than non-nerve-sparing procedures (54%) (P = 0.01).

CONCLUSIONS

Less than half of the prostatic surfaces examined were covered by adipose tissue. The absence of adipose tissue over large areas of the prostatic surface, especially the posterior surface, makes the evaluation of extraprostatic extension difficult and unreliable. Further refinement of the prostate carcinoma staging system is needed. Cancer 2003;97:1639–43. © 2003 American Cancer Society.

DOI 10.1002/cncr.11231

Pathologic staging is an important predictor for prognosis in patients with prostate carcinoma. In the 2002 TNM staging system,1 prostate carcinoma confined within the prostatic capsule is classified as T2, whereas carcinoma with extraprostatic extension is classified as T3a. Patients with T1 or T2 prostate carcinoma have a significantly better prognosis than those with T3. In 1972, Byar and Mostofi observed 208 patients who had undergone radical prostatectomies for prostate carcinoma, and found that those with carcinoma invading only the prostatic capsule had a significantly longer 7-year survival than those with tumor penetrating through the capsule into the periprostatic tissues.2 These findings were later confirmed by other studies.3–6

Standardization of terminology and definitions permits comparison of treatment results at different institutions. Because a true prostatic capsule does not exist,7 the term “extraprostatic extension” was adopted at the 1996 International Consensus Conference on Prostatic Intraepithelial Neoplasia and Pathologic Staging8–10 to replace other terms, including “capsular invasion,” “capsular penetration,” and “capsular perforation,” thus eliminating the need to recognize the prostatic capsule. Extraprostatic extension is defined strictly by three criteria: tumor in adipose tissue, tumor in perineural spaces of large neurovascular bundles, or tumor in anterior muscle.8–11 Because carcinoma in large neurovascular bundles or in anterior muscle is less common, recognition of extraprostatic extension usually depends on the identification of carcinoma cells in periprostatic adipose tissue. In this study, we determined the distribution of adipose tissue in radical prostatectomy specimens prepared with the whole mount technique and discussed its significance to the recognition of extraprostatic extension.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

One hundred radical prostatectomy specimens were analyzed from prostate carcinoma patients who underwent radical retropubic prostatectomy and bilateral pelvic lymphadenectomy from 1999 to 2000 at Indiana University Hospital. Sixty-seven patients had nerve-sparing prostatectomies, and 33 patients had non-nerve-sparing prostatectomies. The operations were performed by five different surgeons. This study was approved by the Indiana University Institutional Review Board.

Each radical prostatectomy specimen was totally embedded and processed by the whole mount method.8, 12, 13 Each prostate was weighed, measured, inked, and fixed in 10% neutral formalin. After fixation, the apex and bladder base were amputated and serially sectioned in the vertical parasagittal plane. The seminal vesicles were sectioned parallel to the junction with the prostate and submitted entirely for examination. The remaining prostate was serially sectioned perpendicular to the long axis of the gland from the apex to the tips of the seminal vesicles, and whole mount sections were prepared.

Tumor volume, defined as the sum of the volumes of individual tumor foci,13 was determined by the grid method.13, 14 Surgical margins were considered positive when tumor cells were in contact with the inked margin.15 The 2002 TNM system1 was used for pathologic staging. Grading of the primary tumor was performed according to the Gleason system.16

Slides of the prostates were examined with a microscope for the presence or absence of adipose tissue on the prostatic surfaces. The method of mapping periprostatic adipose tissue along the surfaces is illustrated in Figure 1. The circumference of the prostate was divided into anterior, posterior, left, and right quadrants. The distribution of adipose tissue on these surfaces was recorded and analyzed. On each slide, the circumference of the prostate and the length covered by adipose tissue were recorded for each quadrant; these values were summed over all of the slides. The ratio of total length covered by adipose tissue to the sum of prostate circumferences was recorded as the amount of adipose tissue on the prostate surface (%).

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Figure 1. Mapping of periprostatic adipose tissue in whole mount prostate. Arrows indicate holes where tissue was taken for the tissue bank.

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Spearman's coefficient of rank correlation was calculated between all pairs of continuous variables, because this method does not require the assumption of a bivariate normal distribution. Significant correlation exists if P < 0.05. The Shapiro-Wilk test was used to test % adipose tissue for normality. Because normality was not rejected, the Student t test was used to compare the mean % adipose tissue for T2 patients with the % adipose tissue for T3 patients. In addition, the Student t test was used to compare the mean % adipose tissue between patients with positive versus those with negative surgical margins.

Comparison of surgeons for differences in % adipose tissue was made using a one-way analysis of variance (ANOVA). Pairwise differences between the five surgeons (two surgeons performed four prostatectomies combined and were classified as “Others” for the analysis, as shown in Table 4) were also examined. The Sidak multiple comparison adjustment method was used to control the overall confidence level at 95%. The Student t test was used to test for differences in % adipose tissue between nerve-sparing and non-nerve-sparing specimens.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Examination of 100 radical prostatectomy specimens revealed the presence of periprostatic adipose tissue along 48% of the prostatic surfaces, with a wide range of 11% to 85% (Table 1, Fig. 2). The distribution of periprostatic adipose tissue varied among the different surfaces of the prostate, with the lateral surfaces having the highest frequency of associated adipose tissues (57% on the left side, and 59% on the right side). The posterior surface had the lowest frequency of associated adipose tissue (36%). The anterior prostate had adipose tissue over 44% of its surface. Figure 3 shows the lack of periprostatic adipose tissue along inked prostatic surface.

Table 1. Distribution of Periprostatic Adipose Tissue along the Prostatic Surface
Prostatic surfacePeriprostatic adipose tissue (%)a
MeanS.D.
  • S.D.: standard deviation.

  • a

    The amount of periprostatic adipose tissue was determined by detailed mapping of whole mount prostates.

Anterior4419
Posterior3622
Right lateral5921
Left lateral5721
Overall4816
thumbnail image

Figure 2. Distribution of periprostatic tissue.

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thumbnail image

Figure 3. (A, B) Lack of periprostatic adipose tissue on the prostate).

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Twenty-five cases were classified as T3 or higher, all with evidence of extraprostatic extension; 16 of these cases were found to show positive surgical margins. Thirteen cases were found to have positive surgical margins and no evidence of extraprostatic extension (Table 2).

Table 2. Correlation between Extraprostatic Extension and Positive Surgical Margins
EPEPositive surgical marginsNo. of patients (%)
  1. EPE: extraprostatic extension; +: present; −: absent.

++16 (16)
+ 9 (9)
+13 (13)
62 (62)

Five different surgeons performed radical prostatectomies, with 3 surgeons performing 96 prostatectomies combined (96%, Surgeons A–C, Table 3). Statistical analysis of the data revealed no significant difference in the proportion of adipose tissue on the prostatic surface among different surgeons (P = 0.72, Table 3). However, the nerve-sparing procedure appeared to affect the amount of adipose tissue on the surface of the specimens, with nerve-sparing prostatectomy showing 46% adipose tissue, and non-nerve-sparing prostatectomy showing 54% adipose tissue (P = 0.01, Table 4).

Table 3. Effect of Different Surgeons on the Amount of Periprostatic Adipose Tissue
SurgeonsNo. of patientsPeriprostatic adipose tissue (%)a
MeanS.D.
  • S.D.: standard deviation.

  • a

    Sidak multiple comparison showed no statistically significant differences (P > 0.05) between any pair of surgeons.

  • b

    Two surgeons performed four prostatectomies combined.

Surgeon A664917
Surgeon B164515
Surgeon C144813
Othersb45311
Table 4. Effect of Nerve-Sparing Procedure on the Amount of Periprostatic Adipose Tissue
ProstatectomyNo. of patientsPeriprostatic adipose tissue (%)a
MeanS.D.
  • S.D.: standard deviation.

  • a

    Student t test revealed a significant difference between nerve-sparing and non-nerve-sparing specimens (P = 0.01).

Nerve-sparing335415
Non-nerve-sparing674616

No correlation was found between the percentage of adipose tissue and patient age, prostate specific antigen (PSA) level at presentation, prostate weight, Gleason score, largest tumor dimension, or tumor volume (data not shown). In addition, no differences in the percentage of adipose tissue were found between different pathologic stages or positive/negative surgical margins.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this study, 100 prostatectomy specimens were analyzed, and it was determined that adipose tissue covered only 48% of the prostatic surfaces. The different surfaces of the resected prostate were covered with varying amounts of adipose tissue, with the posterior surface having the least adipose tissue (36%). The amount of periprostatic adipose tissue on the resected prostate was not affected by individual surgeons. However, nerve-sparing procedures resulted in less periprostatic adipose tissue than non-nerve-sparing procedures.

The prostate does not have a well defined capsule. Ayala et al. found that the prostatic capsule is composed of fascicles of fibromuscular tissue that are an inseparable component of the prostatic stroma.7 The outer surface of this fibromuscular tissue merges with the periprostatic connective tissue and blends with periprostatic adipose tissue in some areas. In addition, these fibromuscular tissues are absent in the apex of the prostate. As a result, the authors concluded that a clearly defined prostatic capsule does not exist.7 In the absence of a common standard, different terms, such as “capsular invasion,” “capsular penetration,” and “capsular perforation” were used in the literature, causing confusion. The term “extraprostatic extension” was introduced recently to replace confusing terms.8, 9 Recognition of extraprostatic extension relies heavily on the identification of carcinoma in periprostatic adipose tissue. However, the distribution of adipose tissue along the prostatic surfaces has not been well characterized.

The finding that large areas of the prostatic surface are not covered by adipose tissue makes it necessary to reevaluate the criteria for extraprostatic extension, the breakpoint between Stage II and Stage III carcinoma in the current TNM system.1 Although the absence of adipose tissue on the surfaces of prostatectomy specimens may be caused partially by the operative procedure or tissue processing, much of the prostatic surface is free of adipose tissue. It is difficult to diagnose extraprostatic extension on these adipose-free prostatic surfaces, and some patients may present with positive surgical margins without evidence of extraprostatic extension. Therefore, it may be appropriate to incorporate surgical margin status into the TNM staging systems.9, 10, 12, 17–19 The 2002 TNM staging system recommends that positive surgical margins should be indicated by an R1 descriptor (residual microscopic disease) for pT3 classification.1 The confusion remains in the group of patients who had positive margins without extraprostatic extension. In this study, we observed 13 patients who had positive margins, but whose lack of adipose tissue precluded evaluation of extraprostatic extension (Table 2). Should we subclassify these patients into different prognostic groups? In our previous study,12 excluding patients with seminal vesicle invasion or higher stage tumors, we found that patients with positive margins and positive extraprostatic extension had the highest rate of disease progression, followed by patients with positive extraprostatic extension and negative margins, and then patients with negative extraprostatic extension and positive margins. Patients with negative margins and negative extraprostatic extension had the lowest disease progression rate.12

This study was not designed to study the anatomic structure of the prostate and its surroundings. The presence of adipose tissue was observed in surgical prostate specimens submitted for routine evaluation by pathologists. The techniques of different surgeons were thought to have a potential effect on the amount of adipose tissue on radical prostatectomy specimens. However, our results revealed that the amount of adipose tissue is similar among different surgeons (Table 3). Different operative procedures (nerve-sparing vs. non-nerve-sparing) did result in significant differences in the presence of adipose tissue, with the non-nerve-sparing procedure leaving more periprostatic adipose tissue on the specimens (Table 4). Preoperative clinical information, such as serum PSA, may affect a surgeon's decision in choosing operative procedures, but our results did not reveal any correlation between the amount of adipose tissue and those clinical data.

In summary, large areas of the surfaces of surgically excised prostate glands are not covered by adipose tissue, making the evaluation of extraprostatic extension difficult and unreliable. Further refinement of TNM staging system, such as incorporating surgical margin status,9, 10, 12, 17–19 may be useful.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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