A number of prior studies have attempted to determine patterns of prostate cancer spread to lymph nodes, reporting a 10 to 46% incidence of LN metastasis contralateral to the dominant tumor mass among LN positive cases (
10,
12,
26,
29). Since these investigations encompass different eras in the clinical application of PLND, the conclusions drawn from the data have varied. Harrison et al writing at a time when LN metastasis detected at frozen section was cause for aborting RP, argue that since only eleven of 100 cases showed exclusively contralateral LN metastasis to DRE-detected dominant masses, ipsilateral LNs should be sampled first (
12). Spiess et al evaluated the ability of DRE, TRUS and/or PNB to predict side of pelvic LN metastasis. They found a 10–17% rate of contralateral-only LN metastasis and false negative predictive rates between 14 to 29% with these modalities and conclude that they are not accurate enough to reliably guide physicians (
26). Similarly, Weckermann et al studied 564 men with negative or unilaterally positive DRE as well as PNB positive in one lobe only and found up to 30% contralateral-only positive LNs (
29). Results from imaging studies are conflicting, with some reporting little “crossover” of injected contrast medium to contralateral LN (
24), others demonstrating some lymphatic crossover on lymphoscintigraphy (
30), and a general consensus that standard imaging techniques consistently fail to identify pelvic lymph node spread with sufficient specificity (
21,
25). Given these findings, a number of authors (
10,
26,
29) have recommended complete bilateral PLND as the only appropriate LN staging method.
A drawback of previous studies, however, is the use of surrogates (DRE, TRUS, PNB and/or imaging findings) for determination of primary tumor location. To our knowledge, this is the first study to comprehensively assess prostate cancer topography, as seen in RP specimens, and corresponding lymph node metastasis. Herein, we demonstrate that, in the setting of standard (external iliac, obturator and hypogastric) LN dissection, 15% of metastasis occurs exclusively contralateral to the dominant prostatic tumor mass. Including cases with bilateral LN metastasis, over 25% of prostate cancers associated with positive LNs show contralateral spread. These findings are similar to those demonstrated by Leissner et al who recommend extended radical lymphadenectomy to all patients undergoing radical cystectomy for bladder cancer, based on ~ 20% risk of contralateral LN metastasis (
17) and may suggest that a unilateral lymph node dissection for prostate cancer staging is unwise.
Evidence to support a therapeutic benefit of PLND in prostate cancer comes from studies showing that standard dissection (including external iliac, obturator, and hypogastric LN packets) results in detection of more positive LNs than limited (external iliac packet only) dissection (
2,
27) and others demonstrating that the number of LN dissected correlates with time of PSA recurrence, relapse of symptoms, and prostate cancer-related mortality (
4). Furthermore, Burkhard et al have reported that meticulous LN dissection results in a 7% rate of LN metastasis even in patients with PSA less than 10 ng/ml and GS less than 7 (
7).
In spite of this data, selective application of PLND is currently the norm owing to the low reported contemporary incidence of positive LNs (2% to 6%), the rise of minimally-invasive surgery and the development of risk stratification tools to better identify men at risk for advanced disease (
8,
11,
13,
15,
19). As highlighted by Kawakami et al in their review of an observational disease registry (CaPSURE), marked variation among institutions and individual surgeons exists in the selection of patients for and anatomic extent of PLND in prostate cancer. These authors report that although fewer overall patients underwent PLND in the ten year period from 1992–2001, LN dissection was still performed in 75% and >80% of low and intermediate risk patients in whom the actual incidence of LN metastasis was < 1% and 2%, respectively. Importantly, they question the adequacy of PLND in achieving accurate staging, based on the small mean number of LN dissected in CaPSURE-enrolled patients (
15). While it is clear from these collective analyses that the application of PLND remains controversial, our median of 13 lymph nodes dissected per case as well as high incidence of positive LNs in the obturator and hypogastric LN packets (among those cases with available data), supports the contention that standard PLND yields higher LN counts and will detect more metastatic foci than dissections limited to external iliac LNs (
2–
3,
27).
It is rather intuitive that the large – 6.39 cc mean and 3.92 cc median – tumor volumes seen presently would be associated with pelvic LN metastasis. However, it is interesting to note that more extensive breakdown of this data reveals 6, 12 and 26% of the cohort with <0.5 cc, <1 cc, and < 2 cc TTV, respectively. The relationship of tumor volume and pelvic LN metastasis has previously been explored by McNeal who reported that the volume of Gleason patterns 4 or 5 cancer (i.e. multiplying TTV by % high-grade tumor) was most strongly predictive of LN metastasis. In their hands, tumors with greater than 3.2 cc Gleason grade 4/5 cancer showed a 100-fold increase in the proportion of cases with nodal spread (
20). Although we found predominantly Gleason grade 4/5 encompassed ≥ 50% of TTV in 84% of cases and ≥ 90% of TTV in 58% of cases, more than half of our cohort (65/125; 52%) had volumes of Gleason grade 4/5 less than 3.2 cc. In a similar vein, though the majority of our cohort displayed EPE, SVI, or both, 13% showed otherwise organ-confined primary tumors, the majority of which were located in the apex-mid prostate. It is apparent therefore, that LN positivity is not uniformly associated with tumors exhibiting high TTV, large volumes of high grade disease or stage ≥ pT3a.
A remarkable finding that emerges from this topographic analysis is the small number (4%) of LN positive cases associated with an anterior dominant tumor. Contemporary studies have shown an increasing rate – up to 20–25% – of anterior dominant tumors (
1,
5) and no significant difference in the rate of LN metastasis compared with posterior tumors generally (
16,
18). However, no prior study has focused exclusively on LN positive patients to discern these patterns. This result raises a number of interesting possibilities regarding anterior dominant tumors and PLND. First is the suggestion that anterior dominant cancers do not exhibit LN metastasis as frequently as posterior tumors. While there is some evidence that anterior tumors are typically of lower stage due to stromal boundaries of the transition zone (
20) and/or a relative paucity of nerves in the anterior prostate leading to less perineural invasion and EPE (
23,
28), this does not adequately account for the dearth of LN metastasis observed in the present study. A review of the LN data from our previous report on a large series of anterior dominant tumors reveals that 139 of 167 patients (97 anterior peripheral zone tumors and 70 transition zone tumors) underwent PLND (mean and median LN dissected: 10.4 and 10, respectively). While it was not the study’s focus, we found that only 3 of 139 (2.2%) cases displayed LN metastases, providing further evidence of the paucity of LN metastasis in the setting of anterior dominant tumors (
1). In the present study, we also note that the mean TTV among the five anterior dominant tumors is 14.1 cc, a value well beyond the mean TTV for all cases in this series, suggesting that only exceptionally large anterior tumors may metastasize to pelvic LNs. Another intriguing possibility is that the standard PLND performed in all of our patients does not include the main drainage pathways of the anterior prostate. Investigations of prostate lymphatic drainage have shown that removing external iliac, obturator, and hypogastric LNs covers the major regions to which the prostatic parenchyma empties, but not LN zones such as presacral nodes which may contain a small, but significant number of metastases (
6). Further study with increased limits of dissection may be necessary to determine whether anterior dominant tumors have a divergent pattern of LN drainage compared with the majority of the prostate.
Another notable feature of this analysis is the high incidence of LVI detected. A wide selection of RP-based studies have reported an incidence of LVI ranging from 5% to 53%, data which is confusing due to non-uniform criteria for its evaluation as well as marked variation in the cohorts studied (
9). Even with strict criteria that required unequivocal identification of tumor within endothelial-lined spaces and excluded suspicious lesions within the tumor mass, we were still able to identify LVI in 64% of patients on H&E alone. LVI was noted not only in the immediate periphery of tumors but frequently in the posterior periurethral region and within/around the ejaculatory duct complex. While statistical associations with larger TTV and volumes of high grade tumor are similar to those reported previously (
14), the potential role of LVI in select patient groups is informative. For example, four of 5 anterior dominant tumors displayed LVI, suggesting that intraprostatic lymphatic infiltration plays a key role in anterior tumor metastasis to LN. Additionally, LVI was present in four of the otherwise organ-confined primary tumors with an additional four of these cases being among the 13 pre-operatively treated cases (which may have increased the difficulty of evaluation for LVI). The association of LN metastasis in these cases with intraprostatic LVI mirrors the phenomenon of SVI in cases lacking tumor contiguous to the ejaculatory duct complex or in the peri-seminal vesicle extraprostatic space (
22). Finally, while the finding of multiple LN metastases in those patients with SVI was double that of patients without SVI, it is possible that the markedly different rates of LVI among these groups (83% of patients with SVI v. 46% of patients without SVI) largely accounts for this discrepancy.
In this large, well-annotated cohort of patients with pelvic LN metastasis, we have demonstrated that 30–40% of LN metastases occur contralateral to the dominant prostatic tumor mass. Moreover, while LN positive cases are overwhelmingly associated with high grade, high stage and large volume disease, subsets of patients with lower volume tumors or organ-confined primary disease may be identified in which intraparenchymal lymphovascular invasion likely plays a key role. LN positivity is rarely associated with anterior dominant tumors.
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