Pathologic Lymph Node-positive Prostate Cancer: Some Answers … with Many More Questions.

A decade ago, prostate cancer (PCa) involving lymph nodes (pN1 stage) at the time of either diagnostic pelvic lymph node dissection (PLND) or radical prostatectomy (RP) was thought to be reflective of systemically disseminated disease. When found at diagnostic PLND, positive nodes might disqualify a man from curative RP and instead lead to treatment by external beam radiotherapy (EBRT) combined with systemic androgen deprivation therapy (ADT). When found at RP, pN1 status was often a trigger for immediate ADT. Thismanagement strategywas supportedby the results of Eastern Cooperative Oncology Group trial 3886, which demonstrated improved overall survival (OS) and cancerspecific survival (CSS) formenwith pN1 disease after RPwho underwent immediate (rather than deferred) ADT [1,2]. Emerging evidence, however, has shed new light on pN1 PCa at RP and has generated important insights into improving disease management for this complex disease state. Owing to stage migration secondary to less frequent prostate-specific antigen screening and increasing surgical selection bias towards high-risk PCa, pN1 PCa is likely to become increasingly prevalent. Pierorazio et al [3], reporting on 505 pN1 patients from Johns Hopkins, found 10-yr CSS rates of 72–82% (depending on treatment era) even though 52% of men never underwent secondary EBRT or ADT. Decreased CSS was predicted by pathologic Gleason sum and burden of lymph node positivity (two or more nodes). Touijer et al [4], reporting on 369 pN1 patients from theMemorial Sloan Kettering Cancer Center, observed 10-yr CSS of 72% (only 11% of these men received adjuvant ADT). Risk factors for distant metastasis and cancer-specific mortality in this series were pathologic Gleason sum and three or more positive lymph nodes. Seiler et al [5] reported that for 88 pN1 patients from the University of Bern the 10yr CSS was 58% overall in a series in which only 5% of men received adjuvant ADT. Two or more positive lymph nodes was an adverse predictor of CSS. In an interesting analytic regression-tree approach for a combined series of 1107 pN1 patients from the Mayo Clinic and San Raffaele Hospital, Abdollah et al [6] found that the men most likely to benefit from adjuvant EBRT were those with three or more positive nodes. In summary, pN1 is not uniformly lethal. It can be associated with excellent CSS, even in the absence of immediate treatment (and sometimes without any secondary treatment whatsoever). Second, pN1 PCa is heterogeneous: different clinical subtypes (both prognosis and potential response to treatment) are defined by the burden of cancer-involved lymph nodes and pathologic Gleason sum. In this issue of European Urology, Nini et al make an important contribution to our understanding of the natural history of pN1 disease by characterizing oncologic outcomes according to thesiteof subsequent clinical recurrence [7]. Ina series of 800 pN1 patients at San Raffaele Hospital (87% of whom underwent adjuvant EBRT and/or ADT, in contrast to the series described above) 370 men went on to experience biochemical recurrence. Among these 370 men, the first site of clinical recurrence was an independent predictor of CSS. In those with prostatic bed or pelvic nodal recurrence, 5-yr CSS was 79%; retroperitoneal nodal recurrence, 76%; skeletal recurrence, 51%; and visceral recurrence, 35%. These findings closely parallel observations by Moschini et al [8], who studied 1011 pN1 men from the Mayo Clinic and found that CSSdependedon the location of clinical recurrence,with the best CSS for local and/or pelvic nodal recurrence, E U RO P E AN URO LOGY 6 8 ( 2 0 1 5 ) 7 8 5 – 7 8 6