Surgeons Perspective: LN as a Draining Pattern Jose A. Karam, MD, FACS Associate Professor Department of Urology
Disclosures EMD Serono, Pfizer, Novartis: Advisory board/consultant
Disclosures I perform lymph node dissection in selected patients
Why Even Bother with Lymph Node Dissection?
A BIT OF HISTORY
Historical Studies on Lymph Nodes Nuck A. 1692 Mascagni P. 1787 Poirier P, Cuneo B. 1904 Kubik S. 2006
LND BASED ON SENTINEL NODE MAPPING
Sentinel Lymph Nodes-Pilot Study N=8 99m Tc colloid Lymphoscintigraphy SPECT/CT Bex A. Eur J Nucl Med Mol Imaging. 2010
Bex A et al Sentinel Lymph Nodes 20 patients (16 ccrcc) 14 patients with at least 1 SNL (Total SNL=26) Sherif A et al 11 patients (all ccrcc) 10 patients with at least 1 SNL (Total SNL=32) Bex A. World J Urol. 2011 Sherif A. BJU Int. 2012
Issues to Keep in Mind in Sentinel Node Studies Size of tumor Dose of radiotracer Location of tracer injection (periphery vs center) Tumors can undergo different levels of lymphangiogenesis causing significant variations in lymphatic remodeling Timing of lymphoscintigraphy Preoperative SPECT/CT type Intraoperative sampling (in situ vs ex situ) Padera TP. Science. 2002 Karmali R. BJU Int. 2014
Summary of Renal Lymphatic Drainage Right Kidney Left Kidney Anterior Efferent Lymphatic Vessels A. Paracaval B. Precaval C. Interaortocaval a. Retrocaval D. Preaortic E. Para-aortic Posterior Efferent Lymphatic Vessels A. Paracaval a. Retrocaval C. Interaortocaval - Thoracic duct D. Para-aortic b. Retroaortic - Thoracic duct Karmali R. BJU Int. 2014
Silvester CF. Am J Anat. 1912 Job TT. Am J Anat. 1918 Engeset TA. J Anat. 1959 Roddenberry H. Anat Rec. 1967 Lympho-Venous Communications (Animals) Primate Rat Primate
Drainage into Thoracic Duct Drainage into thoracic duct without any retroperitoneal node metastasis 4 patients underwent lymphoscintigraphy and SPECT/CT Early lymphatic drainage into the thoracic duct 1 patient had no retroperitoneal metastasis Assouad J. Lymphology. 2006 Assouad J. Eur J Cardiothorac Surg. 2007 Brouwer OR. Lymphat Res Biol 2013
Other Techniques for Sentinel Nodes FDG PET High specificity (100%), low sensitivity (75%) for detecting lymph node metastasis Lymphotropic nanoparticle-enhanced MRI High specificity (100%) and sensitivity (95.5%) PET/MRI (preclinical animal models) using 89 Zrfurmoxytol Kang DE. J Urol. 2004 Guimaraes AR. Urology. 2008 Thorek DL. Nature Commun. 2014
Future of Sentinel Node Mapping? IndoCyanine Green (ICG) with Near-Infrared Imaging (NIR) Used/studied in: Uterine/cervical cancers Melanoma Breast cancer Lung cancer
Proposed Protocol-MD Anderson Patients at high-risk of lymph node metastasis Clinical stage T2 or higher, fat invasion, or renal vein/ivc invasion Methods: CT renal protocol will be performed on all patients preoperatively Sentinel lymph node mapping will be performed on all patients intraoperatively using ICG RPLND will be performed on all patients CT findings and sentinel lymph node mapping results will be correlated with postoperative pathology evaluation
LND BASED ON PREOPERATIVE FACTORS
Preoperative Prediction of pn+ (2007) 4,658 patients 12 institutions (1984-2001) pt3-4 in ~30% pn+ in 207 (4.2%)-N nodes removed? M+? Hilar LND only Hutterer GC. Int J Cancer. 2007
Preoperative Prediction of pn+ (2007) AUC= 78.4% Hutterer GC. Int J Cancer. 2007
Preoperative Prediction of pn+ (2013) 1,983 patients, single-institution (1987-2011) No LND (n= 1109, 55.9%) Limited LND (n= 394, 19.9%) Side-specific LND (n= 293, 14.8%) Extended LND (n= 187, 9.4%) Capitanio U. BJU Int. 2013
Preoperative Prediction of pn+ (2013) ct3-4 = 9.6% cn1 = 12.9% M1 = 12.1% pn+ or LN progression = 8.8% Capitanio U. BJU Int. 2013
Preoperative Prediction of pn+ (2013) Accuracy 86.9% Capitanio U. BJU Int. 2013
Preoperative Prediction of pn+ (2015) 1,270 patients with M0 RCC 564 had RPLND (cn+ in 28.7%) 131 patients (23%) had pn+ Babaian KN. J Urol. 2015
Preoperative Prediction of pn+ (2015) Variable OR (95% CI) P ECOG PS (1 or greater vs 0) 2.03 (1.12-3.70) 0.02 cn stage (cn1 vs cn0) 16.58 (9.04-30.40) <0.0001 Local symptoms (yes vs no) 3.29 (1.59-6.80) 0.001 LDH (increased vs normal) 2.56 (1.37-4.76) 0.003 Babaian KN. J Urol. 2015
Nomogram Predicting Probability Of LN Metastasis C-index 0.89 Babaian KN. J Urol. 2015
Radiographic Prediction of pn+ Mayo Clinic 220 patients RN+LND (2000 to 2010) Two variables associated with pn+ Maximum LN short axis diameter (OR 1.19) Radiographic perinephric/sinus fat invasion (OR 44.64) AUC 0.85 Gershman B. BJU Int. 2016
LND BASED ON INTRAOPERATIVE FACTORS
1652 patients (1970-2000) ccrcc cn0m0 had radical nephrectomy 955 patients had concurrent LND pn1: 57 (3%) pn2: 11 (1%) Blute ML. J Urol. 2004
Intraoperative Predictors of pn+ Feature OR (95% CI) p Grade 3+4 (vs. 1+2) 5.25 (1.99 13.82) <0.001 Sarcomatoid component 4.11 (2.08 8.12) <0.001 Tumor 10 cm 2.17 (1.27 3.70) 0.005 pt3+pt4 (vs. pt1+pt2) 2.00 (1.13 3.55) 0.017 Histological tumor necrosis 1.86 (1.00 3.48) 0.051 Blute ML. J Urol. 2004
Number of Features Associated with pn+ Number of Features pn0 pn+ 0 726 (99.6) 3 (0.4) 1 299 (99.0) 3 (1.0) 2 264 (95.7) 12 (4.4) 3 183 (87.6) 26 (12.4) 4 105 (86.8) 16 (13.2) 5 7 (46.7) 8 (53.3) Blute ML. J Urol. 2004
Validation Study 415 patients ccrcc (2002-2006) had radical nephrectomy 169 patients had 2 high risk features on intraoperative pathology 64 (38%) had pn+ Crispen PL. Eur Urol. 2011
Keep in Mind 35% of the patients had M1 disease Median number of lymph nodes = 6 (IQR: 3 13) Crispen PL. Eur Urol. 2011
Number Of Risk Factors And Presence Of Positive Lymph Nodes Number Of Positive Risk Factors Percentage Of Total Patients Percentage Of Patients With Positive Lymph Nodes 2 21% (35/169) 20% (7/35) 3 42% (71/169) 37% (26/71) 4 31% (53/169) 49% (26/53) 5 6% (10/169) 50% (5/10) Crispen PL. Eur Urol. 2011
Location Of Positive Lymph Nodes Based On Side Of Primary Tumor Crispen PL. Eur Urol. 2011
OUTCOMES FOR CONCURRENT LND IN N+MO PATIENTS AT TIME OF NEPHRECTOMY
Survival after Concurrent LND for pn+m0 MD Anderson Cancer Center 2,521 patients M0 (1995-2009) had RN 68 patients pn+ Delacroix SE. J Urol. 2011
Survival after Concurrent LND for pn+m0 5-year OS = 37% Median 32 months 5-year DSS = 39% Median 32 months Delacroix SE. J Urol. 2011
Survival after Concurrent LND for pn+m0 Surgery could help a group of patients with pn+ M0 Papillary histology Complete resection Low number of positive nodes Absence of sarcomatoid dedifferentiation ECOG PS 0 or 1 Delacroix SE. J Urol. 2011
Survival after Concurrent LND for pn+m0 Mayo Clinic 138 patients with isolated pn1m0 RCC Median time to metastases 4.2 months 5-year CSS 26% 5-year OS 25% Gershman B. Eur Urol. 2017
Survival after Concurrent LND for pn+m0 Poor prognostic indicators: Symptoms at presentation Clear cell and collecting duct/nos pt3b/c pt4 Coagulative tumor necrosis Gershman B. Eur Urol. 2017
OUTCOMES FOR SALVAGE LND IN N+ PATIENTS, AFTER NEPHRECTOMY
Salvage LND at Recurrence-1 MD Anderson Cancer Center Databases of patients who had partial or radical nephrectomy (>6,000 patients) 41 patients (<1%) with isolated LN recurrence after radical nephrectomy 5-yr CSS 50% Thomas AZ. J Urol. 2015
Salvage LND at Recurrence-2 Mayo, Moffitt, Roswell Park, McGill Databases of patients who had radical nephrectomy (>5,000 patients) 50 patients (<1%) with isolated LN recurrence after radical nephrectomy 5-yr PFS 35.4% Russell CM. J Urol. 2015
Potential Algorithm cn1 Yes LND (Concurrent) N status at time of RN in M0 cn0 No LND Later pn1 M0 (<1%) Yes LND (Salvage) M1 No LND
Take Home Messages Need to refine sentinel node mapping (Use ICG?) LN involvement is usually a harbinger of systemic disease In cn0m0, is there a difference in survival for immediate LND for pn+ versus salvage LND for pnx with later LN recurrence? LND is mostly diagnostic Might help put the rare patient with pt1-2pn1 on adjuvant trials LND is rarely therapeutic -in select cases (LN-mets-only phenotype?) Papillary, low volume nodal disease, good PS, no sarcomatoid
Questions? JAKaram@mdanderson.org