A retrospective analysis of the prognosis of prostate cancer patients with lymph node involvement on MR lymphography: who might be cured

Lymph node metastases in prostate cancer patients can only be detected with conventional imaging methods as computed tomography (CT) or magnetic resonance imaging (MRI) when nodal enlargement exists, which does not occur until late in the disease process [1]. Nodal involvement is therefore generally detected through a lymph node dissection. Patients with nodal involvement are historically considered to be incurable [2]. However, several studies have shown that their prognosis is highly variable [3, 4]. Patients with a low nodal metastastic tumor burden have a favorable outcome after prostatectomy and lymph node dissection. They can remain disease-free for many years [2].

The development of new imaging methods, such as MR lymphography (MRL), has created the opportunity to detect lymph node metastases at an early stage, in non-enlarged lymph nodes [5]. MRL is a technique that uses the contrast agent ferumoxtran-10 to enhance MRI. This method has a sensitivity of 80-100% and a specificity of 87-99% for the detection of involved lymph nodes in prostate cancer [6, 7].

Patients in whom lymph node metastases are diagnosed non-invasively at an early stage, before enlargement of the lymph node occurs, form a new category, with an unknown prognosis. Their outcome might be comparable to that of patients with clinically occult metastases detected by pelvic lymph node dissection.

With this new category of node-positive patients, a treatment dilemma has arisen. Should we pursue cure with surgery or locoregional radiotherapy, and if yes, how should we select those patients that are most likely to benefit? To address this issue, it is necessary to obtain more data are about the course of the disease in these patients.

The purpose of the present study was to investigate the prognosis of CT-negative patients with positive lymph nodes on MRL and to identify a subgroup of MRL positive patients with a good prognosis, who might be candidates for curative treatment.

The presence of lymph node metastases in prostate cancer is a poor prognostic sign [2], and patients with lymph node metastases generally are considered incurable [2, 4]. The present study shows that patients with a negative MRL indeed have a far better outcome than MRL-positive patients. However, within the group of MRL-positive patients, a subgroup could be defined with a better prognosis, consisting of patients with only small nodal metastases. In these patients cure might be pursued, for example by locoregional radiotherapy or resection of the positive nodes.

CT and MRI have a very low sensitivity for the detection of lymph node metastases in prostate cancer [9]. The presence of lymph node metastases is therefore usually detected at pelvic lymph node dissection. However, the development of more accurate imaging methods has created the opportunity to detect lymph node involvement at an early stage, in a non-invasive manner. MRL is a very accurate imaging method, with a sensitivity of 85-100%, which can detect lymph node metastases even in non-enlarged lymph nodes [6, 7].

Thus a new category of patients emerges, whose prognosis and the treatment from which they benefit require further investigation. The present study aimed to take the first steps in describing this group of patients.

MRL-positive patients had a significantly worse prognosis compared to MRL-negative patients. Five-year OS was 57%, which is comparable to the survival of lymph node positive patients treated with androgen suppression therapy alone in other reports [10]. However, patients with small MRL positive lymph nodes (a short axis of the largest positive lymph node of ≤8 mm or a long axis of ≤10 mm), had a 5-year DMFS and OS of more than 70%. This was despite the fact that these patients were treated palliatively. This is comparable to the prognosis of high-risk node-negative patients treated with radiotherapy [11, 12]. Patients in whom all positive lymph nodes had been removed had the best prognosis.

These findings reinforce the results from previous studies investigating outcome after prostatectomy and lymph node dissection. These retrospective studies have shown that patients with limited lymph node involvement have a far better outcome compared to patients with more extensive lymph node involvement [2, 4]. The number of positive lymph nodes [3, 4] and the size of the largest positive lymph node [2] were prognostic factors. Disease-specific survival was 99% at 5 years for patients with a single lymph node metastasis [4], 84% at 15 years for patients with up to 2 positive lymph nodes [3], and over 80% at 5 years for patients in whom the largest positive lymph node was ≤ 10 mm. Five-year recurrence-free survival of the latter group was around 40% [2].

Although patients with limited lymph node involvement seem to have a better outcome compared to patients with more extensive nodal disease, the question remains: can they be cured? The answer may be ‘yes’ for at least part of the MRL-positive patients. The finding of the present study that DMFS is high for patients with limited nodal involvement, indicate a window of opportunity for cure with locoregional treatment, before distant metastases develop. This was also found by Leibel et al., who described the outcome in patients with nodal disease treated with pelvic lymphadenectomy and brachytherapy [13]. N1 (single lymph node metastasis <2 cm) patients had a better DMFS than N2 (multiple lymph node metastases or single lymph node metastasis >2 cm but <5 cm) patients. This is further supported by the results of the above mentioned studies [2‐4]. Our finding that patients in whom all MRL-positive lymph nodes had been removed at pelvic lymph node dissection had a very high 5-year DMFS of 80%, further substantiate this. This is also in line with the findings of several retrospective studies indicating that the larger the extent of a lymph node dissection, and thus the higher the chance of removal of all nodal disease, the better the prognosis [14, 15].

Preferably, only lymph node positive patients without distant micrometastases would be selected for locoregional treatment. The findings of the present study that patients with small MRL-positive lymph nodes less often and less early develop clinically apparent distant metastases, can guide MRL-based patient selection for a potentially curative locoregional treatment. When selecting node positive patients for locoregional treatment with MRL, the size of the short axis of the largest lymph node should be the main selection criterion, as there was significant overlap between the group with a short axis of the largest MRL-positive lymph node of ≤8 mm and the group with a long axis of ≤10 mm, with the short axis being a stronger prognostic factor at ROC analysis.

MRL can yield important progress in locoregional treatment for node positive patients. First, geographical miss of positive lymph nodes can be reduced. Studies using the sentinel node procedure or MRL to map the pattern of lymph drainage in prostate cancer patients, have shown that this is a larger problem than was previously thought. Positive lymph nodes and sentinel nodes were found outside the area of routine lymph node dissection [16], as well as outside the standard target volume for elective pelvis irradiation in more than half of the patients [17, 18]. The possibility to target pathological lymph nodes more accurate, will increase the effectiveness of locoregional treatment in these patients.

Further, for radiotherapy, the use of MRL gives the opportunity to boost the positive lymph nodes. This has shown to be theoretically feasible, using an intensity modulated radiotherapy technique [19]. Dose escalation to the prostate has shown to improve outcome [20], and this may also account for the involved lymph nodes.

A limitation of the present study is the small number of MRL-positive patients. The findings of this study should therefore be interpreted as a first step towards identification of MRL-positive patients with a good prognosis in whom cure might be feasible.

A second limitation is that histopathological examination was negative in 10 of 24 MRL- positive patients. In 4 of these patients, however, the tissue sampling was not representative, because the MRL-positive lymph nodes were not removed, as was shown by a repeated MRL within 3 months after the initial MRL. We elected to include all MRL-positive patients for analysis. This because the aim of the present study was to find prognostic factors based on MRL without subsequent histopathological confirmation. This might have influenced our results, certainly as the histopathologically negative patients received a different (curative) treatment. As the group was too small for multivariate analysis, the influence of this factor on outcome relative to that of the prognostic factors found in our study could unfortunately not be investigated.

Whereas lymph node involvement on MRL was a poor prognostic factor, a subgroup of MRL-positive patients with a relatively good prognosis could be identified. Patients with a short axis of the largest lymph node ≤8 mm or a long axis ≤10 mm had a good outcome, comparable to that of high-risk node-negative prostate cancer patients. These seem to be the patients in whom cure might be pursued. Patients in whom all MRL-positive lymph nodes had been resected, had a better prognosis than patients in whom part of the nodal disease was left in situ. This encourages the application of a locoregional curative treatment in these patients.