Impact of lymphovascular invasion on lymph node metastasis for patients undergoing radical prostatectomy with negative resection margin

The association between lymphovascular invasion and lymphatic or hematogenous metastasis has been suspected since 1994, when the College of American Pathologists recommended to routinely report lymphovascular invasion (LVI) for radical prostatectomy specimens; however, current evidence remains controversial [1‐5]. There are several factors that make it difficult for LVI to establish its value as an independent prognostic factor for recurrence. Definitions of LVI vary from author to author, and there are issues of overdetection with artifacts, all of which contribute to the confusion regarding this particular pathologic finding [6]. In other malignancies, such as thyroid [7], lung [8], stomach [9], bladder [10], kidney [11], and breast cancers [12], LVI is considered as an independent prognostic factor. Regarding the prostate, despite the unclear prognostic value of LVI in prior studies conducted in the general population, more recent investigations of patients in particular stages show some promising aspects [1, 13, 14]. Although the migration of cancer cells into vessels is generally regarded as a necessary early step for nodal or distant metastasis in other cancers, evidence remains scarce for the prostate cancer [2, 15].

Under the hypothesis that LVI is associated with increased risk of recurrence by accelerating lymph node metastasis, we have analyzed the association between LVI and risk of biochemical recurrence (BCR) according to pathologic T stage and resection margin status, as well as its influence on the risk of lymph node metastasis.

Our study is, to our knowledge, the largest to demonstrate that LVI increases the recurrence risk in patients with T3 tumors independent of resection margin status. Our results indicate that increased BCR rate in LVI tumors is mainly mediated by increased lymph node metastasis, a cause different from residual cancer cells by PSM cancers. Although previous studies generally agree that LVI is associated with disease progression and aggressive tumor behavior, its value as an independent prognostic factor remains debatable. According to Loeb et al., LVI was not an independent predictor of progression in a multivariate model, although it showed a significant association with tumor volume, Gleason score > 6, PSM, extraprostatic extension (EPE), positive lymph nodes, and seminal vesicle invasion (SVI) [3]. Shariat et al., in their study involving 630 patients, have concluded that a correlation between BCR and LVI is mediated via an association with established features of biologically aggressive prostate cancer, and that LVI is a lethal phenotype of prostate cancer, leading to early metastasis and lower overall survival [2]. A close association of LVI with features of aggressive disease were highlighted again in the study by Yee et al. Whereas LVI was shown to have an independent prognostic value of its own in multivariate analysis, only marginal improvement was noted with the addition of LVI in the model, rendering the parameter not clinically meaningful [4].

Conversely, other evidence suggests that LVI is an independent prognostic factor, aside from its close association with the features of disease aggressiveness. Cheng et al. reported LVI to be an independent prognostic factor of BCR and cancer-specific survival for clinically localized prostate cancer patients, increasing BCR risk by 1.6 fold in their multivariate model (95% CI 1.12–2.38) [15]. Similarly, May et al. found that in addition to high Gleason score (HR 3.51, 95% CI 2.06–6.00), LVI is the factor that significantly increases the BCR risk for organ confined cancer patients (HR 4.39, 95% CI 2.47–7.80) [5]. Our results from Kaplan-Meier analysis indicate that LVI increases BCR rate and cancer-specific mortality up to 20% and 5%, respectively (Fig. 2). Controlling for the other known parameters, our regression model found LVI to retain statistical significance in its association with increased BCR risk (HR 1.352, 95% CI 1.045–1.749, p = 0.022). This disproves the belief that the increased recurrences in the LVI patients are due to the strong association with other established prognostic factors.

Especially in the cancers of T3 stage, we identified that there exists difference in the pattern of disease progression between LVI positive and negative patients. Radical prostatectomy has been not recommended on T3 patient up until recently as it was reported to be rarely curative [17]. However, from several randomized clinical trials, operation is now proven to be a valid option as it grants improved survival benefit in T3 patients [18]. Among the factors associated with recurrence risk, incomplete resection and unsuspected lymph node metastasis remains a major obstacle [17]. PSM suggests the presence of remnant cancer in the prostate bed, whether viable or not [19, 20]. It is recognized as a strong predictive factor for BCR, and attempting regional control with radiotherapy is known to yield favorable results [21]. Along with PSM, LVI is reported to increase BCR as well in T3 patients. Herman et al. evaluated pT3N0 disease and found that LVI was an independent predictor of disease recurrence [13]. Similar conclusions were drawn from the studies by Yamamoto et al. and Epstein et al., where LVI was found to be an independent prognostic factor in pT3a and pT3b tumors, respectively [1, 14]. Our results indicate that both PSM and LVI increase BCR risk, but in an independent manner. Presence of LVI significantly increased BCR rate in both positive and negative resection margin T3 groups (Fig. 3) as well as in multivariate model with PSM as a covariate (Table 2). It was shown by Mitsuzuka et al. that, LVI can increase BCR risk without PSM in T2 patients (p < 0.001, HR 3.809) [22]. Our result extends the finding to T3 cancers, adding to the evidence that mechanism by which cancer progresses for LVI positive cancer is different from PSM cancer where local tumor recurrence is believed to be a major cause of treatment failure [23].

LVI may serve as a portal of entry for systemic progress via regional lymph nodes. Liauw et al. [24] in the study on the role of of SVI and LVI for salvage radiotherapy patients, they demonstrated that LVI was associated with increased risk of BCR after radiotherapy (p = 0.019) and resulted in treatment failure in all patients, concluding that salvage radiotherapy was ineffective in LVI patients. It is likely that this is due to metastatic regions being present beyond the coverage of radiotherapy but currently, little is known about the association between LVI and metastasis regarding prostate cancer. Cheng et al. reported increased rate of LVI in lymph node metastasis patients (61% vs. 20%, p < 0.0001), but the evidence was inconclusive as LVI was also increased in patients with several other established prognostic factors [15]. Shariat et al. also suggested the association between LVI and lymph node metastasis by demonstrating that 5-year metastasis free rate was significantly lower as 63.0% in LVI group, compared to 96.7% in no LVI group [2]. In search of association between LVI and metastasis, we identified that LVI is associated with increased 10-year distant organ metastasis rate (16.9% vs. 5.1%, p = 0.001). The association was independent of other prognostic factors in the multivariate analysis (HR 1.738, 95% CI 1.024–2.950; p = 0.040), and we speculate that increased progression to metastatic disease stems from the early access to lymphatic channel, as LVI (OR 4.317, 95% CI 2.092–8.910, p < 0.001) was strongly associated with concomitant lymph node metastasis in our Logistic regression model (Table 3). Only parameter to show stronger association than LVI was Gleason score ≥ 8 (OR 5.745), which is a well-known prognostic factor of lymph node metastasis [25]. According to our results, occult metastasis should be suspected when LVI is detected, and meticulous follow-up examinations for the evidence of metastasis should be ready.

Our study has some important limitations. Firstly, no discrimination between lymphatic and vascular invasion has been made. While it is possible to identify blood vessels from the lymphatic channel by immunohistochemical analysis, its clinical significance is not clear, and we have made no effort in describing the nature of vessels [6]. In addition, due to the retrospective nature of our study, radiologic images were interpreted by several other radiologists, allowing possible inter-observer variations. Utilization of pre-set criteria in the prospective setting may improve accuracy of results.

LVI increased the risk of recurrence in T3 patients independent of margin status. With its close association to lymph node metastasis, occult metastasis via lymphatic channel should be suspected in patients with LVI.