Prostate cancer (PCa) is the most frequent tumor in men and a major leading cause of cancer-related deaths in developed countries [1]. Many men have tumors that grow very slowly, whereas others develop very aggressive disease, which metastasizes rapidly spreading to elsewhere in the body. The majority of patients with localized PCa will be cured after local therapy with five-year survival near 100% [2]; but once the tumor progresses developing distant metastasis, the disease often become incurable [2, 3]. Indeed advanced prostate cancer still accounts for the majority of the mortality from this disease [4, 5], although survival might be extensive [6]. The most common metastatic sites are bone and lymph nodes (LN) [4, 7–14], but visceral metastases may also be present [4, 5, 7, 8, 10–14] and may be associated with a more severe clinical course [5, 8, 12, 13, 15–17].

In the last years several studies have suggested the prognostic importance of the site of metastasis in men with de novo metastatic PCa [8, 11] or metastatic castration-resistant prostate cancer (mCRPC) [5, 13]. To our knowledge, few studies [9, 12, 14, 18] have assessed the impact of location of metastatic disease on the outcome of men with PCa after receiving curative treatment. Shao et al. [18] firstly demonstrated that primary treatment may make a difference with regard to survival time after metastasis; both Nini et al. [12] and Moschini et al. [14] found that nodal and local recurrence have a more favorable prognosis compared with skeletal and visceral metastases in pN+ patients treated with radical prostatectomy. Local and nodal site were the most frequent primary location of metastasis in patients treated with both radiotherapy [9] and prostatectomy [12, 14].

In this work we sought to address this issue by using a cohort of non-metastatic primary PCa patients who underwent prostatectomy or radiotherapy with curative intent with the aim of evaluating the impact of the first metastatic event on PCa-specific survival in order to respond to the need to improve the treatment-decision making process following metastatic progression.

In this data set analysis of men receiving curative radiotherapy or surgery for primary PCa, the site of the first metastasis was an independent prognostic factor for PCa death. In the entire cohort, men initially developing LN or locoregional metastases, which were the most frequent along with bone in our series as already reported by other authors [4, 9, 12, 14], had the best survival followed by those with osseous metastases. Men having metastases at multiple locations exhibited the worst prognosis; moreover, a shorter survival was associated with disease involving visceral sites too. These data are consistent with other authors who showed that multiple recurrences had a poorer prognosis than a single recurrence in pN+ patients treated with radical prostatectomy [14] and a worse outcome in presence of visceral involvement in newly metastatic patients [8, 10]. This trend in PCaSS was confirmed when the analysis was done separately for curative surgery or radiotherapy. The Locoregional/LN-only subgroup had the best prognosis in both therapy subgroups confirming previous findings in pN+ patients treated with radical prostatectomy [12, 14]. Therefore, our study highlights that PCa-specific survival strongly depends on the time after metastasis. In fact, median survival from primary diagnosis to initial metastasis (MFS) was independent of the site of the first metastatic event; indeed, each metastatic subgroup exhibited a very similar MFS with a median value of 49.6 months, very alike to that found by Ost et al. [9] in patients treated with radiotherapy. This result was confirmed also for each therapy subgroup, separately.

Our findings could be explained by the expression of different biologic characteristics that underlie the spread of PCa cells to metastatic sites. Indeed, it seems that tumor cells that spread only to LNs may have acquired specific phenotypic modifications that predispose to the preferential invasion of lymphatic vessels and access to lymph nodes [10, 12, 20, 19]. These cells might acquire the ability to spread from lymph nodes to distant organs via blood or lymphatic channels only after subsequent neoplastic transformations [3, 12, 20, 21]. Thus, PCa cells that disseminate to nodes harbor a less aggressive phenotype compared with those spreading systemically to other sites. This may explain the more favorable prognosis of patients with local/nodal recurrence compared with those with systemic disease, as already suggested by others [12]. On the other hand, visceral disease seems to be a very adverse prognostic factor, especially in de novo metastatic PCa [8] and mCRPC patients [5, 13, 15, 17]. However, it was reported as having a favorable outcome in the absence of extensive bone metastases [16] and in metastatic patients at initial diagnosis [10, 11, 22]. Interestingly, Pouessel et al. [22] analyzing patients with localized or locally advanced disease at diagnosis found that median overall survival was 6 months for patients who had a late diagnosis of liver metastasis and 14 months for whom liver was part of the initial pattern of metastases. This finding was consistent with Wang et al. [23] that showed that the outcome of liver metastasis was worse for patients whose liver metastasis was synchronous at primary PCa diagnosis than in those for whom the liver was a site of progressive PCa. In our series men having visceral-only disease were under-represented and it was impossible to make a definitive conclusion on the outcome of those patients; however, we found that the presence of visceral disease worsened the outcome of men having other metastases, as previously shown by others [8, 10]. Of note, Gleason score was the only baseline parameter predicting PCaSS endorsing its prognostic value for disease-specific survival [24] and further reinforcing that poorly differentiated cancers tend to have a more aggressive biological behavior, including high risk of metastasis [25].

Finally, the prevalence of metastasis to specific sites, mostly to bone and nodal/locoregional area [4, 9, 12, 14], has been explained biologically by the interaction between metastatic tumor cells and the organ microenvironment [26], favored by a preferential homing [27], or purely by the anatomy of vascular and lymphatic drainage from the site of the primary tumor [28].

Our work is certainly limited by its observational design and institutional registry-based study; thus, non-standardized timing for imaging, changes in treatment indication and imaging over years, inherent biases in the institution and other confounders may have been affected the results. On the other hand, being a single-center study it has allowed us to analyze a homogeneous curative cohort of non-metastatic PCa managed by standard local protocol and to demonstrate the prognostic role of the location of the metastatic hormone-sensitive disease independently in both intervention groups. Moreover, our data clarify that the time after metastatic progression rather than the time from diagnosis to metastasis strongly impacts on patients’ outcome and above all that the first metastatic event is an important factor in defining the prognosis of patients treated with curative intent and it will help in the treatment-decision making process following metastatic progression. Further studies addressing this topic are imperative to find additional parameter to stratify men with PCa into prognostic groups according to their metastatic disease. Moreover, studies investigating the biologic mechanisms underlying metastatic spread to specific locations are also needed. All these data might have important implications for the development of novel therapeutic approaches targeting the specific metastatic site that will help in selecting the optimal therapy for individual patients according to the metastatic disease they will experience.

In PCa patients initially treated with curative intent, the PCa-specific survival strongly depends on the time after metastatic progression and the first location of metastasis. Thus, metastatic site may confer a differential prognostic impact and may be used to identify patients at the highest risk of death. Our results provide the conceptual framework for treating patients according to the metastatic disease and advance arguments to introduce location of metastasis as a research parameter in PCa studies.