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Lymphovascular Invasion is a Pathological Feature of Biologically Aggressive Disease in Patients Treated With Radical Prostatectomy
0022-5347/04/1713-1122/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 171, 1122–1127, March 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000113249.82533.28
LYMPHOVASCULAR INVASION IS A PATHOLOGICAL FEATURE OF BIOLOGICALLY AGGRESSIVE DISEASE IN PATIENTS TREATED WITH RADICAL PROSTATECTOMY SHAHROKH F. SHARIAT,* SEYED M. KHODDAMI,* HOSSEIN SABOORIAN, KENNETH S. KOENEMAN, ARTHUR I. SAGALOWSKY,† JEFFREY A. CADEDDU, JOHN D. MCCONNELL, MARISA N. HOLMES AND CLAUS G. ROEHRBORN‡ From the Departments of Urology (SFS, SMK, KSK, AIS, JAC, JDM, MNH, CGR) and Pathology (HS), University of Texas Southwestern Medical Center, Dallas, Texas
ABSTRACT
We examined whether invasion of lymphatic and/or vascular vessels (LVI), or perineural spaces (PNI) is associated with prostate cancer features and outcome. Materials and Methods: A total of 630 consecutive men underwent radical retropubic prostatectomy for clinically localized disease. LVI and PNI examination was part of the routine specimen evaluation. Results: Foci of LVI were identified in 32 patients (5%) and 381 (60.5%) had PNI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p ⬍0.001). LVI was associated with metastases to regional lymph nodes and higher preoperative serum prostate specific antigen (p ⬍0.001 and 0.004, respectively). PNI and LVI were associated with an increased risk of rapid biochemical progression after radical prostatectomy on univariate (p ⬍0.001 and 0.001, respectively) but not on multivariate analysis. LVI was associated with shorter prostate specific antigen doubling time after biochemical progression (p ⫽ 0.012) and higher probabilities of failed local salvage radiation therapy (p ⫽ 0.0169), distant metastases (p ⬍0.001) and death (p ⬍0.001). Conclusions: Only LVI is associated with metastases to regional and distant sites, and most importantly with overall survival. LVI and PNI are associated with established markers of biologically aggressive disease and rapid biochemical progression in patients who underwent radical prostatectomy. Our findings support the routine evaluation of LVI status in radical prostatectomy specimens and its inclusion in predictive models for clinical outcomes, since it appears to be a pathological marker of the lethal phenotype of prostate cancer. KEY WORDS: prostate, prostatic neoplasms, lymph nodes, prostatectomy, disease progression
In 1994 the College of American Pathologists recommended reporting lymphovascular invasion (LVI) and perineural invasion (PNI) in radical prostatectomy (RP) specimens using routine light microscopic examination.1 However, few studies to date have evaluated the rate and prognostic significance of LVI. The reported frequency of LVI ranges widely from 14% to 53%.2–7 While some studies showed that LVI is a predictor of poor clinical outcome after adjusting for the effects of pathological features,2–5 others did not.6 Compared to LVI PNI has received growing attention. PNI on prostate biopsy is associated with an increased likelihood of extraprostatic extension, higher Gleason sum, seminal vesicle invasion, lymph node involvement and/or biochemical progression in patients treated with RP.8 –10 However, most groups found that prostate biopsy PNI had no predictive value after consideration of standard preoperative fea-
tures.10, 11 Only 2 studies investigated the prognostic significance of PNI in RP specimens. Ozcan found that PNI in the RP specimen was independently associated with biochemical progression in 191 consecutive patients who underwent RP in an 8-year period.12 Endrizzi and Seay reported that PNI was the most sensitive predictor of early biochemical progression in 131 patients with pathologically organ confined disease, although no formal pathological or statistical analysis was performed in that study.13 We hypothesized that a proportion of men with clinically localized prostate cancer (PCa) harboring occult metastases would also have LVI and/or PNI associated with clinical disease progression despite effective local disease control. Therefore, in a large cohort of consecutive patients with clinically localized PCa we investigated the association of LVI and PNI in RP specimens with PCa features and clinical outcomes.
Accepted for publication October 10, 2003. MATERIAL AND METHODS Study received institutional review board approval. Supported by the Austrian Program for Advanced Research and Patient population. All 630 patients admitted to 2 teaching Technology. hospitals who underwent radical retropubic prostatectomy * Equal study contribution. † Financial interest and/or other relationship with Searle, with bilateral lymphadenectomy for clinically localized PCa Matritech and Schering. by surgeons at the department of urology at our institution ‡ Correspondence: Department of Urology, University of Texas from July 1994 through December 2002 were potential canSouthwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9110 (telephone: 214-648-2941; FAX: 214-648-3453; didates for this analysis. No disease followup information was available on 4 men, who were excluded from time depene-mail: [email protected]). 1122
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dent analyses. The mean number of lymph nodes per patient ⫾SE removed at RP was 7.7 ⫾ 5.2 (median 8). The operative surgeon assigned clinical stage according to the 1992 American Joint Committee on Cancer/TNM system. Mean patient age in this study was 60.4 ⫾ 6.7 years (median 60.9, range 40 to 75). Serum total prostate specific antigen (PSA) was measured by the Tandem-E assay (Hybritech, Inc., San Diego, California). The percent positive biopsy was defined using the formula, (number of positive biopsy cores/total number of biopsy cores) ⫻100. Pathological examination. Staff pathologists from our institution who were blinded to clinical outcome examined all prostatectomy specimens pathologically. Whole RP specimens were submitted. RP specimen evaluation was performed in accordance with the guidelines of the College of American Pathologists.1 External aspects (surgical margins) were inked. Apical and bladder neck margins were removed, sectioned perpendicular to the ink and embedded on end in conventional and/or whole mount blocks with positive margins defined as tumor extending to ink on histological sections. In addition to apical and bladder neck margins, the positive anterior, lateral, posterior and posterolateral surgical margins were defined as tumor in direct contact with the indicated inked surface of the prostate in sections, according to standard protocols. Tumor extending to the anterior inked surface was considered a positive anterior margin and not extracapsular extension with the latter reserved for tumor extending through prostatic capsule and into adipose tissue anterior to the prostate. Longitudinal seminal vesicle sections from the junction with the prostate base were also submitted in routine cassettes with additional sections included in subsequent blocks. Pelvic lymph node dissections were examined grossly and all lymphoid tissue was submitted for histological examination. Multiple, well oriented quadrant sections from the whole or almost whole prostate were processed (approximately 25 to 30 blocks). The 1997 American Joint Committee on Cancer/TNM system was used for pathological staging. Primary tumor grading was performed according to the Gleason system. To ensure outcome validity 2 clinicians read pathology reports while blinded to patient clinical parameters and the finding of the other reviewer. Interreader reliability measured using the intraclass correlation coefficient was greater than 0.95 for all pathological parameters. PNI was defined as PCa tracking along or around a nerve within the perineural space. LVI was defined as the unequivocal presence of tumor cells within an endothelium lined space without underlying muscular walls. Equivocal cases and tumor cells that merely encroached on a vascular lumen were considered negative and a perivascular reaction was not required.2, 3 No attempt was made to differentiate between vascular and lymphatic vessels because of the difficulty and
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lack of reproducibility when using routine light microscopic examination. Postoperative followup. Patients generally were scheduled to undergo digital rectal examination and serum PSA evaluation postoperatively every 3 months for year 1, semiannually from years 2 through 5 and annually thereafter. Biochemical progression was defined as a sustained elevation on 2 or more occasions of serum total PSA of greater than 0.2 ng/ml and it was assigned to the date of the first value greater than 0.2 ng/ml. Patients who received adjuvant radiation therapy before biochemical progression because of clinical or pathological characteristics were considered to have disease progression from the date of the first value greater than 0.2 ng/ml. In patients who had biochemical progression postprogression serum PSA doubling time was calculated using the formula, PSA doubling time ⫽ ln(2)⫻T/[log(final PSA)⫺log(initial PSA)].14 All patients had at least 3 PSA measurements available after progression. Statistical analysis. The Fisher exact and chi-square tests were used to evaluate associations between categorical variables. Differences in variables with a continuous distribution between dichotomous categories were assessed using the Mann Whitney U test. The Kaplan-Meier method was used to calculate survival functions and differences were assessed with the log rank statistic. Multivariate survival analysis was performed with the Cox proportional hazard regression model. Preoperative PSA had a skewed distribution and, therefore, was it modeled with a log transformation. Statistical significance in this study was set as p ⱕ0.05. All reported p values are 2-sided. All analyses were performed with SPSS, version 10.0 for Windows (SPSS, Chicago, Illinois). RESULTS
Association of LVI and PNI with clinical and pathological characteristics. Figure 1 shows representative images of tumor invasion in lymphatic vessels, blood vessels and perineural spaces. Table 1 lists clinical and pathological characteristics of the 630 patients treated with prostatectomy, and associations with LVI and PNI. Mean preoperative serum total PSA was 8.1 ⫾ 8.0 ng/ml (median 6.1, IQR 4.5 to 8.7, range 0.1 to 99.0). Of the 630 patients 32 (5.1%) had LVI and 381 (60.5%) had PNI. LVI foci were usually located at or near the cancer. Tumor emboli were occasionally identified. Most patients had 1 or 2 foci of LVI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p ⬍0.001). LVI was further associated with metastases to regional lymph nodes (p ⬍0.001) and
FIG. 1. LVI (A) and PNI (B) in PCa specimens. Reduced from ⫻400
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LYMPHOVASCULAR INVASION AND AGGRESSIVE PROSTATE CANCER
TABLE 1. Association of LVI and PNI with clinical and pathological features of 630 consecutive patients who underwent radical RP for clinically localized disease No. Pts (%) No. clinical stage (%):* T1 425 (68) T2 204 (32) No. Biopsy Gleason sum (%):† 2–6 412 (66) 7 176 (28) 8–10 39 (6) No. extraprostatic extension only (%): Neg 448 (71) Pos 182 (29) No. seminal vesicle involvement (%):* Neg 572 (91) Pos 57 (9) No. surgical margin status (%): Neg 451 (72) Pos 179 (28) No. final Gleason sum (%): 2–6 256 (41) 7 309 (49) 8–10 65 (10) No. regional lymph node metastases (%): Neg 620 (98) Pos 10 (2) Median age at RP (range) 630 (100) Median % pos biopsy cores 605 (95.1) (range) Median ng/ml preop serum 628 (99.4) PSA (range) * Not available for 1 patient. † Not available for 3 patients.
LVI Neg
PNI Pos
p Value
Neg
Pos
p Value
⬍0.001
191 (44.9) 57 (27.9)
234 (55.1) 147 (72.1)
⬍0.001 (Fisher’s exact test)
223 (54.1) 121 (68.8) 35 (89.7)
⬍0.001 (Fisher’s exact test)
413 (97.2) 184 (90.2)
12 (2.8) 20 (9.8)
407 (98.8) 160 (90.9) 28 (71.8)
5 (1.2) 16 (9.1) 11 (28.2)
⬍0.001
189 (45.9) 55 (31.3) 4 (10.3)
442 (98.7) 156 (85.7)
6 (1.3) 26 (14.3)
⬍0.001
222 (49.6) 27 (14.8)
226 (50.4) 155 (85.2)
⬍0.001 (Fisher’s exact test)
562 (98.3) 35 (61.4)
10 (1.7) 22 (38.6)
⬍0.001
241 (42.1) 8 (14)
331 (57.9) 49 (86)
⬍0.001 (Fisher’s exact test)
439 (97.3) 159 (88.8)
12 (2.7) 20 (11.2)
⬍0.001
200 (44.3) 49 (27.4)
251 (55.7) 130 (72.6)
⬍0.001 (Fisher’s exact test)
255 (99.6) 294 (95.1) 49 (75.4)
1 (0.4) 15 (4.9) 16 (24.6)
⬍0.001
150 (58.6) 85 (27.5) 14 (21.5)
106 (41.4) 224 (72.5) 51 (78.5)
⬍0.001 (Fisher’s exact test)
248 (40) 1 (10) 60.9 (40.4–74.3) 16.7 (3.0–83.3)
372 (60) 9 (90) 60.9 (40.0–75.2) 33.3 (2.8–100)
0.098 (Mann-Whitney U test) 0.822 (Mann-Whitney U test) ⬍0.001 (Mann-Whitney U test)
6.1 (0.1–52)
6.10 (1.0–99.0)
0.750 (Mann-Whitney U test)
596 (96.1) 2 (20) 61.0 (40.0–75.2) 23.1 (3.0–100)
24 (3.9) 8 (80) 59.6 (43.3–72.2) 50.0 (15.4–100)
⬍0.001 0.100 ⬍0.001
6.0 (0.1–52.0)
7.8 (4.0–99.0)
0.004
higher preoperative serum PSA (p ⫽ 0.004). The statistical significance of all except 1 association remained unchanged when evaluated in patients with negative lymph nodes. In patients with negative lymph nodes LVI was not associated with preoperative PSA (p ⫽ 0.065). Association of LVI and PNI with biochemical progression after RP. Overall only 80 of 626 patients (13%) had cancer progression at a median postoperative followup of 21.4 months (range 1.0 to 101.3). Mean overall PSA progressionfree survival was 81.9% ⫾ 2.5% at 3 years and 77.6% ⫾ 1.3% at 5 years. Using the log rank test we found that patients with vs without LVI had an increased probability of PSA progression (p ⬍0.001, fig. 2, A). Likewise, patients with PNI vs without were at increased risk for biochemical progression (p ⫽ 0.0012, fig. 2, B). On univariate Cox proportional hazards regression analyses all standard postoperative pathological characteristics and preoperative PSA were significantly associated with an increased risk of rapid biochemical progression after surgery (table 2). On postoperative multivariate analysis only preoperative PSA, seminal vesicle involvement, lymph node metastases and final Gleason sum were associated with biochemical progression (p ⬍0.001, 0.043 and 0.015, and p for trend ⫽ 0.008, respectively, table 2). The statistical significance of these associations remained unchanged when evaluated in patients with negative lymph nodes. In 4 patients on whom pathologically organ confined disease and followup data were available PNI (HR 2.730, 95% CI 1.114 to 6.690, p ⫽ 0.028) and preoperative PSA (HR 4.747, 95% CI 2.430 to 9.270, p ⬍0.001) were associated with biochemical progression when adjusted for the effects of LVI (p ⫽ 0.985), surgical margin status (p ⫽ 0.285) and final Gleason sum (p for trend ⫽ 0.644). In 192 patients who had pathologically nonorgan confined disease metastases to regional lymph nodes (HR 2.798, 95%
CI 1.211 to 6.465, p ⫽ 0.016), surgical margin status (HR 2.178, 95% CI 1.109 to 4.281, p ⫽ 0.24), preoperative PSA (HR 1.768, 95% CI 1.190 to 2.627, p ⫽ 0.005) and final Gleason sum (overall p ⬍0.001, 2 to 6 vs 7 HR 0.841, 95% CI 0.289 to 2.448, p ⫽ 0.750 and 2 to 6 vs 8 to 10 HR 3.336, 95% CI 1.146 to 9.710, p ⫽ 0.027) were associated with biochemical progression when adjusted for the effects of LVI (p ⫽ 0.905), PNI (p ⫽ 0.547), extracapsular extension (p ⫽ 0.934) and seminal vesicle involvement (p ⫽ 0.176). Association of LVI and PNI with PSA doubling time and response to salvage radiation therapy. Seven patients did not undergo additional treatment after disease progression at last followup, 21 underwent local salvage radiation therapy at our institution and 43 underwent hormonal therapy as primary treatment for PCa progression. PSA doubling time calculation was performed in 68 patients who had PSA progression prior to the administration of salvage therapy. PSA doubling time between RP failure and the initiation of salvage therapy was shorter in patients with vs without LVI (median 3.3 months, range 0.4 to 7.1 vs 6.9, range 0.9 to 26.0, p ⫽ 0.012). However, PSA doubling time was not different between patients with vs without PNI (median 4.2 months, range 0.9 to 26.0 vs 6.4, range 0.4 to 16.9, p ⫽ 0.132). The median time from the start of salvage local radiation therapy to last followup in patients who had a favorable response was 43.7 months (range 4.4 to 71.1). Overall PSA progression-free survival after salvage local radiation therapy was 45% ⫾ 11% at 2 years and 20% ⫾ 10% at 4. Patients with vs without LVI were at higher likelihood for rapid biochemical progression after salvage radiation therapy (100% vs 43.5% at 3 years, p ⫽ 0.0169). However, at 3 years the risk of progression was not different between patients with vs without PNI (66% vs 50%, p ⫽ 0.8583). Association of LVI and PNI with clinically evident distant PCa metastases and patient survival. Staging evaluation,
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LYMPHOVASCULAR INVASION AND AGGRESSIVE PROSTATE CANCER
FIG. 2. Probabilities of PSA progression-free survival in 626 patients who underwent RP for clinically localized disease according to LVI (A) and PNI (B).
TABLE 2. Univariate and multivariate Cox regression analyses of postoperative features for biochemical progression prediction in 630 patients who underwent radical RP for clinically localized PCa Univariate
Preop serum PSA* LVI PNI Extracapsular extension Seminal vesicle involvement† Surgical margin status Lymph node metastasis Final Gleason sum: 2–6 7 8–10 * Logarithmically transformed. † Not available for 1 patient.
Multivariate
HR
95% CI
p Value
3.830 6.380 2.292 4.715 6.859 3.322 19.441
2.804–5.230 3.629–11.215 1.368–3.841 2.971–7.483 4.320–10.890 2.130–5.180 9.516–39.721
⬍0.001 ⬍0.001 0.002 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
2.248 1.671 0.900 1.721 1.939 1.566 2.862
1.611–3.136 0.935–2.986 0.379–2.172 0.951–3.112 1.022–3.676 0.932–2.630 1.225–6.689
⬍0.001 0.083 0.815 0.073 0.043 0.090 0.015
1.000 2.201 11.484
Referent 1.165–4.161 6.004–21.967
⬍0.001 0.015 ⬍0.001
1.000 1.082 2.546
Referent 0.533–2.195 1.124–5.766
0.008 0.828 0.025
including bone scan or ProstaScint (Cytogen Corp., Princeton, New Jersey) scan, was performed at our institution in 56 patients who had biochemical progression after RP. Of the patients 14 had bone metastases on imaging. Median followup in patients who had PSA progression after surgery
HR
95% CI
p Value
but no metastases was 43.0 months (range 4 to 100). Patients with vs without LVI were at significantly increased risk for early PCa metastases (p ⬍0.001). The 5 and 7-year actuarial risks of metastasis were 63.0% ⫾ 14.4% and 47.3% ⫾ 17.4% for patients with LVI, and 96.7% ⫾ 1.4% and 93.8% ⫾ 3.2%
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LYMPHOVASCULAR INVASION AND AGGRESSIVE PROSTATE CANCER
for patients without LVI. However, there was no difference in the risk of metastases between patients with and without PNI when analyzed in all patients (p ⫽ 0.2950) or in those with organ confined disease (p ⫽ 0.3282). The statistical significance of these associations remained unchanged when evaluated in patients with negative lymph nodes. Overall survival data were available on 629 of the 630 patients. Seven of the 629 patients (1%) were dead of any cause at analysis. Median followup in patients who experienced PSA progression after surgery and were alive at last followup was 43.9 months (range 4 to 100). Patients with LVI had a significantly decreased probability of survival (p ⬍0.001). Five and 7-year actuarial survival was 81.7% ⫾ 12.3% and 70.0% ⫾ 15.1% for patients with LVI, and 99.0% ⫾ 0.6% and 98.1% ⫾ 1.1% for patients without LVI. However, there was no difference in the probability of overall survival between patients with vs without PNI when analyzed in all patients (p ⫽ 0.4905) or in those with organ confined disease (p ⫽ 0.5479).
DISCUSSION
We found that only 5% of patients who underwent radial prostatectomy for clinically localized disease had tumor invasion of lymphatic and/or vascular vessels. Previous studies have shown higher rates of lymphatic and/or vascular tumor invasion in prostatectomy specimens (ie 12% to 53%).2–7 The discrepancy among studies may be due to various factors, such as specimen handling, the definition of lymphatic and/or vascular invasion, interobserver interpretation variations or differences in the distribution of pathological stages between our and other studies.2–7 We confirmed the association of LVI with features of biologically aggressive PCa.2–7 The strong association between LVI and metastases to regional lymph nodes in the current study supports the hypothesis that LVI precedes or occurs coincidently with lymph node metastasis. However, LVI was associated with biochemical progression after RP on univariate but not on multivariate analysis that adjusted for the effects of standard pathological features. This association remained when evaluated in patients with negative lymph nodes. While our study failed to demonstrate an independent association between LVI and biochemical progression after RP, only 13% of our patient cohort had disease progression at a median followup of 21 months. This progression rate, which is lower than other reported progression rates after RP, may increase with longer followup.15, 16 Four previous studies have shown an independent association between LVI and biochemical progression after surgery.2–5 However, 3 studies did not adjust for the effects of metastases to regional lymph nodes.2, 3, 5 In addition, patients in previous studies had more advanced disease and higher rates of LVI foci,2–7 which are 2 features associated with PSA progression.3 Finally, biochemical progression may result from local failure related to residual disease present after RP, to occult metastatic nodal or distant metastatic disease present at surgery, or to some combination. These forms of recurrent disease have variable progression rates with regard to metastases and eventual death. The lack of an independent association of LVI with biochemical progression after surgery may be due to a lack of association with local and/or biologically more indolent disease. Therefore, the ability to predict the progression of clinical disease and the development of metastases has a greater impact on managing PCa cases than an association with pathological characteristics or the anticipation of simply biochemical progression. We found that LVI was significantly associated with shorter PSA doubling times after biochemical failure, rapid failure to respond to salvage local radiation therapy and most remarkably an increased likelihood of early distant metasta-
ses and death. These associations remained when evaluated in patients with negative lymph nodes. We confirmed that PNI is a frequent feature in RP specimens.12, 13 In addition, we found that PNI was associated with established markers of poor clinical outcome. We identified areas of PNI arising in the peripheral zone in 50% of patients with organ confined PCa and 85% with nonorgan confined disease. PNI represents cancer spread along tissue planes of least resistance next to nerves.17 It was demonstrated that a major mechanism by which prostate adenocarcinoma extends from the prostatic parenchyma to periprostatic soft tissue is via PNI.18, 19 We found that PNI was associated with biochemical progression after RP on univariate analysis when analyzed in all patients and on multivariate analysis when analyzed in those with organ confined disease. However, PNI was not associated with more profound end points, such as the response to salvage radiation therapy, clinically evident distant metastases or survival. Several limitations in this study should be considered. Some variables that were inconclusive due to limited statistical power may attain statistical significance if sample size or followup were increased. In addition, the population in this study underwent RP as performed by multiple surgeons and specimens were evaluated by multiple pathologists. Most studies of LVI or PNI used cohorts assembled from populations at large academic hospitals serving as tertiary referral centers and patients were treated by a single surgeon. While prognostic factors may perform well in the select group of patients treated at these centers, it remains to be determined whether they are applicable to the greater population of patients with PCa. Similarly while it may be preferable for a single pathologist specialized in genitourinary pathology to review each prostatectomy specimen, the setup at our institution reflects real-world practice, in which local pathologists review tissue specimens and their interpretations are then used in clinical decision making with the patient. CONCLUSIONS
Our study demonstrates a statistically and clinically significant association of LVI in prostatectomy specimens with established features of biologically aggressive PCa, biochemical progression after local therapy, regional and distant PCa metastases, and decreased overall survival. The associations of LVI with early biochemical and clinical disease progression suggest that LVI is a feature of the metastatic process, putting patients at the highest risk for early metastasis and death. Therefore, we believe that prostatectomy specimens should be routinely examined for LVI using hematoxilin and eosin staining, and routine light microscopy. After confirming these results in larger studies with longer followup LVI could be added to standard predictive models to improve the level of prognostic accuracy and establish recommendations for adjuvant and salvage therapies. In contrast, PNI in the prostatectomy specimen did not improve the ability to predict clinical disease progression in patients with clinically localized PCa and, hence, it has limited clinical usefulness. REFERENCES
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LYMPHOVASCULAR INVASION AND AGGRESSIVE PROSTATE CANCER carcinoma. Am J Surg Pathol, 20: 1351, 1996 4. van den Ouden, D., Kranse, R., Hop, W. C., van der Kwast, T. H. and Schroder, F. H.: Microvascular invasion in prostate cancer: prognostic significance in patients treated by radical prostatectomy for clinically localized carcinoma. Urol Int, 60: 17, 1998 5. de la Taille, A., Rubin, M. A., Buttyan, R., Olsson, C. A., Bagiella, E., Burchardt, M. et al: Is microvascular invasion on radical prostatectomy specimens a useful predictor of PSA recurrence for prostate cancer patients? Eur Urol, 38: 79, 2000 6. Bahnson, R. R., Dresner, S. M., Gooding, W. and Becich, M. J.: Incidence and prognostic significance of lymphatic and vascular invasion in radical prostatectomy specimens. Prostate, 15: 149, 1989 7. Salomao, D. R., Graham, S. D. and Bostwick, D. G.: Microvascular invasion in prostate cancer correlates with pathologic stage. Arch Pathol Lab Med, 119: 1050, 1995 8. Bastacky, S. I., Walsh, P. C. and Epstein, J. I.: Relationship between perineural tumor invasion on needle biopsy and radical prostatectomy capsular penetration in clinical stage B adenocarcinoma of the prostate. Am J Surg Pathol, 17: 336, 1993 9. de la Taille, A., Rubin, M. A., Bagiella, E., Olsson, C. A., Buttyan, R., Burchardt, T. et al: Can perineural invasion on prostate needle biopsy predict prostate specific antigen recurrence after radical prostatectomy? J Urol, 162: 103, 1999 10. Egan, A. J. and Bostwick, D. G.: Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: perineural invasion lacks significance on multivariate analysis. Am J Surg Pathol, 21: 1496, 1997 11. O’Malley, K. J., Pound, C. R., Walsh, P. C., Epstein, J. I. and
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Vol. 171, 1122–1127, March 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000113249.82533.28
LYMPHOVASCULAR INVASION IS A PATHOLOGICAL FEATURE OF BIOLOGICALLY AGGRESSIVE DISEASE IN PATIENTS TREATED WITH RADICAL PROSTATECTOMY SHAHROKH F. SHARIAT,* SEYED M. KHODDAMI,* HOSSEIN SABOORIAN, KENNETH S. KOENEMAN, ARTHUR I. SAGALOWSKY,† JEFFREY A. CADEDDU, JOHN D. MCCONNELL, MARISA N. HOLMES AND CLAUS G. ROEHRBORN‡ From the Departments of Urology (SFS, SMK, KSK, AIS, JAC, JDM, MNH, CGR) and Pathology (HS), University of Texas Southwestern Medical Center, Dallas, Texas
ABSTRACT
We examined whether invasion of lymphatic and/or vascular vessels (LVI), or perineural spaces (PNI) is associated with prostate cancer features and outcome. Materials and Methods: A total of 630 consecutive men underwent radical retropubic prostatectomy for clinically localized disease. LVI and PNI examination was part of the routine specimen evaluation. Results: Foci of LVI were identified in 32 patients (5%) and 381 (60.5%) had PNI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p ⬍0.001). LVI was associated with metastases to regional lymph nodes and higher preoperative serum prostate specific antigen (p ⬍0.001 and 0.004, respectively). PNI and LVI were associated with an increased risk of rapid biochemical progression after radical prostatectomy on univariate (p ⬍0.001 and 0.001, respectively) but not on multivariate analysis. LVI was associated with shorter prostate specific antigen doubling time after biochemical progression (p ⫽ 0.012) and higher probabilities of failed local salvage radiation therapy (p ⫽ 0.0169), distant metastases (p ⬍0.001) and death (p ⬍0.001). Conclusions: Only LVI is associated with metastases to regional and distant sites, and most importantly with overall survival. LVI and PNI are associated with established markers of biologically aggressive disease and rapid biochemical progression in patients who underwent radical prostatectomy. Our findings support the routine evaluation of LVI status in radical prostatectomy specimens and its inclusion in predictive models for clinical outcomes, since it appears to be a pathological marker of the lethal phenotype of prostate cancer. KEY WORDS: prostate, prostatic neoplasms, lymph nodes, prostatectomy, disease progression
In 1994 the College of American Pathologists recommended reporting lymphovascular invasion (LVI) and perineural invasion (PNI) in radical prostatectomy (RP) specimens using routine light microscopic examination.1 However, few studies to date have evaluated the rate and prognostic significance of LVI. The reported frequency of LVI ranges widely from 14% to 53%.2–7 While some studies showed that LVI is a predictor of poor clinical outcome after adjusting for the effects of pathological features,2–5 others did not.6 Compared to LVI PNI has received growing attention. PNI on prostate biopsy is associated with an increased likelihood of extraprostatic extension, higher Gleason sum, seminal vesicle invasion, lymph node involvement and/or biochemical progression in patients treated with RP.8 –10 However, most groups found that prostate biopsy PNI had no predictive value after consideration of standard preoperative fea-
tures.10, 11 Only 2 studies investigated the prognostic significance of PNI in RP specimens. Ozcan found that PNI in the RP specimen was independently associated with biochemical progression in 191 consecutive patients who underwent RP in an 8-year period.12 Endrizzi and Seay reported that PNI was the most sensitive predictor of early biochemical progression in 131 patients with pathologically organ confined disease, although no formal pathological or statistical analysis was performed in that study.13 We hypothesized that a proportion of men with clinically localized prostate cancer (PCa) harboring occult metastases would also have LVI and/or PNI associated with clinical disease progression despite effective local disease control. Therefore, in a large cohort of consecutive patients with clinically localized PCa we investigated the association of LVI and PNI in RP specimens with PCa features and clinical outcomes.
Accepted for publication October 10, 2003. MATERIAL AND METHODS Study received institutional review board approval. Supported by the Austrian Program for Advanced Research and Patient population. All 630 patients admitted to 2 teaching Technology. hospitals who underwent radical retropubic prostatectomy * Equal study contribution. † Financial interest and/or other relationship with Searle, with bilateral lymphadenectomy for clinically localized PCa Matritech and Schering. by surgeons at the department of urology at our institution ‡ Correspondence: Department of Urology, University of Texas from July 1994 through December 2002 were potential canSouthwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9110 (telephone: 214-648-2941; FAX: 214-648-3453; didates for this analysis. No disease followup information was available on 4 men, who were excluded from time depene-mail: [email protected]). 1122
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dent analyses. The mean number of lymph nodes per patient ⫾SE removed at RP was 7.7 ⫾ 5.2 (median 8). The operative surgeon assigned clinical stage according to the 1992 American Joint Committee on Cancer/TNM system. Mean patient age in this study was 60.4 ⫾ 6.7 years (median 60.9, range 40 to 75). Serum total prostate specific antigen (PSA) was measured by the Tandem-E assay (Hybritech, Inc., San Diego, California). The percent positive biopsy was defined using the formula, (number of positive biopsy cores/total number of biopsy cores) ⫻100. Pathological examination. Staff pathologists from our institution who were blinded to clinical outcome examined all prostatectomy specimens pathologically. Whole RP specimens were submitted. RP specimen evaluation was performed in accordance with the guidelines of the College of American Pathologists.1 External aspects (surgical margins) were inked. Apical and bladder neck margins were removed, sectioned perpendicular to the ink and embedded on end in conventional and/or whole mount blocks with positive margins defined as tumor extending to ink on histological sections. In addition to apical and bladder neck margins, the positive anterior, lateral, posterior and posterolateral surgical margins were defined as tumor in direct contact with the indicated inked surface of the prostate in sections, according to standard protocols. Tumor extending to the anterior inked surface was considered a positive anterior margin and not extracapsular extension with the latter reserved for tumor extending through prostatic capsule and into adipose tissue anterior to the prostate. Longitudinal seminal vesicle sections from the junction with the prostate base were also submitted in routine cassettes with additional sections included in subsequent blocks. Pelvic lymph node dissections were examined grossly and all lymphoid tissue was submitted for histological examination. Multiple, well oriented quadrant sections from the whole or almost whole prostate were processed (approximately 25 to 30 blocks). The 1997 American Joint Committee on Cancer/TNM system was used for pathological staging. Primary tumor grading was performed according to the Gleason system. To ensure outcome validity 2 clinicians read pathology reports while blinded to patient clinical parameters and the finding of the other reviewer. Interreader reliability measured using the intraclass correlation coefficient was greater than 0.95 for all pathological parameters. PNI was defined as PCa tracking along or around a nerve within the perineural space. LVI was defined as the unequivocal presence of tumor cells within an endothelium lined space without underlying muscular walls. Equivocal cases and tumor cells that merely encroached on a vascular lumen were considered negative and a perivascular reaction was not required.2, 3 No attempt was made to differentiate between vascular and lymphatic vessels because of the difficulty and
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lack of reproducibility when using routine light microscopic examination. Postoperative followup. Patients generally were scheduled to undergo digital rectal examination and serum PSA evaluation postoperatively every 3 months for year 1, semiannually from years 2 through 5 and annually thereafter. Biochemical progression was defined as a sustained elevation on 2 or more occasions of serum total PSA of greater than 0.2 ng/ml and it was assigned to the date of the first value greater than 0.2 ng/ml. Patients who received adjuvant radiation therapy before biochemical progression because of clinical or pathological characteristics were considered to have disease progression from the date of the first value greater than 0.2 ng/ml. In patients who had biochemical progression postprogression serum PSA doubling time was calculated using the formula, PSA doubling time ⫽ ln(2)⫻T/[log(final PSA)⫺log(initial PSA)].14 All patients had at least 3 PSA measurements available after progression. Statistical analysis. The Fisher exact and chi-square tests were used to evaluate associations between categorical variables. Differences in variables with a continuous distribution between dichotomous categories were assessed using the Mann Whitney U test. The Kaplan-Meier method was used to calculate survival functions and differences were assessed with the log rank statistic. Multivariate survival analysis was performed with the Cox proportional hazard regression model. Preoperative PSA had a skewed distribution and, therefore, was it modeled with a log transformation. Statistical significance in this study was set as p ⱕ0.05. All reported p values are 2-sided. All analyses were performed with SPSS, version 10.0 for Windows (SPSS, Chicago, Illinois). RESULTS
Association of LVI and PNI with clinical and pathological characteristics. Figure 1 shows representative images of tumor invasion in lymphatic vessels, blood vessels and perineural spaces. Table 1 lists clinical and pathological characteristics of the 630 patients treated with prostatectomy, and associations with LVI and PNI. Mean preoperative serum total PSA was 8.1 ⫾ 8.0 ng/ml (median 6.1, IQR 4.5 to 8.7, range 0.1 to 99.0). Of the 630 patients 32 (5.1%) had LVI and 381 (60.5%) had PNI. LVI foci were usually located at or near the cancer. Tumor emboli were occasionally identified. Most patients had 1 or 2 foci of LVI. LVI and PNI were associated with clinical stage T2 disease, higher biopsy and final Gleason sum, extraprostatic extension, seminal vesicle involvement, positive surgical margins and a higher percent of positive biopsy cores (p ⬍0.001). LVI was further associated with metastases to regional lymph nodes (p ⬍0.001) and
FIG. 1. LVI (A) and PNI (B) in PCa specimens. Reduced from ⫻400
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TABLE 1. Association of LVI and PNI with clinical and pathological features of 630 consecutive patients who underwent radical RP for clinically localized disease No. Pts (%) No. clinical stage (%):* T1 425 (68) T2 204 (32) No. Biopsy Gleason sum (%):† 2–6 412 (66) 7 176 (28) 8–10 39 (6) No. extraprostatic extension only (%): Neg 448 (71) Pos 182 (29) No. seminal vesicle involvement (%):* Neg 572 (91) Pos 57 (9) No. surgical margin status (%): Neg 451 (72) Pos 179 (28) No. final Gleason sum (%): 2–6 256 (41) 7 309 (49) 8–10 65 (10) No. regional lymph node metastases (%): Neg 620 (98) Pos 10 (2) Median age at RP (range) 630 (100) Median % pos biopsy cores 605 (95.1) (range) Median ng/ml preop serum 628 (99.4) PSA (range) * Not available for 1 patient. † Not available for 3 patients.
LVI Neg
PNI Pos
p Value
Neg
Pos
p Value
⬍0.001
191 (44.9) 57 (27.9)
234 (55.1) 147 (72.1)
⬍0.001 (Fisher’s exact test)
223 (54.1) 121 (68.8) 35 (89.7)
⬍0.001 (Fisher’s exact test)
413 (97.2) 184 (90.2)
12 (2.8) 20 (9.8)
407 (98.8) 160 (90.9) 28 (71.8)
5 (1.2) 16 (9.1) 11 (28.2)
⬍0.001
189 (45.9) 55 (31.3) 4 (10.3)
442 (98.7) 156 (85.7)
6 (1.3) 26 (14.3)
⬍0.001
222 (49.6) 27 (14.8)
226 (50.4) 155 (85.2)
⬍0.001 (Fisher’s exact test)
562 (98.3) 35 (61.4)
10 (1.7) 22 (38.6)
⬍0.001
241 (42.1) 8 (14)
331 (57.9) 49 (86)
⬍0.001 (Fisher’s exact test)
439 (97.3) 159 (88.8)
12 (2.7) 20 (11.2)
⬍0.001
200 (44.3) 49 (27.4)
251 (55.7) 130 (72.6)
⬍0.001 (Fisher’s exact test)
255 (99.6) 294 (95.1) 49 (75.4)
1 (0.4) 15 (4.9) 16 (24.6)
⬍0.001
150 (58.6) 85 (27.5) 14 (21.5)
106 (41.4) 224 (72.5) 51 (78.5)
⬍0.001 (Fisher’s exact test)
248 (40) 1 (10) 60.9 (40.4–74.3) 16.7 (3.0–83.3)
372 (60) 9 (90) 60.9 (40.0–75.2) 33.3 (2.8–100)
0.098 (Mann-Whitney U test) 0.822 (Mann-Whitney U test) ⬍0.001 (Mann-Whitney U test)
6.1 (0.1–52)
6.10 (1.0–99.0)
0.750 (Mann-Whitney U test)
596 (96.1) 2 (20) 61.0 (40.0–75.2) 23.1 (3.0–100)
24 (3.9) 8 (80) 59.6 (43.3–72.2) 50.0 (15.4–100)
⬍0.001 0.100 ⬍0.001
6.0 (0.1–52.0)
7.8 (4.0–99.0)
0.004
higher preoperative serum PSA (p ⫽ 0.004). The statistical significance of all except 1 association remained unchanged when evaluated in patients with negative lymph nodes. In patients with negative lymph nodes LVI was not associated with preoperative PSA (p ⫽ 0.065). Association of LVI and PNI with biochemical progression after RP. Overall only 80 of 626 patients (13%) had cancer progression at a median postoperative followup of 21.4 months (range 1.0 to 101.3). Mean overall PSA progressionfree survival was 81.9% ⫾ 2.5% at 3 years and 77.6% ⫾ 1.3% at 5 years. Using the log rank test we found that patients with vs without LVI had an increased probability of PSA progression (p ⬍0.001, fig. 2, A). Likewise, patients with PNI vs without were at increased risk for biochemical progression (p ⫽ 0.0012, fig. 2, B). On univariate Cox proportional hazards regression analyses all standard postoperative pathological characteristics and preoperative PSA were significantly associated with an increased risk of rapid biochemical progression after surgery (table 2). On postoperative multivariate analysis only preoperative PSA, seminal vesicle involvement, lymph node metastases and final Gleason sum were associated with biochemical progression (p ⬍0.001, 0.043 and 0.015, and p for trend ⫽ 0.008, respectively, table 2). The statistical significance of these associations remained unchanged when evaluated in patients with negative lymph nodes. In 4 patients on whom pathologically organ confined disease and followup data were available PNI (HR 2.730, 95% CI 1.114 to 6.690, p ⫽ 0.028) and preoperative PSA (HR 4.747, 95% CI 2.430 to 9.270, p ⬍0.001) were associated with biochemical progression when adjusted for the effects of LVI (p ⫽ 0.985), surgical margin status (p ⫽ 0.285) and final Gleason sum (p for trend ⫽ 0.644). In 192 patients who had pathologically nonorgan confined disease metastases to regional lymph nodes (HR 2.798, 95%
CI 1.211 to 6.465, p ⫽ 0.016), surgical margin status (HR 2.178, 95% CI 1.109 to 4.281, p ⫽ 0.24), preoperative PSA (HR 1.768, 95% CI 1.190 to 2.627, p ⫽ 0.005) and final Gleason sum (overall p ⬍0.001, 2 to 6 vs 7 HR 0.841, 95% CI 0.289 to 2.448, p ⫽ 0.750 and 2 to 6 vs 8 to 10 HR 3.336, 95% CI 1.146 to 9.710, p ⫽ 0.027) were associated with biochemical progression when adjusted for the effects of LVI (p ⫽ 0.905), PNI (p ⫽ 0.547), extracapsular extension (p ⫽ 0.934) and seminal vesicle involvement (p ⫽ 0.176). Association of LVI and PNI with PSA doubling time and response to salvage radiation therapy. Seven patients did not undergo additional treatment after disease progression at last followup, 21 underwent local salvage radiation therapy at our institution and 43 underwent hormonal therapy as primary treatment for PCa progression. PSA doubling time calculation was performed in 68 patients who had PSA progression prior to the administration of salvage therapy. PSA doubling time between RP failure and the initiation of salvage therapy was shorter in patients with vs without LVI (median 3.3 months, range 0.4 to 7.1 vs 6.9, range 0.9 to 26.0, p ⫽ 0.012). However, PSA doubling time was not different between patients with vs without PNI (median 4.2 months, range 0.9 to 26.0 vs 6.4, range 0.4 to 16.9, p ⫽ 0.132). The median time from the start of salvage local radiation therapy to last followup in patients who had a favorable response was 43.7 months (range 4.4 to 71.1). Overall PSA progression-free survival after salvage local radiation therapy was 45% ⫾ 11% at 2 years and 20% ⫾ 10% at 4. Patients with vs without LVI were at higher likelihood for rapid biochemical progression after salvage radiation therapy (100% vs 43.5% at 3 years, p ⫽ 0.0169). However, at 3 years the risk of progression was not different between patients with vs without PNI (66% vs 50%, p ⫽ 0.8583). Association of LVI and PNI with clinically evident distant PCa metastases and patient survival. Staging evaluation,
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FIG. 2. Probabilities of PSA progression-free survival in 626 patients who underwent RP for clinically localized disease according to LVI (A) and PNI (B).
TABLE 2. Univariate and multivariate Cox regression analyses of postoperative features for biochemical progression prediction in 630 patients who underwent radical RP for clinically localized PCa Univariate
Preop serum PSA* LVI PNI Extracapsular extension Seminal vesicle involvement† Surgical margin status Lymph node metastasis Final Gleason sum: 2–6 7 8–10 * Logarithmically transformed. † Not available for 1 patient.
Multivariate
HR
95% CI
p Value
3.830 6.380 2.292 4.715 6.859 3.322 19.441
2.804–5.230 3.629–11.215 1.368–3.841 2.971–7.483 4.320–10.890 2.130–5.180 9.516–39.721
⬍0.001 ⬍0.001 0.002 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
2.248 1.671 0.900 1.721 1.939 1.566 2.862
1.611–3.136 0.935–2.986 0.379–2.172 0.951–3.112 1.022–3.676 0.932–2.630 1.225–6.689
⬍0.001 0.083 0.815 0.073 0.043 0.090 0.015
1.000 2.201 11.484
Referent 1.165–4.161 6.004–21.967
⬍0.001 0.015 ⬍0.001
1.000 1.082 2.546
Referent 0.533–2.195 1.124–5.766
0.008 0.828 0.025
including bone scan or ProstaScint (Cytogen Corp., Princeton, New Jersey) scan, was performed at our institution in 56 patients who had biochemical progression after RP. Of the patients 14 had bone metastases on imaging. Median followup in patients who had PSA progression after surgery
HR
95% CI
p Value
but no metastases was 43.0 months (range 4 to 100). Patients with vs without LVI were at significantly increased risk for early PCa metastases (p ⬍0.001). The 5 and 7-year actuarial risks of metastasis were 63.0% ⫾ 14.4% and 47.3% ⫾ 17.4% for patients with LVI, and 96.7% ⫾ 1.4% and 93.8% ⫾ 3.2%
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LYMPHOVASCULAR INVASION AND AGGRESSIVE PROSTATE CANCER
for patients without LVI. However, there was no difference in the risk of metastases between patients with and without PNI when analyzed in all patients (p ⫽ 0.2950) or in those with organ confined disease (p ⫽ 0.3282). The statistical significance of these associations remained unchanged when evaluated in patients with negative lymph nodes. Overall survival data were available on 629 of the 630 patients. Seven of the 629 patients (1%) were dead of any cause at analysis. Median followup in patients who experienced PSA progression after surgery and were alive at last followup was 43.9 months (range 4 to 100). Patients with LVI had a significantly decreased probability of survival (p ⬍0.001). Five and 7-year actuarial survival was 81.7% ⫾ 12.3% and 70.0% ⫾ 15.1% for patients with LVI, and 99.0% ⫾ 0.6% and 98.1% ⫾ 1.1% for patients without LVI. However, there was no difference in the probability of overall survival between patients with vs without PNI when analyzed in all patients (p ⫽ 0.4905) or in those with organ confined disease (p ⫽ 0.5479).
DISCUSSION
We found that only 5% of patients who underwent radial prostatectomy for clinically localized disease had tumor invasion of lymphatic and/or vascular vessels. Previous studies have shown higher rates of lymphatic and/or vascular tumor invasion in prostatectomy specimens (ie 12% to 53%).2–7 The discrepancy among studies may be due to various factors, such as specimen handling, the definition of lymphatic and/or vascular invasion, interobserver interpretation variations or differences in the distribution of pathological stages between our and other studies.2–7 We confirmed the association of LVI with features of biologically aggressive PCa.2–7 The strong association between LVI and metastases to regional lymph nodes in the current study supports the hypothesis that LVI precedes or occurs coincidently with lymph node metastasis. However, LVI was associated with biochemical progression after RP on univariate but not on multivariate analysis that adjusted for the effects of standard pathological features. This association remained when evaluated in patients with negative lymph nodes. While our study failed to demonstrate an independent association between LVI and biochemical progression after RP, only 13% of our patient cohort had disease progression at a median followup of 21 months. This progression rate, which is lower than other reported progression rates after RP, may increase with longer followup.15, 16 Four previous studies have shown an independent association between LVI and biochemical progression after surgery.2–5 However, 3 studies did not adjust for the effects of metastases to regional lymph nodes.2, 3, 5 In addition, patients in previous studies had more advanced disease and higher rates of LVI foci,2–7 which are 2 features associated with PSA progression.3 Finally, biochemical progression may result from local failure related to residual disease present after RP, to occult metastatic nodal or distant metastatic disease present at surgery, or to some combination. These forms of recurrent disease have variable progression rates with regard to metastases and eventual death. The lack of an independent association of LVI with biochemical progression after surgery may be due to a lack of association with local and/or biologically more indolent disease. Therefore, the ability to predict the progression of clinical disease and the development of metastases has a greater impact on managing PCa cases than an association with pathological characteristics or the anticipation of simply biochemical progression. We found that LVI was significantly associated with shorter PSA doubling times after biochemical failure, rapid failure to respond to salvage local radiation therapy and most remarkably an increased likelihood of early distant metasta-
ses and death. These associations remained when evaluated in patients with negative lymph nodes. We confirmed that PNI is a frequent feature in RP specimens.12, 13 In addition, we found that PNI was associated with established markers of poor clinical outcome. We identified areas of PNI arising in the peripheral zone in 50% of patients with organ confined PCa and 85% with nonorgan confined disease. PNI represents cancer spread along tissue planes of least resistance next to nerves.17 It was demonstrated that a major mechanism by which prostate adenocarcinoma extends from the prostatic parenchyma to periprostatic soft tissue is via PNI.18, 19 We found that PNI was associated with biochemical progression after RP on univariate analysis when analyzed in all patients and on multivariate analysis when analyzed in those with organ confined disease. However, PNI was not associated with more profound end points, such as the response to salvage radiation therapy, clinically evident distant metastases or survival. Several limitations in this study should be considered. Some variables that were inconclusive due to limited statistical power may attain statistical significance if sample size or followup were increased. In addition, the population in this study underwent RP as performed by multiple surgeons and specimens were evaluated by multiple pathologists. Most studies of LVI or PNI used cohorts assembled from populations at large academic hospitals serving as tertiary referral centers and patients were treated by a single surgeon. While prognostic factors may perform well in the select group of patients treated at these centers, it remains to be determined whether they are applicable to the greater population of patients with PCa. Similarly while it may be preferable for a single pathologist specialized in genitourinary pathology to review each prostatectomy specimen, the setup at our institution reflects real-world practice, in which local pathologists review tissue specimens and their interpretations are then used in clinical decision making with the patient. CONCLUSIONS
Our study demonstrates a statistically and clinically significant association of LVI in prostatectomy specimens with established features of biologically aggressive PCa, biochemical progression after local therapy, regional and distant PCa metastases, and decreased overall survival. The associations of LVI with early biochemical and clinical disease progression suggest that LVI is a feature of the metastatic process, putting patients at the highest risk for early metastasis and death. Therefore, we believe that prostatectomy specimens should be routinely examined for LVI using hematoxilin and eosin staining, and routine light microscopy. After confirming these results in larger studies with longer followup LVI could be added to standard predictive models to improve the level of prognostic accuracy and establish recommendations for adjuvant and salvage therapies. In contrast, PNI in the prostatectomy specimen did not improve the ability to predict clinical disease progression in patients with clinically localized PCa and, hence, it has limited clinical usefulness. REFERENCES
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