1 LINFOADENECTOMIA Alessandro Volpe Università del Piemonte Orientale AOU Maggiore della Carità, Novara 1

LND IN RENAL CANCER The value of LND in patients with renal cell carcinoma (RCC) still remains controversial No data have clearly demonstrated which candidates should undergo LND and which template should be used for LND in RCC surgical management Many urologists have abandoned systematic and standardized LND at the time of nephrectomy because of the lack of a proven benefit

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383 RN+LND vs. 389 RN alone OUTCOMES Time-to-progression Overall survival Progression-free survival 383 RN+LND vs. 389 RN alone

pN+ = 4%

Low-risk population All cN0 patients

Prognostic implications of nodal metastasis Positive nodes have been clearly shown to have an independent adverse effect on oncologic outcome, regardless of other prognostic factors The estimated cancer specific survival rates at 1, 5, and 10 yr following radical nephrectomy for patients with pN1 RCC are 52– 72%, 21–38%, and 11–29%, respectively Patients with nodal involvement have a 7.8-fold greater chance of dying from their disease than those without nodal involvement Lymph node stage has even an impact on the survival of patients with established metastatic RCC Lughezzani G et al. Cancer 2009;115:5680–7 Blute ML et al. J Urol 2004;172: 465–9

LNI rates increase with tumor stage

Mean tumor diameter (mm) when one notes that presently there is no curative adjuvant therapy. Extended LND cN+ LND No LND n 531 (51%) 199 (19%) 305 (30%) LN removed 18 6 3 p<0.001 Mean age (ys) 55 60 66 Mean tumor diameter (mm) 81 77 64 pT3ab (%) 56 47 p<0.05 Furhman G3 (%) 30 25 21 5 years CSS (%) 70 61 65 p<0.01 10 years CSS (%) 58 50 44

Can we predict LNI ? - Non standardized LND in 415 cN0 patients - 5 risk factors: Tumor size > 10 cm Fuhrman 3-4 Sarcomatoid component pT3-pT4 Histologic tumor necrosis 169 high-risk patients LNI 38%

cN+ patients “Histologically positive nodes were found in only 42% of patients with enlarged nodes at preoperative CT”

M+ patients

“Patients who can potentially be cured by LND have early lymph node metastasis and no systemic disease” Canfield et al., J Urol 175:864-869, 2006 24

LND in RCC. Which template? Predilection of RCC for early haematogenic dissemination ≈57% TanyN0M1 Directly to the thoracic duct ≈30% Many possible different lymphatic routes in normal retroperitoneal anatomy Collateral lymphatic drainage and invasion of tissue with different lymphatic drainage (e.g. perinephric fat) Isolated metastases in the ipsilateral iliac and supraclavicular nodes ≈10%

RCC: LYMPH NODE LANDING SITES

Distribution of first landing sites with direct tracer injection 28

Some cases of sentinel nodes from RCC outside the known templates RCC = renal cell carcinoma. 29

LND IN RCC: TEMPLATE Lymph node dissection (LND) should include: - (a) for the right kidney, the paracaval, retrocaval, and precaval nodes from the adrenal vein to the level of the inferior mesenteric artery - (b) for the left kidney, the para-aortic and preaortic nodes from the crus of the diaphragm to the inferior mesenteric artery - Interaortocaval nodes (overlapping purple area) should always be removed as well when extended LND is sought

as pN + increased with the number of lymph nodes examined as pN + increased with the number of lymph nodes examined. In RCC, >12 lymph nodes need to be assessed for optimal staging.

p=0.02 In conclusions, C.Terrone et al ,Eur Urol. 2006 33

BACKGROUND AND OBJECTIVES The optimal classification for lymph node staging in RCC is still debated. Aim of the study was to assess the prognostic value of the number of positive LNs using different cut-offs (0 vs. 1 vs. >1 LN+; 0 vs. 1-4 vs >4 LN+). PATIENTS AND METHODS 1550 patients underwent radical nephrectomy and lymphadenectomy for RCC 3 tertiary care centers (Milan, Turin, Novara) November 1983 - December 2012 Prognostic value of the number of LNs: 2009 TNM classification (0 vs. 1 vs.>1 LN+) vs. new proposed classification (0 vs. 1-4 vs >4 LN+) Age Follow up (months) LNs removed LNs involved Median 60.0 57.6 7 3 IQR 52-68 18-130 4-12 1-6   pN0 pN+ Tot pT1a 196 1 197 pT1b 363 12 375 pT2a 172 15 187 pT2b 75 11 86 pT3a 335 79 414 pT3b 154 35 189 pT3c 23 17 40 pT4 25 37 62 1343 207 1550   % pN1 61 3.9 pN2 146 9.4   pN0 pN+ Tot cM0 1145 111 1256 cM1 198 96 294 1343 207 34

Regressor HR 95% CI p pN (1 vs 0) 1.31 (0.93-1.86) 0.119 pN (2 vs 0) 2.76 (2.14-3.56) <0.001 pT (2 vs 1) 2.04 (1.45-2.89) pT (3 vs 1) 3.20 (2.28-4.30) pT (4 vs 1) 6.30 (4.08-9.66) cM (1 vs 0) 4.91 (3.97-6.08) Grade (High vs Low) 1.60 (1.30-1.98) RESULTS The 2009 TNM classification correlates significantly with 5-year CSS only in M1 pts, but not in Mall and M0 pts. The proposed classification correlates significantly with 5-year CSS for Mall and M1 pts, but not for M0 pts. Regressor HR 95% CI p pN (1 vs 0) 1.90 (1.47-2.45) <0.001 pN (2 vs 0) 2.58 (1.84-3.61) pT (2 vs 1) 2.07 (1.47-2.92) pT (3 vs 1) 3.17 (2.36-4.27) pT (4 vs 1) 6.11 (3.95-9.45) cM (1 vs 0) 4.71 (3.80-5.82) Grade (High vs Low) 1.62 (1.32-2.00) CONCLUSIONS The number of positive lymph nodes correlates with prognosis after RN in RCC, especially in patients with distant metastases. The current TNM classification of nodal involvement should be modified.

n = 850; TanyN0–1Many RCC + LND (1987-2011) 90% 15 nodes