lymph node metastasis

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Editorial: Preoperative PSMA‐targeted PET imaging: more than just a tool for prostate cancer staging?

July 10, 2019/by Michael Gorin

The presence of lymph node metastases at the time of prostate cancer diagnosis has significant implications for treatment. According to current guidelines from the National Comprehensive Cancer Network, men with positive lymph nodes on initial staging imaging should be offered treatment with androgen deprivation (± abiraterone) along with consideration for external beam radiation therapy [1]. In contrast, men with clinically localised high‐ or very‐high‐risk prostate cancer have the option of undergoing radical prostatectomy. Unfortunately, currently available diagnostic imaging modalities (i.e. contrast‐enhanced CT and MRI) fall short in their ability to accurately identify lymph node metastases, which are often small and difficult to discern from other structures within the pelvis. Thus, there exists a conundrum: if we cannot accurately detect lymph node involvement, how can we appropriately manage it?

In this edition of the BJUI, Leeuwen et al. [2] report on the utility of molecular imaging with ⁶⁸Ga‐PSMA‐11 positron emission tomography (PET)/CT in the preoperative staging of men with prostate cancer. To date, the greatest clinical utility of PSMA‐targeted PET has been in the management of men with biochemically recurrent prostate cancer [3]. In the present study by Leeuwen et al. [2], 140 patients with newly diagnosed intermediate‐ or high‐ risk prostate cancer underwent ⁶⁸Ga‐PSMA‐11 PET/CT before radical prostatectomy with extended pelvic lymph node dissection. Surgical pathology served as the reference standard to which findings on ⁶⁸Ga‐PSMA‐11 PET/CT were compared. In total, 27.1% of men were found to have radiotracer uptake in their pelvic lymph nodes, resulting in a sensitivity of 53% and a specificity of 88%. In contrast, multiparametric MRI had a sensitivity of only 14%, albeit with a higher specificity of 99%. These findings are in line with prior studies evaluating the diagnostic performance of PSMA‐targeted PET imaging for preoperative prostate cancer staging [4]. Of greater interest, however, is the authors’ observation that positivity on ⁶⁸Ga‐PSMA‐11 PET/CT was strongly associated with postoperative PSA persistence (i.e. failure to cure). More specifically, after controlling for Gleason score, surgical margin status, and preoperative PSA level, positivity on PET/CT had an odds ratio of 5.87 (95% CI 1.30–26.59) for biochemical persistence. Furthermore, men with pN1 disease and a positive preoperative PET/CT (i.e. true positives) were over three times more likely to experience biochemical persistence than patients with pN1 disease and negative imaging (71.4% vs 21.4%). Thus, PSMA‐targeted PET not only stands to inform clinical staging, but also has the potential to offer independent prognostic information.

A future line of investigation is to explore the biological basis of the authors’ observation regarding PSMA as a prognostic marker. One explanation is that PET/CT identified men with higher volume lymph node metastases (a known prognostic factor), whilst patients with smaller more curable nodes were negative on imaging. After all, the authors state that the imaging test did not detect any pathologically positive lymph nodes <2 mm. Furthermore, only 27% of positive lymph nodes between 2 and 4 mm showed radiotracer uptake. Unfortunately, the authors did not account for differences in the volume of nodal metastases in their analysis. A second possible explanation for the authors’ observation is that PSMA is upregulated through the same signaling pathways that drive an aggressive prostate cancer phenotype, allowing for PSMA expression to provide prognostic information independent of tumour volume. Indeed, others have previously shown that PSMA expression, as measured by immunohistochemistry, corresponds with increasing tumour grade, stage and risk of biochemical failure [5]. Of course, these concepts are not mutually exclusive and further investigation is needed in order for PSMA‐targeted imaging to be rationally applied as a prognostic test.

References

NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer (Version 4.2018). 2018. Accessed November 2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
Leeuwen, PJ, Donswijk, M, Nandurkar, R et al. Gallium‐68‐prostate‐specific membrane antigen (⁶⁸Ga‐PSMA) positron emission tomography (PET)/computed tomography (CT) predicts complete biochemical response from radical prostatectomy and lymph node dissection in intermediate‐ and high‐risk prostate cancer. BJU Int 2019; 124: 62– 8
Han, S, Woo, S, Kim, YJ, Suh, CH. Impact of ⁶⁸Ga‐PSMA PET on the management of patients with prostate cancer: a systematic review and meta‐analysis. Eur Urol 2018; 74: 179– 90
Gorin, MA, Rowe, SP, Patel, HD et al. Prostate specific membrane antigen targeted ¹⁸F‐DCFPyL positron emission tomography/computerized tomography for the preoperative staging of high risk prostate cancer: results of a prospective, phase II, single center study. J Urol 2018; 199: 126– 32
Minner, S, Wittmer, C, Graefen, M et al. High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer. Prostate 2011; 71: 281– 8

Article of the Week: Detecting SNs in patients with BCa intra-operatively

September 13, 2017/by admin Z.9

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study

Firas Aljabery^1,2,*, Ivan Shabo^2,3,4, Hans Olsson^2,5, Oliver Gimm^2,6 and Staffan Jahnson^1,2

¹Department of Urology, Region Östergötland, Linköping University Hospital, Linköping, Sweden, ²Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, sweden ³Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden ⁴Department of Breast and Endocrine Surgery, Karolinska University Hospital, Solna Stockholm, Sweden ⁵Department of Pathology, Region Östergötland, Linköping University Hospital, Linköping, Sweden ⁶Department of Surgery, Region Östergötland, Linköping University Hospital, Linköping, Sweden

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Abstract

Objectives

To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field.

Patients and Methods

We studied 103 patients with BCa pathological stage T1–T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005–2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides.

Results

The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1–12 (12%), T2–20 (19%), T3–48 (47%) and T4–23 (22%). A mean (range) number of 31 (7–68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001).

Conclusion

We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.

Editorial: Positive messages for bladder cancer management in negative sentinel lymph node study

September 13, 2017/by admin Z.9

I encourage you to read the study by Aljabery et al. [1] in this edition of BJUI. Their findings are based on some very solid methodology and I think provide a robust answer to their question, which often in science means a ‘negative’ result. The principle of sentinel lymph node biopsy (SLNB) needs no introduction. It is primarily intended to detect the principal LN draining a tumour, allowing its removal and pathological determination of LN metastasis status in that individual [2].The avoidance of an unnecessary LN dissection (LND) and its associated risks is at the heart of any SLNB strategy. On the other hand, particularly for bladder cancer, there is a recognition that a higher number of LNs removed at the time of surgery confers a survival advantage to patients through more accurate staging [3]. With greater numbers of LNs removed pN0 patients are more likely to be truly N0 and pN1 patients with limited metastases have a greater chance that all disease has been completely excised. Thus, when considering SLNB in bladder cancer there is the usual conflict between maximising oncological benefit and minimising surgical harm.Aljabery et al. [1] present an excellent series of cystectomies with a 100% negative margin rate and mean LN count of 30. The 40% rate of LN involvement, is perhaps partly due to the meticulous triple sectioning of each excised LN. Their SLN technique involved four cystoscopic injections to the bladder wall surrounding the tumour and focused on the biggest lesion in multiple tumour cases. The LNs were removed in their packets and studied after removal from the patient. While this is likely to be a more precise method for determining the site of the SLN, it clearly differs from the approach one would take if trying to avoid LND in negative-SLN cases. Furthermore, examination of LNs was performed after formalin fixation. Typically when using SLN techniques frozen sections are also used to guide surgeons during surgery.The results clearly show that SLNB using radiolabelled nanocolloid does not allow accurate identification of pathologically LN-negative patients who could then avoid a complete LN dissection. Sensitivity of the technique in the detection of positive LNs ranged from 67% to 90% at the various LN stations. Overall, of patients with an identifiable SLN that was negative, 19% of patients had positive LNs elsewhere (81% negative predictive value). Effectively one in five patients who might be reassured by a negative SLN result would in fact have undetected positive LNs left behind if this technique were employed. Furthermore, this estimation does not consider errors likely to be introduced with in situ SLN identification and the use of frozen-section analysis rather than non-time-critical analysis of formalin-fixed sections.In such a dangerous disease such inaccuracy is not tolerable and so I totally agree with the authors’ [1] findings that SLNB of pelvic LNs at the time of radical cystectomy for bladder cancer is not a reliable technique for identifying LN metastasis.The positive messages from this study [1] are worth noting by those learning and undertaking cystectomy. The authors’ meticulous approach to surgery is evident from the methodology described and the accumulation of such a well-characterised series. This must be a contributing factor in achieving a 100% negative surgical margin rate and such consistently high LN yields. This should certainly be the aim of all cystectomists. The appropriate time, skill and patience should be given to this step and it should not be compromised upon, particularly when developing robot-assisted or laparoscopic cystectomy services.The findings that T-stage, N-stage and lymphovascular invasion are linked to survival are not that surprising. However, the use of LN metastatic density as a prognostic marker is interesting, as it is not usually discussed in our multidisciplinary meetings. This measure incorporates nodal tumour burden and the extent of LND. The finding of better outcomes in those with a LN metastatic density of <8% reinforces the message that even in those with LN metastases, removing greater numbers of LNs may improve prognosis. Furthermore, the finding that 30% of unilateral LN-positive tumours also had contralateral LNs settles any arguments for unilateral LN dissections.In a recent systematic review of SLNB in bladder cancer [4], the negative predictive value was found to be 92% compared to 81% in the Aljabery et al. [1] study. The authors of the systematic review suggested that SLNB is a promising technique; perhaps in view of technology advances they reviewed that might improve future outcomes of SLNB. While improvements may be possible, current evidence would not encourage me to consider SLNB using radiolabelled nanocolloid for fear of impairing cancer outcomes.

Congratulations to Aljabery et al. [1] on their work. I hope you find reading their paper as constructive as I did.

Tim Dudderidge
Department of Urology, University Hospital Southampton,
Southampton, Hampshire, UK

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References

1 Aljabery F, Shabo I, Olson H, Gimm O, Jahnson S. Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study. BJU Int 2017; 120: 329–36

2 Gould EA, Winship T, Philbin PH, Kerr HH. Observations on a “sentinel node” in cancer of the parotid. Cancer 1960; 13: 77–8

3 Koppie TM, Vickers AJ, Vora K, Dalbagni G, Bochner BH. Standardization of pelvic lymphadenectomy performed at radical cystectomy. Cancer 2006; 107: 2368–74

4 Liss M, Noguchi J, Lee H, Vera D, Kader AK. Sentinel lymph node biopsy in bladder cancer: systematic review and technology update. Indian J Urol 2015; 31: 170–5

Video: Detecting SNs in patients with BCa intra-operatively

September 13, 2017/by admin Z.9

Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study

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Abstract

Objectives

Patients and Methods

Results

Conclusion

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Article of the Week: Assessing extranodal extension and the size of the largest lymph node metastasis after RP

October 22, 2014/by admin Z.9

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

If you only have time to read one article this week, it should be this one.

Prognosis of patients with pelvic lymph node metastasis following radical prostatectomy: value of extranodal extension and size of the largest lymph node metastasis

Niccolo M. Passoni, Harun Fajkovic*, Evanguelos Xylinas†, Luis Kluth‡, Christian Seitz*, Brian D. Robinson§, Morgan Rouprêt¶, Felix K. Chun‡, Yair Lotan**, Claus G. Roehrborn**, Joseph J. Crivelli§, Pierre I. Karakiewicz††, Douglas S. Scherr§, Michael Rink‡, Markus Graefen‡, Paul Schramek*, Alberto Briganti, Francesco Montorsi, Ashutosh Tewari§ and Shahrokh F. Shariat*§**

Department of Urology, Urological Research Institute, University Vita-Salute San Raffaele, Milan, Italy, *Department of Urology, Medical University of Vienna, Vienna, Austria, †Department of Urology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, University Paris Descartes, ¶Academic Department of Urology of la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Faculté de medicine Pierre et Marie Curie, University Paris VI, Paris, France, ‡Medical Centre Hamburg-Eppendorf, Martini Clinic, Prostate Cancer Center at University Medical Center Hamburg-Eppendorf, Hamburg, Germany, §Department of Urology and Pathology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, **Department of Urology, Southwestern Medical Center, University of Texas, Dallas, TX, USA, and ††Department of Urology, University of Montreal, Montreal, QC, Canada

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OBJECTIVE

To assess the prognostic role of extranodal extension (ENE) and the size of the largest lymph node (LN) metastasis in predicting early biochemical relapse (eBCR) in patients with LN metastasis after radical prostatectomy (RP).

PATIENTS AND METHODS

We evaluated BCR-free survival in men with LN metastases after RP and pelvic LN dissection performed in six high-volume centres.
Multivariable Cox regression tested the role of ENE and diameter of largest LN metastasis in predicting eBCR after adjusting for clinicopathological variables.
We compared the discrimination of multivariable models including ENE, the size of largest LN metastasis and the number of positive LNs.

RESULTS

Overall, 484 patients were included. The median (interquartile range, IQR) follow-up was 16.1 (6–27.5) months. The median (IQR) number of removed LNs was 10 (4–14), and the median (IQR) number of positive LNs was 1 (1–2).
ENE was present in 280 (58%) patients, and 211 (44%) had their largest metastasis >10 mm. Patients with ENE and/or largest metastasis of >10 mm had significantly worse eBCR-free survival (all P < 0.01).
On multivariable analysis, number of positive LNs (≤2 vs >2) and the diameter of LN metastasis (≤10 vs >10 mm), but not ENE, were significant predictors of eBCR (all P < 0.003).
ENE and diameter of LN metastasis increased the area under the curve of a baseline multivariable model (0.663) by 0.016 points.

CONCLUSIONS

The diameter of the largest LN metastasis and the number of positive LNs are independent predictors of eBCR.
Considered together, ENE and the diameter of the largest LN metastasis have less discrimination than the number of positive LNs.

Editorial: Extent of lymph node metastases

October 22, 2014/by Henk G. van der Poel

The role of prostatectomy in lymph node metastasized prostate cancer has been subject to changing opinions. Classically, a nodal dissection was performed as the initial step in the procedure and prostatectomy was avoided in men with cryosection-proven metastases. Biochemical recurrence during the first 3 years occurs in the majority of men with pN1 disease [1]. Early data from randomized trials shows only a 50% prostate cancer-specific survival 12 years after prostatectomy and nodal metastases without immediate adjuvant treatment [2]. Recently, Passoni et al. [3] showed a higher 10-year overall survival of 82.8% in men with nodal metastases, of whom the majority were treated with adjuvant androgen ablation and/or radiotherapy. This percentage is remarkably similar to the treatment arm of the earlier-mentioned study reported by Messing et al. [2], which showed a 10-year disease-specific survival of >80%. At 10 years about half the patients who died, did so from prostate cancer; therefore, although reasonable intermediate range survival can be obtained in men with nodal metastases of prostate cancer, the major cause of death remains prostate cancer when surgery is applied at the age of 65 years. Although adjuvant androgen ablation may improve survival, as suggested by the above-mentioned observations, some men may not experience recurrence after resection of nodal metastases and would experience the toxicity of androgen ablation unnecessarily. The identification of these men would reduce costs and toxicity.

Passoni et al. [3] presented a multicentre study on prognostic factors after prostatectomy for node-positive disease. The number of removed nodes (median 10) seems relatively low compared with the 17 reported in their earlier single-centre study, but may be a good reflection of urological practice in general. By comparison, the percentage of men who underwent adjuvant radiotherapy in the multicentre study was low (16%). Data from da Pozzo et al. [4] suggest that adjuvant radiotherapy may be of benefit in men with limited nodal metastases. It would be of interest to study whether men with a later biochemical recurrence would be those that did experience recurrence only locally and therefore would be those most likely to benefit from adjuvant (or salvage) radiotherapy.

In the current study by Passoni et al. [1] in the BJUI, the follow-up was relatively short (16 months). Earlier data from this author group showed that number of positive nodes and lymph node density were good predictors of cancer-specific survival after prostatectomy. This earlier observation is now confirmed in a multicentre analysis with a different endpoint: biochemical recurrence. What is notable is the fact that this confirmation was obtained in a series of patients with fewer nodes removed. The value of the marker ≤2 positive nodes becomes limited with the observation that this group contained 85% of men in their series. The second marker found, the size of the node, showed a more general distribution but as a single marker had no predictive value. The differences in Harrel’s c values from the base model containing other clinical characteristics are limited and reproducibility of measures needs attention. Still, the observation that extent of nodal metastases is of prognostic value after surgery is notable.

Ideally, markers could predict the absence of further disease progression in men after prostatectomy for nodal metastasized prostate cancer. None of the studied characteristics fulfill this need because at 36 months after prostatectomy the majority of men, even those in the best prognostic group, do experience biochemical recurrence that will result in prostate cancer-related death. Gleason score is a strong predictor of the presence of nodal metastases [5], and some have suggested that nodal Gleason grade is of prognostic value in men with pN+ disease. Until these markers have been further evaluated, it remains important to address the fact that reported cancer-specific survival in most men with pN+ disease is >10 years [6]. Although tempting to speculate that prostatectomy and (extended) lymph node dissection plays a role in this, the almost inevitable development of biochemical recurrence reported in the current study by Passoni et al. [1], even in patients in the best prognostic group, stresses the systemic nature of this disease which will require a multimodality approach in most men at some point.

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Henk G. van der Poel

Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands

References

1 Passoni N, Fajkovic H, Xylinas E. Prognosis of patients with pelvic lymph node metastasis following radical prostatectomy: value of extranodal extension and size of the largest lymph node metastasis. BJU Int 2014; 114: 503–10

2 Messing EM, Manola J, Yao J et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006; 7: 472–9

3 Passoni NM, Abdollah F, Suardi N et al. Head-to-head comparison of lymph node density and number of positive lymph nodes in stratifying the outcome of patients with lymph node-positive prostate cancer submitted to radical prostatectomy and extended lymph node dissection. Urol Oncol 2013; 29: 29.e21–8

4 Da Pozzo LF, Cozzarini C, Briganti A et al. Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur Urol 2009; 55: 1003–11

5 Ross HM, Kryvenko ON, Cowan JE, Simko JP, Wheeler TM, Epstein JI. Do adenocarcinomas of the prostate with Gleason score (GS)</=6 have the potential to metastasize to lymph nodes? Am J Surg Pathol 2012; 36: 1346–52

6 Touijer KA, Mazzola CR, Sjoberg DD, Scardino PT, Eastham JA. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol 2013; 65: 20–5