Aims To assess the lymph node content of anterior prostatic fat (APF) sent routinely at robot-assisted laparoscopic radical prostatectomy (RALP) and the incidence of positive nodes in the extended pelvic lymph node dissection.
Methods Between September 2008 and April 2012, APF excised from 282 patients who underwent RALP was sent for pathological analysis. This tissue was completely embedded and lymph nodes counted.
Results In total, 49/282 (17%) patients had lymph nodes in the APF, median lymph node yield in this tissue was 1 (range 1–5). In four patients, the lymph nodes contained metastatic deposits. These patients did not have positive nodes elsewhere in the extended lymph node dissection.
Conclusions APF contains lymph nodes in 1 in 6 patients and infrequently these may be malignant. APF should always be removed at radical prostatectomy. APF should be routinely sent for pathological analysis.
- Lymph Node Pathology
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Lymph node metastasis is a poor prognostic feature in prostate cancer.1 ,2 Recent European guidelines have recommended that extended pelvic lymph node dissection (ePLND) be performed at radical prostatectomy for localised prostate cancer in selected intermediate risk and all high-risk patients.3 Although ePLND may enhance staging,4 current opinion is divided as to its therapeutic survival benefit. The accepted anatomical dissection template for ePLND includes the external iliac, internal iliac and obturator nodal regions. A few recent studies have illustrated that metastatic lymph nodes may be identified elsewhere in periprostatic tissue outside the standard dissection template including in the anterior prostatic fat (APF).5–9
During radical prostatectomy, the APF is commonly dissected to identify the pubo-prostatic ligaments, the anterior surface of the dorsal vein complex and the bladder neck. Finley et al6 were the first to describe the presence of lymph nodes in the APF after an anatomical dissection at radical prostatectomy. The nodes, however, were an incidental finding; the original purpose of their study was to investigate whether sending the APF was a means of confirming that non-apical positive anterior prostate margins were artifactual. In robotic-assisted laparoscopic radical prostatectomy (RALP), dissecting the APF is considered an essential step to better visualise pelvic anatomy before performing the apical dissection of the prostate.10
In our institution, we remove the APF during RALP. Two surgeons (DAG and EWR) routinely send this tissue for pathological analysis. This study examines the incidence and significance of lymph nodes identified in the APF when submitted for pathological assessment.
All patients who underwent RALP performed by DAG and EWR, between September 2008 and April 2012, were eligible for inclusion in the study. In total, 282 patients had APF specimens sent for analysis. The boundaries of the APF dissection were superiorly the pubic arch, inferiorly the prostate, bladder neck and endo-pelvic fascia and laterally the edges of the prostate. Standard PLND of obturator, internal and external iliac regions was carried out in D'Amico stratified intermediate and high-risk patients. PLND was performed at the beginning of the RALP before removing the APF. Specimens were removed en bloc through the assistant's port and formalin fixed in theatre. Each specimen was embedded in its entirety and examined histologically. The radical prostatectomy specimens were examined in whole mounts. All tissue from the PLND was embedded and examined histologically.
All statistical analyses were performed using statistical software R, V.2.15.3 (The R Foundation for Statistical Computing, Vienna, Austria).11 Fisher's exact test was used to determine whether there was a statistically significant difference in the surgical and pathological data of the cohorts with positive and negative APF lymph nodes. Preoperative MRI of the pelvis was performed as clinically indicated. Prostate MRI scans were evaluated by two uroradiologists prior to RALP. Effectively these scans were interpreted blinded with regards to knowledge of the presence of APF nodes. After surgery, the ability of MRI to detect APF nodes in patients known to have nodes was also retrospectively examined.
Of 282 patients who had APF sent for pathological analysis, 49 (17%) had lymph nodes present within the specimen. MRI did not identify the presence of APF nodes in the 20/49 who underwent the investigation preoperatively even when retrospectively re-examined. Median maximum diameter of APF specimen size was 40 mm (range 15–115), 85% of the specimens taken had a maximum diameter of less than 60 mm. Median lymph node yield within the APF specimens sent was 1 (range 1–5). Metastatic deposits were present in 4/49 (8%) of APF specimens with lymph nodes present. All positive cases had only one lymph node in their APF. The involved lymph nodes ranged in size from 4 to 8 mm and the tumour deposits from 2 to 8 mm. Of the four patients with metastatic APF nodes, three underwent PLND. None of these three patients had positive nodes elsewhere in their PLND.
Median lymph node count at PLND was five nodes (range=0–17). There was no significant difference in the PLND nodal count between patients with nodes in the APF and those without. There was no difference in nodal yield between patients with metastatic lymph nodes and those with benign lymph nodes in the APF. In the cohort with lymph nodes in the APF, 12/49 (24%) underwent PLND. All were negative. Of the 45/233 (19%) patients who underwent PLND in the cohort without lymph nodes in the APF, one patient had positive nodes at PLND.
Table 1 compares the characteristics of patients with metastatic and non-metastatic lymph nodes present in the APF. Patients with metastatic APF lymph nodes present tended to have a larger tumour volume, a higher pathological stage and a higher Gleason score. All four patients with metastatic nodes in the APF had an anterior prostate cancer component. Although the number of patients with metastatic nodes in the APF was low, when compared with patients with benign APF lymph nodes, those with metastatic nodes were significantly more likely to have an anterior tumour location and higher pathological Gleason score (p=0.0023 and 0.00085, respectively).
Table 2 describes the characteristics of patients with positive APF lymph nodes in this series and their postoperative follow-up to date. Of note, patient 4 with low-volume Gleason score 3+3 disease diagnosed preoperatively did not undergo either a preoperative MRI or a PLND but had a metastatic node in his APF. All four patients with positive APF lymph nodes underwent adjuvant therapy. Three of the four patients with metastatic APF nodes were managed with androgen deprivation therapy alone. These patients are free of biochemical recurrence at median follow-up of 24 months.
This study demonstrates that when APF specimens are sent for analysis, lymph nodes may be identified in 1 in 6 patients. Of the patients with APF nodes present, 8% (or 1.4% of all patients) were positive for malignancy even though lymph nodes elsewhere in the PLND were negative. APF is frequently discarded and assumed to be of little clinical significance because it is not included in acknowledged ePLND dissection templates. This study highlights both the need to remove this tissue and the potential for understaging if the entire APF specimen is not sent for pathological analysis as part of a PLND.
Smaller single institutional series examining the presence of lymph nodes in APF taken at robotic radical prostatectomy have demonstrated results consistent with our series.5–7 Nodal detection rates in these studies were between 11.6% and 16.7%. Metastatic detection rates in APF nodes varied between 1.2% and 2.5%. Half of the men with positive APF nodes in these series did not have nodal metastases elsewhere in their PLND.5–7
Recent literature on ePLND has driven trends towards an increase in the number of nodes removed at radical prostatectomy.12 Currently, there is no consensus on the number of nodes required to define the quality of the dissection.13–15 APF nodes adjacent to the primary tumour may be the first site of metastases. Our study has shown that routine analysis of APF specimens may infrequently improve staging and influence management. This information may be particularly relevant in patients understaged preoperatively and who consequently do not undergo an ePLND.
Analysis of prostate specimens in present and previous studies illustrates that patients with metastatic APF nodes tend to have a significant component of carcinoma in the anterior prostate and are associated with higher-risk disease characteristics. This finding needs to be further investigated in appropriately powered studies.
Other studies have examined the presence of periprostatic lymph nodes at open radical prostatectomy. Kothari et al16 and Deng et al17 reported nodal detection rates and nodal malignancy rates of between 0.8% and 4.4% and between 0.3% and 0.6%, respectively. Nodes were identified predominantly around the base of the prostate and not in the anterior prostatic tissue. The majority of patients with metastatic periprostatic lymph nodes in these series did not have metastatic lymph nodes elsewhere in their PLND.16 ,17 These studies were limited by being retrospective studies of archived pathology slides or pathology reports from a time period when examination of specimens for periprostatic lymph nodes was not standard, perhaps accounting for the low nodal detection rates.
Our study did not use immunohistochemistry to analyse the APF, but all the tissue was embedded as palpable nodes were rarely found. A recent study by Perry-Keene et al18 has shown that the mean number of lymph nodes was increased from 3.7 to 10.8 when all the tissue was embedded in pelvic lymphadenectomies. Deng et al reviewed whether enhanced detection of micrometastases in periprostatic tissue could be achieved using immunohistochemistry. Periprostatic lymph nodes were identified in 21/2663 (0.8%) radical prostatectomy specimens; none were identified anterior to the prostate. Of 22 lymph nodes examined with routine H&E staining, five lymph nodes were metastatic. Immunohistochemistry demonstrated micrometastases in an additional 2/17 (12%) lymph nodes initially considered benign. A weakness of this study is that Deng et al17 did not perform immunohistochemistry on the PLND specimens of included patients as a control.17 Serial sectioning and cytokine staining of nodes taken at radical prostatectomy has not been demonstrated to lead to increased detection of prostate cancer metastases.19 Due to the low incidence of periprostatic lymph node micrometastasis, routine immunohistochemistry is unlikely to be practically useful in every case where periprostatic lymph nodes are identified. Immunohistochemistry may have a role in high-risk cases where nodes are identified in the APF.17 In current practice, the pathological analysis of lymph node specimens obtained at radical prostatectomy is subjective20 and the false negative rate for lymph node assessment by pathologists is yet to be quantified. The important question of whether periprostatic lymph nodes are an early site of metastatic spread needs to be addressed in a specifically designed prospective study.
Contemporary imaging modalities are unlikely to identify APF nodes, and in particular discriminate positive nodes. In this study, no APF nodes were identified in preoperative MRI staging studies, but the majority of the APF nodes including all positive nodes were ≤8 mm in maximum diameter, which is below the optimal size resolution for CT or MRI. The sensitivity and specificity of CT and MRI to detect lymph node metastasis despite improvements in technology remains limited, 0.4 and 0.8, respectively.21 Despite this lack of sensitivity, imaging has contributed to identify the accepted major routes of pelvic lymph node drainage; to the common iliac, external iliac, internal iliac, inguinal, sacral and perivesical nodes.22 Additionally, sentinel lymph node studies in prostate cancer using SPECT/CT or MRI have demonstrated that primary landing sites commonly lie outside the region of an ePLND.23 ,24 Cross-sectional imaging, which demonstrates high-grade anterior prostate tumours, may have a role in risk-stratifying patients with potential to have positive APF nodes.
The long-term prognosis for APF node-positive patients is unknown; in this study, with short-term follow-up 3/4 patients received adjuvant therapy and all are currently free of biochemical recurrence. The small numbers of patients with positive nodes mean that further statistical assessment is not possible.
This study did not address the costs related to APF analysis because as far as the authors are aware it currently has no specific tariff. The histological assessment was small as most required no more than three histological blocks. Previous studies have estimated the cost of analysis to be $170,7 but this seems excessive. In cases where PLND is performed, APF analysis is unlikely to contribute a significant uplift in costs.
Lymph nodes may be found during microscopic analysis of APF if all the tissue is embedded. These nodes may infrequently contain metastases and APF should therefore always be removed at radical prostatectomy. This study adds to the literature suggesting an association between anterior tumours, high-risk disease and positive lymph nodes in the APF. The authors therefore conclude that APF specimens may add prognostic information without increasing morbidity or compromising margin rates if routinely sent for pathological analysis in patients with these characteristics. Despite the limitations of retrospective data, the evidence is accumulating to consider including APF tissue in ePLND dissection template sent for pathological analysis.
Take home messages
Lymph nodes may be found during microscopic analysis of anterior prostatic fat if all the tissue is embedded.
These nodes may infrequently contain metastases.
Anterior prostatic fat should therefore always be removed at radical prostatectomy and routinely analysed if sent as a pathology specimen.
The authors thank Robert Bell of the Vancouver Prostate Centre for his help with the statistical analysis and Dr Mark Thornton and Dr Paul Macoubrie, Consultant Radiologists at North Bristol Trust, for reviewing the MRI images.
Contributors JJA and RT contributed to data collection, analysis and manuscript preparation. DAG, AJK, EWR and JO contributed to data analysis and manuscript preparation.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The authors have shared their data in its entirety and declare that there are no additional unpublished data that have been withheld.