Is extended pelvic lymph node dissection really required for staging of prostate cancer in the psma-pet era?

An extended pelvic lymph node dissection (ePLND) at time of radical prostatectomy remains a recommended approach by most international prostate cancer guidelines. Enthusiasts for ePLND argue

that it provides optimal staging compared to any imaging with possible oncological benefit and helps patient selection for early salvage therapies. The overall benefit of ePLND to a

patient, when balancing the risks of complications and the absence of level 1 evidence of improved long term prostate cancer specific survival outcomes is uncertain. However, does knowledge

of some, but not all, pelvic lymph node histopathology (N-stage) following an ePLND REALLY justify the additional risks? Prospective trials have examined the performance of Prostate Specific

Membrane Antigen (PSMA)-PET for lymph node staging compared to ePLND [1, 2]. PSMA-PET has a high specificity (95%) and positive predictive value (PPV; 87%) to detect lymph node metastases

in high (specificity 93%, PPV 81%) and intermediate (specificity 96%, PPV 93%) risk patients [1, 2]. Positive lymph nodes on PSMA-PET can indicate greater histopathological lymph node burden

than negative PSMA-PET and the incorporation of positive PSMA-PET findings into established nomograms has also been shown to improve their discriminative ability [3]. Therefore, a positive

PSMA-PET adds value for patient management and may identify metastases outside the boundaries of an ePLND. The impact of a false negative PSMA-PET result is a concern for clinicians. The

sensitivity of PSMA-PET (40–58%) [1, 2] is higher than CT and MRI. Reassuringly, the negative predictive value (NPV) is 75–79%. Within both studies, the NPV (96%, 87%) was higher in

intermediate risk patients. Novel nomograms may further enhance patient selection for ePLND. They have been shown to be applicable to all patients (regardless of MRI use) and demonstrate

superior discriminative ability than older nomograms [4]. Furthermore, no metastases were found in patients with intermediate risk CAPRA scores, negative PSMA-PET and mpMRI PIRADS score of

<5 with no mpMRI evidence of seminal vesicle invasion [5]. Therefore, combining negative PSMA-PET with clinical information [5] and nomograms (to indicate lymph node invasion prevalence)

may serve to reduce unnecessary ePLND further [3, 4]. PSMA-PET lymph node staging performance in _HIGH-RISK_ patients is sub-optimal (sensitivity 51%, NPV 73%) [1]. However, NPV is

influenced by prevalence of lymph node invasion, where NPV of 99%, 87 and 84% are reported for prevalences of 5%, 20 and 40%, respectively. Therefore, the use of nomogram cutoffs to guide

ePLND selection may be superseded by this multifaceted, bespoke approach for individual patients. Gold standard staging should sample all metastasis sites, yet it has been clinically

acceptable for the usual ePLND template to miss up to one third of pelvic metastases according to SPECT/CT/MRI with intraoperative gamma probe localisation [6]. Additionally,

histopathological evaluation has limitations, detecting less positive lymph nodes than a combined molecular analysis (PSA qPCR within lymph nodes; 23% vs 52%) [7]. Within both studies,

missed metastases were outside the usual ePLND template (common iliac 16–37%, para-aortic/caval 12%, pre-sacral/para-rectal 8%). PSMA-PET has confirmed anatomical limitations of ePLND, where

up to 47% of patients with lymph node metastases would fall outside the ePLND template [8]. Technical expertise required for ePLND can also influence outcomes [9]. A sub-group comparison

between pre-operative and post-operative PSMA-PET available for 37% of patients showed that 81% of patients with PSMA-PET suggestive of pelvic lymph node metastases on pre-operative staging

had positive lymph nodes on restaging, of which 57% were persistent and 24% were recurrent to new pelvic sites [9]. A similar post-operative outcome for biochemical persistence after surgery

was observed in the Hope study [2]. Use of ePLND as staging method carries morbidity, including perioperative complications (in up to 15% of patients), longer operating time, thromboembolic

disease (6–10 fold increase), lymphocele formation, and potentially longer time in hospital [10]. Longer-term morbidity from the LAPPRO trial reported that patient reported moderate to

severe lower limb and genital lymphoedema for 13.7% at 3 months (adjusted Risk Ratio 6.9) if they received ePLND causing significantly worse quality of life (adjusted for incontinence and

erectile dysfunction). Symptoms remained at 12 and 24 months and were higher than doctor reported measures (4–5% for ePLND, 0.5–1.5% for no ePLND). ePLND should not be mandated for any

patients undergoing surgery, many factors should be considered in the PSMA PET era (Table 1). So, what is the optimal staging modality for prostate cancer patients? It is clear that risk

calculators and PSMA-PET are complementary and should be used together to inform patient selection for ePLND. Therefore, we propose some alternative care pathways instead of routine ePLND. A

positive PSMA-PET for staging at diagnosis, may prompt a plan for post-operative pelvic lymph node radiotherapy, either after an ePLND to confirm pN1 or no ePLND if pN1 is assumed from the

PSMA-PET. In this scenario, radical prostatectomy is largely for local control, until trials assessing the role of surgery in oligometastatic disease are available. Radiotherapy

incorporating pelvic lymph nodes is likely to be more oncologically effective than ePLND (due to wider coverage outside surgical template), whilst limiting morbidity such as lymphoedema,

especially in the absence of a prior ePLND [10]. For patients with a negative pre-operative PSMA-PET, an ePLND should not be mandatory, even in high risk disease. Instead, underlying lymph

node invasion prevalence should be considered to guide decision-making. If predicted LNI prevalence is high, a negative PSMA-PET should prompt the discussion about the risks and benefits of

ePLND due to sub-optimal detection of lymph node metastasis with both ePLND and PSMA-PET. Ideally, a post-operative plan made a priori, with adjuvant or early salvage radiotherapy to be

considered in the event of post-operative PSA persistence or recurrence. For intermediate risk patients, (low prevalence) with a negative PSMA-PET, ePLND can be omitted with almost 90%

confidence that significant metastases will not be missed [1], potentially with even higher confidence if a PIRADS < 5 lesion is present [5]. In the absence of contemporary level 1

evidence that early knowledge of the histological pelvic lymph node status improves outcomes with adjuvant therapy compared to an early-salvage approach, especially in a PSMA-PET triaged

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supported by a Clinician Research Fellowship from the Metro North Office of Research, Queensland Health and Research Support Package from The University of Queensland. FUNDING Open Access

funding enabled and organized by CAUL and its Member Institutions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Royal Brisbane and Women’s Hospital, Department of Urology, Brisbane, QLD,

Australia Matthew J. Roberts & John W. Yaxley * The University of Queensland, UQ Centre for Clinical Research, Brisbane, QLD, Australia Matthew J. Roberts * The University of Queensland,

Faculty of Medicine, Brisbane, QLD, Australia Matthew J. Roberts & John W. Yaxley * The Wesley Hospital, Brisbane, QLD, Australia John W. Yaxley * Department of Urology, Institute of

Clinical Science, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Johan Stranne * Department of Urology, Region Västra Götaland, Sahlgrenska University Hospital,

Gothenburg, Sweden Johan Stranne * Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Inge M. van Oort * Martini-Klinik Prostate Cancer Center, University

Hospital Hamburg Eppendorf, Hamburg, Germany Derya Tilki * Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany Derya Tilki * Department of Urology, Koc University

Hospital, Istanbul, Turkey Derya Tilki Authors * Matthew J. Roberts View author publications You can also search for this author inPubMed Google Scholar * John W. Yaxley View author

publications You can also search for this author inPubMed Google Scholar * Johan Stranne View author publications You can also search for this author inPubMed Google Scholar * Inge M. van

Oort View author publications You can also search for this author inPubMed Google Scholar * Derya Tilki View author publications You can also search for this author inPubMed Google Scholar

CONTRIBUTIONS MJR wrote the manuscript; JWY, JS, IMO and DT revised and edited the manuscript for important intellectual content. CORRESPONDING AUTHOR Correspondence to Matthew J. Roberts.

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and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Roberts, M.J., Yaxley, J.W., Stranne, J. _et al._ Is extended pelvic lymph node dissection REALLY required for staging of prostate cancer

in the PSMA-PET era?. _Prostate Cancer Prostatic Dis_ 28, 345–347 (2025). https://doi.org/10.1038/s41391-024-00821-3 Download citation * Received: 29 January 2024 * Revised: 04 March 2024 *

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