Validation of lymphovascular invasion is an independent prognostic factor for biochemical recurrence after radical prostatectomy

doi:10.1016/j.urolonc.2015.10.013

Urologic Oncology: Seminars and Original Investigations

Volume 34, Issue 5, May 2016, Pages 233.e1-233.e6

https://doi.org/10.1016/j.urolonc.2015.10.013 Get rights and content

Highlights

•
About 10% of localized prostate cancers show lymphovascular invasion.
•
Lymphovascular invasion is linked with adverse pathological features.
•
Lymphovascular invasion is associated with an increased risk of biochemical recurrence.

Abstract

Objective

To validate the impact of lymphovascular invasion (LVI) on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) in a large multiinstitutional cohort.

Material and methods

Retrospective data from 6,678 patients treated with a RP and bilateral lymphadenectomy for prostate cancer (PC) from 8 centers were collected. The primary endpoint was BCR.

Results

Overall, 767 patients (11.5%) had LVI. Patients with LVI had significantly higher Gleason scores (P = 0.01). After a median follow-up of 28 months (interquartile range: 21–44), patients with LVI had a 1.66 fold increased risk of BCR (P<0.001). The 1-, 2- and 5-year biochemical recurrence-free survival probabilities for LVI vs. no LVI were 94% vs. 97%, 91% vs. 94%, and 76% vs. 84%, respectively. On multivariable analysis that adjusted for the effects of established prognostic factors, LVI was an independent predictor of BCR (hazard ratio = 1.42, P<0.001). Adding LVI to a multivariable base model increased the discrimination by a small but significant margin (+0.2%, P = 0.0005). In subgroup analyses, LVI remained an independent predictor for BCR in patients with worse pathological features.

Conclusions

About 10% of patients with localized PC have LVI on their RP specimen. We confirm that LVI is associated with features of biologic aggressive PC such as high Gleason grade and BCR after RP. Adverse further studies with strict definitions of LVI and longer follow-up periods are needed to determine the prognostic and predictive utility of LVI in the management of PC.

Introduction

Although radical prostatectomy (RP) results in long-term local disease control, approximately 20% to 30% of patients experience a biochemical recurrence (BCR), which is detected by a rise in serum prostate-specific antigen (PSA) levels after RP. The association of certain clinicopathological features such as Gleason score, pathological stage, and lymph node metastasis with BCR has been previously described [1], [2], and understanding how these factors affect prognosis is paramount in guiding treatment. Over the past decade, pathological lymphovascular invasion (LVI) has been identified as an independent predictor of disease recurrence after curative treatment for multiple cancer types, including prostate cancer (PC) [3], [4], [5], [6], [7].

Previous retrospective studies have reported conflicting results regarding the role of LVI for predicting BCR [8], [9], [10], [11], [12], [13], [14], [5], [7], [6]. In their consensus conference on handling and staging of RP specimens in 2009, the International Society of Urological Pathology (ISUP), considered the reporting of microscopic LVI part of the standard pathologic evaluation for RP specimens [15]. Despite this, a recent review suggested that there is insufficient evidence to recommend the routine use of LVI for clinical prognostication [16].

In this present study, we analyzed data from a large multiinstitutional contemporary cohort of patients undergoing RP for clinically localized PC to determine the association of LVI with BCR and whether addition of LVI status would help us better prognosticate PCA outcomes after RP.

Section snippets

Patient selection and data collection

Data was collected in retrospective fashion from 8 institutions worldwide. All participating sites provided Institutional Review Board approval and the necessary data sharing agreements before the initiation of the study. A central computerized databank was generated for data collection. The initial cohort was composed of 7,427 patients treated with a RP and bilateral standard pelvic lymph node dissection for clinically localized PC between 2000 and 2011. Patients who received preoperative

Cohort characteristics

Of the 6,678 patients, 767 (11.5%) showed LVI at RP. Among the 1,702 patients with pT3 disease, 213 (12.5%) had LVI. Clinical and pathological characteristics are listed in Table 1. The LVI group showed significantly higher Gleason scores (P = 0.01). Preoperative PSA levels and the frequencies of extracapsular extension, seminal vesicle invasion, and positive margins were similarly distributed between the 2 groups. Patients with LVI tended to be older than those without (P = 0.054).

Association between LVI and BCR

After a

Discussion

In this study, we found LVI in 11.5% of RP specimens. The reported rate of LVI on RP specimens is highly variable ranging between 5% and 53% [8], [11], [12], [13], [14], [18], [5], [7], [10]. In our patients with pT3N0 disease, the rate of LVI was 12.5%, which was lower than that reported by others, i.e., 16% to 35% [19], [7], [14]. The variation can be attributed to several factors including differences in specimen handling, interobserver variability and length of follow-up and the population

Conclusion

LVI is found in approximately 11.5% of patients undergoing RP for clinically localized PC. LVI was found to be associated with adverse pathologic features such as high Gleason score. LVI was also found to predict BCR, adding minimally to established clinicopathological predictors. In subgroup analyses, LVI remained an independent predictor for BCR in patients with worse pathological features. Adverse further studies with strict definitions of LVI and longer follow-up periods are needed to

Compliance with ethical standards

The authors declare no conflict of interest. The study was conducted according to local and national regulations. This article does not contain any studies with human participants or animals performed by any of the authors.

Authors contributions

Project Development: Fajkovic, Shariat.

Data Collection: Fajkovic, Shariat, Briganti, Karakiewicz, Lotan, Roupret, Rink, Kluth, Seitz.

Data analysis: Fajkovic, Shariat, Mathieu, Lucca, Hiess, Hübner, Karakiewicz, Susani Manuscript writing: Fajkovic, Shariat, Mathieu, Al Awamlh, Lee.

Manuscript revision/editing: Fajkovic, Shariat, Mathieu, Lucca, Lotan, Loidl, Seitz, Klatte, Kramer Statistical Analysis: Fajkovic, Shariat, Mathieu, Lucca.

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We report a series of 12 prostatic adenocarcinoma cases with unusual urothelial-like morphology, diagnosed at two academic institutions in Toronto between 2018 and 2023, and analyzed by immunohistochemistry for prostatic, urothelial, and neuroendocrine marker expression. We collected patient age, androgen deprivation therapy (ADT) status, tumour site, histomorphology, Grade group (GG) and results of genetic testing.
The median age of the 12 patients included in this case series was 75.5 years (range 41–85). A history of prostatic cancer was noted in 7/12 (58%) patients. Five of nine (56%) patients had elevated serum PSA level at diagnosis. Six of eleven (55%) patients had prior ADT. Tumour sites were prostate (n = 6), bladder (n = 3), liver metastases (n = 2), and lung metastasis (n = 1). GGs of the primary tumours were GG3 (n = 1) and GG5 (n = 8). The observed urothelial-like morphology was diffuse in ten cases, and focal in two cases. CK7 was strong/diffuse in 8/11 tested cases, and focal weak in one case. CK20, HMWK, p63 and GATA3 were patchy/focal/weak/moderate in 3/6, 4/7, 4/8 and 2/9 cases, respectively. Ten (83%) cases were positive for at least one prostatic marker; eight (67%) cases had loss/weak staining of at least one prostatic marker. AR loss was seen in 2/7 (29%) cases. Seven of ten (70%) cases had diffuse/strong expression of at least one neuroendocrine marker. No trend was evident between prior ADT/AR status and any IHC result. Molecular analyses for DNA damage repair (DDR) genes (n = 6) demonstrated one ATM deletion (bladder). In addition, one TMPRSS2:ERG fusion (lung metastasis) was identified.
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Impact of Lymphovascular Invasion on Overall Survival in Patients With Prostate Cancer Following Radical Prostatectomy: Stage-per-Stage Analysis
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Citation Excerpt :
This limitation may contribute to either an overestimation or underestimation of the rates of LVI in radical prostatectomy specimens. It has been reported previously that processing artifacts may mimic LVI, and only unequivocal cases of LVI should be reported as so.6,22,23 Therefore, it may be difficult to ascertain the impact of a lack of centralized pathologic review and hence the use of a large cohort may represent more of a realistic representation of the general population.
The detrimental impact of lymphovascular invasion (LVI) in prostate cancer (PCa) on biochemical recurrence has been described; the impact of LVI on overall survival (OS) remains unclear. This investigation sought to evaluate the impact of LVI on OS in patients with PCa.
We examined men with nonmetastatic PCa treated with radical prostatectomy between 2010 and 2015. Only men with documented LVI status were included (n = 232,704). Patients were stratified according to final pathologic T stage (pT2, pT3a, and pT3b).
Of the 232,704 patients who met inclusion criteria, 17,758 (8%) were found to have LVI on final pathology. Overall, 174,838 (75%), 40,281 (17%), and 17,585 (8%) patients had pT2, pT3a, and pT3b disease, respectively. Median follow-up was 42.7 months (27.1-58.7). At 5 years, the OS in LVI versus non-LVI patients was 94% versus 95% in pT2 (P = .0004), 92% versus 95% in pT3a (P < .0001), and 86% versus 92% in pT3b (P < .0001). On multivariable analysis, LVI status was not an independent predictor of OS in pT2 disease (hazard ratio, 1.12; 95% confidence interval [CI], 0.93-1.36; P = .2). In pT3a and pT3b disease, presence of LVI had 1.2-fold (95% CI, 1.03-1.44; P = .02) and 1.4-fold (95% CI, 1.20-1.59; P < .001) higher overall mortality than their counterparts without LVI.
Our report demonstrates the detrimental impact of LVI on OS in locally advanced PCa (pT3a and higher). This information may prove valuable when risk stratifying based on final pathology.
Evaluation of lymphovascular invasion as a prognostic predictor of overall survival after radical prostatectomy
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Citation Excerpt :
This is further complicated by the lack of an unequivocally identified sentinel node for CaP [9], the significant morbidity associated with an all-encompassing lymph node dissection, and the lack of standardization in the number of lymph nodes removed by various surgeons [10]. On the other hand, lymphovascular invasion (LVI) at time of RP is recognized as an adverse pathological feature in patients with prostate cancer [11-14]. Theoretically, assessment of LVI status should mirror LNI status, and there have been multiple studies that have identified a strong link between LVI and LNI [13,15].
To assess the prognostic ability of lymphovascular invasion (LVI) as a predictor of overall survival (OS).
We included 126,682 prostate cancer (CaP) cM0 patients who underwent radical prostatectomy with lymph node dissection between 2010 and 2015, within the National Cancer Database. Patients who received androgen deprivation therapy were included. Patients were divided into four sub-cohorts based on LVI and lymph node invasion (LNI) status: pL₀N₀, pL₁N₀, pL₀N₁, and pL₁N₁. Kaplan-Meier curves estimated OS and Cox-regression analysis tested the relationship between LVI and OS.
Median (IQR) age and PSA at diagnosis were 62 (57-66) years and 5.7 (4.5-8.9) ng/ml, respectively. Most patients had pT2 stage (68.5%), and pathological Gleason 3+4 (46.7%). 10.0% and 4.0% patients had LVI and LNI, respectively. Median follow-up was 42 months (27-58). At 5-years, OS was 96.5% in pL₀N₀ patients vs 93.1% pL₁N₀ patients vs 93.3% in pL₀N₁ patients vs 86.6% pL₁N₁ patients. LVI was an independent predictor of OS (hazard ratio [HR]:1.28). LVI showed interaction with LNI, as LVI was associated with a higher overall-mortality in patients with LNI (HR:1.66), than in patients without LNI (HR:1.22). (all P<0.0001)
Our report highlights the detrimental impact of LVI on OS. Patients with LVI alone fared similarly to patients with LNI alone. Patients with both LVI and LNI had worse OS than those with only LVI or LNI, implying a synergetic detrimental interaction. Our findings demonstrate an important utility that LVI can provide in deciding patients’ prognoses.
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Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.
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The median BMI was 28 kg/m² (interquartile range: 24–32 kg/m²); 2,155 patients (33.1%) had a BMI = 25 to 29.9 kg/m² and 2,462 patients (37.7%) had a BMI≥30 kg/m². Overweight and obese status were associated with extracapsular extension (P = 0.001) and seminal vesicle invasion (P = 0.005). The median follow-up was 28 months, and the estimated 5-year BCR-free survival rates for patients with a BMI<25 kg/m², 25 to 29.9 kg/m², and≥30 kg/m² were 92%, 86%, and 79%, respectively (P<0.001). Multivariable analyses (adjusted for preoperative prostate-specific antigen levels, biopsy Gleason score, and clinical stage) revealed that obesity was associated with the risk of extracapsular extension (P<0.001), seminal vesicle invasion (P<0.001), and BCR (hazard ratio: 1.37, P<0.001). BMI and obesity remained associated with BCR after adjusting for postoperative characteristics. Addition of BMI slightly increased the discrimination of the multivariable clinical prognostic model (from 79.9%–80.9%).
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Original articleValidation of lymphovascular invasion is an independent prognostic factor for biochemical recurrence after radical prostatectomy

Highlights

Abstract

Objective

Material and methods

Results

Conclusions

Introduction

Section snippets

Patient selection and data collection

Cohort characteristics

Association between LVI and BCR

Discussion

Conclusion

Compliance with ethical standards

Authors contributions

Eur Urol

J Urol

J Urol

Urology

Kaohsiung J Med Sci

Mod Pathol

J Urol

Eur Urol

Significant upgrading affects a third of men diagnosed with prostate cancer: predictive nomogram and internal validation

BJU Int

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy

BJU Int

Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma

J Clin Oncol

Original article
Validation of lymphovascular invasion is an independent prognostic factor for biochemical recurrence after radical prostatectomy