Lymph Node Dissection Remains Standard for Patients With UTUC

The recently released American Urological Association/Society of Urologic Oncology guideline on the diagnosis and management of non-metastatic upper tract urothelial carcinoma (UTUC) includes 2 recommendations specific to the indication for lymph node dissection (LND).¹

“For patients with low-risk UTUC, clinicians may perform LND at time of nephroureterectomy or ureterectomy,” according to the guideline, a position that received a conditional recommendation with grade C-level evidence. The recommendation is based on limited data, however, and no randomized, controlled trials support a benefit. The panel determined that “LND may be considered at time of nephroureterectomy or ureterectomy at the discretion of the clinician according to clinically or radiographically suspicious regional lymphadenopathy or other intraoperative findings suggesting more advanced disease for which nodal staging may be warranted,” despite 2 systematic reviews of observational studies that showed no significant difference in oncologic outcomes when LND was performed.^2–3

The second guideline related to LND indicated that “for patients with high-risk UTUC, clinicians should perform LND at the time of nephroureterectomy or ureterectomy,” which received a strong recommendation with grade B-level evidence. The recommendation is based on the same systematic review mentioned in the previous paragraph,³ which showed an association of better recurrence-free survival (RFS) in this patient population (hazard ratio, 0.58; 95% CI, 0.40-0.83). Since the guideline was released, there have been 2 additional cohort studies. One study found a significant association between LND and improved overall survival (OS) for patients with ≤cT4N0M0 disease but worse 90-day mortality.⁴ The second study showed a significant association between performing an LND and cancer-specific survival and OS for patients with T3 or T4 disease, though it did not find a benefit for patients with T1 or T2 disease.⁵

The authors noted there have been no studies investigating the distribution of lymph node metastases in UTUC, but based on anatomic principles, the panel recommended various templates related to primary lesions. For pyelocaliceal tumors, dissection should extend from the renal hilum to at least the inferior mesenteric artery along the ipsilateral great vessel (aorta on the left and inferior vena cava on the right). For tumors on the proximal two-thirds of the ureter, dissection should extend from the renal hilum to the aortic bifurcation along the ipsilateral great vessel, and for the distal third of the ureter, dissection should include the obturator and external iliac nodal packets.

In a recent international, multicenter, retrospective, observational study published in the Journal of Urology, Pallauf et al investigated the diagnostic accuracy of conventional cross-sectional imaging in detecting nodal disease.⁵ The researchers compared the clinical N-stage diagnosed by conventional imaging with the pathologic specimen (pN) of lymph node dissection performed during surgery. The study utilized computed tomography (CT) of the chest, abdomen, and pelvis or, in some cases, magnetic resonance imaging with noncontrast chest CT or x-ray. Patients were found to have clinically node-positive disease based on size, number, and morphology of lymph nodes. A total of 865 patients met the study’s inclusion criteria, and 13% of patients had clinical node-positive disease, with 7.9% of patients having a lymph node >1 cm.

Patients with clinically node-positive disease were more likely to be Caucasian, more likely to have advanced cT stage disease, and more suspected of having multifocal disease. They were less likely to have a history of bladder cancer. Almost all (99.7%) patients underwent a radial nephroureterectomy. Of those patients, 37% underwent an open approach, which was more often chosen in patients with clinical node-positive disease (45% vs 36%). The median number of lymph nodes resected was 6, and the authors noted there was no significant difference between those who had clinically node-positive disease and those who did not.

The authors found that 26% of patients had pN positive disease, which was more common in patients who had clinically node-positive disease (49% vs 22%; P<.001). The median number of tumor-positive resected lymph nodes was 2. Locally advanced disease (≥pT2) was more commonly seen in patients with clinically node-positive disease (71% vs 60%; P=.02). The authors noted that 56% of tumors were pelvicalyceal, 30% ureteral, and 14% involved both. Clinically node-positive disease was more often seen in patients with pelvicalyceal tumors compared with those with ureteral tumors. Lymphovascular invasion was also more frequently found in patients with clinically node-positive disease (45% vs 28%; P<.001). The authors noted no significant differences in lymph node density, tumor grading, multifocal disease, concomitant carcinoma in situ disease, variant histology, or surgical margin status. The rate of patients receiving adjuvant chemotherapy was higher in the clinically node-positive cohort (32% vs 14%; P<.001), and RFS at 24 months was higher in the clinically node-negative cohort (74% vs 50%; P<.001). Overall and cancer-specific survival were also higher in the clinically node-negative cohort.

The authors found that of the 224 patients with pathology-proven, node-positive disease, imaging detected 25% and missed 75%. When applying a cutoff of more than 1 cm, imaging detected 17% and missed 83%. These findings translate into a sensitivity of 25% and a specificity of 91%. The positive predictive value (PPV) was 49%, and the negative predictive value (NPV) was 78%. When a cutoff of 1 cm was applied, the sensitivity was 17% and the specificity was 95%. The PPV was 56% and the NPV was 77%. The area under the curve (AUC) for cN staging as a diagnostic test for pathologic node-positive disease with and without the >1 cm cutoff was 0.58 (95% CI, 0.55; 0.61) and 0.56 (95% CI, 0.54; 0.59), respectively. There was no statistically significant difference between the AUCs.

The authors noted that this study, which addressed a critical gap in knowledge, showed that conventional cross-sectional imaging is lacking in the detection of pathologic node-positive disease and has low diagnostic accuracy, while also indicating that suspicion of lymph node tumor invasion should not be based on lymph node size alone. “Conventional cross-sectional imaging works most effectively as a rule-in, but not a rule-out, test. Therefore, lymph node dissection should remain the standard during radical nephroureterectomy to obtain accurate N-staging. However, cN+ could be a strong argument for early systemic treatment,” the authors concluded.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

 

References

1. Coleman JA, Clark PE, Bixler BR, et al. Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline. J Urol. 2023;209(6):1071-1081. doi:10.1097/JU.0000000000003480
2. Guo R, Zhu Y, Xiong G, Li X, Zhang K, Zhou L. Role of lymph node dissection in the management of upper tract urothelial carcinomas: a meta-analysis. BMC Urology. 2018;18:24. doi:10.1186/s12894-018-0336-5
3. Chan VW, Wong CHM, Yuan Y, Teoh JY. Lymph node dissection for upper tract urothelial carcinoma: a systematic review. Arab J Urol. 2020;19(1):37-45. doi:10.1080/2090598X.2020.1791563
4. Piraino JA, Snow ZA, Edwards DC, Hager S, McGreen BH, Diorio GJ. Nephroureterectomy vs. segmental ureterectomy of clinically localized, high-grade, urothelial carcinoma of the ureter: practice patterns and outcomes. Urol Oncol. 2020;38(11):851.e1-851.e10. doi:10.1016/j.urolonc.2020.08.004
5. Zhai TS, Jin L, Zhou Z, et al. Effect of lymph node dissection on stage-specific survival in patients with upper urinary tract urothelial carcinoma treated with nephroureterectomy. BMC Cancer. 2019;19(1):1207. doi:10.1186/s12885-019-6364-z