Friday, July 11, 2014

Lymph Node Dissection for Renal Cancer

CT Scan showing a large right renal mass and enlarged
lymph node between the kidney and inferior vena cava.
Lymph node dissection (LND) is an integral portion of many cancer surgeries including those of the colon, breast and prostate. However, the role of lymphadenectomy (or lymph node dissection) in the management of renal cell carcinoma (RCC) remains controversial mainly because of the poor overall survival for patients with metastatic RCC in their lymph nodes or beyond.  The cancer-specific survival (CSS) for these patients is in the range of 5-35% at 5 years.[1]

In this blog we will highlight some of the important data regarding LND and RCC.

Certain or Uncertain Lymphatic Drainage of Renal Cell Carcinoma?

Early anatomic studies demonstrate a system of predictable lymphatic drainage from the kidneys; with the right kidney draining through the precaval, retrocaval, and interaortocaval nodal groups from right to left, and the left kidney draining to left-sided only regions including para-aortic, preaortic, and retroaortic nodal groups.[2]  Surgical series confirmed this drainage pattern with primary landing zones (paracaval for right, paraaortic for left) being involved prior to involvement of additional nodes.  However, they also note that perihilar lymph nodes (lymph nodes closest to the kidney) are rarely involved and often skipped, with 45% of hilar nodes negative despite other ipsilateral lymph nodes involved.[3]

Retroperitoneal lymph node locations.  From Crispen et al.
European Urology, 2011. [3]
However, looking at the epidemiologic data, upwards of 30% of patients with RCC will present with metastatic disease; however, only 3-10% will have lymph node involvement only.  Of the patients with metastatic disease, upwards of 40% will have no lymph node involvement - indicating that RCC, unlike other cancer, can spread without first involving the regional lymph nodes.  

Correlation of Clinically-Positive Lymph Nodes to Pathologically-Positive Lymph Nodes

Radical nephrectomy specimen
with tumor and lymph node that
correlate to the CT Scan above.
The subsequent consideration is: how well do we predict lymph node positive disease?  The answer is pretty poorly.  Many patients with large and/or bulky kidney tumors will have enlarged lymph nodes on imaging. However, the correlation with enlarged lymph nodes on imaging and cancer in those nodes is poor.  In fact, enlarged lymph nodes on CT scan correlate to metastatic RCC in only 32-43% of patients and a false-positive rate of 58%.[4-6]  In addition, The false-negative rate is estimated to be 4%, meaning many patients without lymph nodes on imaging will ultimately have positive lymph nodes at the time of surgery.[6]

Improved Staging, Improved Survival?

LND has been demonstrated to improve staging in a number of studies.  Rates of lymph node positive disease have been demonstrated to be higher in patients who had more lymph nodes removed.[7]

While it is generally accepted that LND improves staging, it is not clear if this translates into a tangible survival benefit.  Some studies demonstrate an improvement in cancer-specific survival (CSS) with lymphadenectomy.  This is rooted in the belief that LND may remove metastatic disease and be curative in some patients with lymph node positive disease.[8]

In studies where systematic LND was routinely performed and a benefit was observed:

  • In a study of over 2,500 patients, for those with positive lymph nodes, 22% were disease-free at 44 months [9]
    • Of the recurrences, the majority were detected within 4 months of nephrectomy and 51% were at multiple organ sites
  • In a study of over 500 patients, CSS was significantly better for patients who underwent a systematic, extended lymph node dissection (66%) when compared to those who had only clinically abnormal lymph nodes removed (58%, p<0.01).[10]  
  • In a study on 800 patients, 5% with positive lymph nodes and 9% with positive lymph nodes and metastatic disease:
    • For patients without clinically evident nodal disease, survival was not impacted by LND.
    • For patients with distinct clinical nodal disease, survival was positively impacted by cytoreductive nephrectomy, LND and postoperative immunotherapy.
    • LND was predictive of survival in multivariable analysis of lymph node positive patients.[11]
  • In a study of 10,000 patients in the National SEER (Surveillance, Epidemiology, and End Results) Database:
    • For patients with negative lymph nodes, there was no effect on CSS with increasing extent of LND. 
    • An absolute survival increase of 10 % (39–49 %) at 5 years was seen in patients with one positive lymph node in whom ten lymph nodes were removed indicating that the number of lymph nodes removed correlates to an improvement in CSS.[12]
However, a number of studies fail to find a survival benefit in patients with positive lymph nodes who underwent LND.[13,14]

How about Level 1 Evidence?

The biggest argument against LND is a prospective, randomized trial of LND versus standard radical nephrectomy run by the EORTC (European Organization for Research and Treatment of Cancer) Genitourinary Group.[15]  Nearly 800 patients were randomized to radical nephrectomy alone (n = 389) or nephrectomy plus LND (n = 383). Only 4% of patients had positive lymph nodes and there was no improvement in survival in patients undergoing LND.  However, >70% of the patients had clinically localized and organ-confined (pT1-2) or low-grade RCC, allowing critics to argue that LND would have been unlikely to benefit these patients.  Importantly, there were no differences in complication rates between the two groups - definitively demonstrating that LND does not increase the morbidity of the operation.

Who Should Undergo Lymphadenectomy (LND)?

There are a number of predictive models that identify patients most at risk of having positive lymph nodes at the time of surgery.  Many of these models use criteria like tumor and lymph node size to predict positive lymph nodes; however these models also include pathological features like grade, stage and sarcomatoid features.[16]  Other studies have used pre-operative variables only (clinical tumor stage, clinical nodal status, presence of metastases, and tumor size), however are limited by small number of patients with positive lymph nodes and non-standardized lymph node dissection.[17]

Summary

In general, the evidence is clear that patients with low-risk RCC do not benefit from lymphadenectomy.  These include patients with clinically-localized (T1, 7cm or less) or biopsy-proven, low-grade (Grade 1 or 2) disease.  

LND should be strongly considered in patients with high-risk RCC who have the potential to have positive lymph nodes and therefore benefit from their removal.  These include patients with:

  • Large, clinically-localized tumors: upwards of 40% of cT2 (>7cm) tumors will have pathological T3 disease
  • Locally-invasive tumors: cT3 or cT4 disease
  • Clinically enlarged lymph nodes
  • Limited metastatic disease, especially if an isolated site can be resected
  • Biopsy-proven, high-grade RCC (Grade 3 or 4)
Other considerations:
  • Many radical nephrectomy surgeries can be performed laparoscopically, however LND can be challenging with standard laparoscopy.  Robot-assisted laparoscopy may facilitate lymph node dissection by affording the surgeon more control near the great vessels in the body.
  • There is no, well-agreed upon consensus regarding LND.  While the risks of LND are relatively low, not all patients will benefit from a LND and careful thought should go into the decision to perform a LND.

Phillip M. Pierorazio, MD is an Assistant Professor of Urology & Oncology, Director of the DISSRM Registry for Kidney Cancer and Director of the Division of Testicular Cancer at the Brady Urological Institute at Johns Hopkins.  








[1] Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer. 2003 Jun 15;97(12):2995-3002.
[2] Parker AE (1935) Studies on the main posterior lymph channels of the abdomen and their connections with the lymphatics of the genito-urinary system. Am J Anat 56:409–443
[3] Crispen PL, Breau RH, Allmer C et al (2011) Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates. Eur Urol 59:18–23
[4] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469
[5] Hutterer GC, Patard JJ, Perrotte P, Ionescu C, de La Taille A, Salomon L, Verhoest G, Tostain J, Cindolo L, Ficarra V, Artibani W, Schips L, Zigeuner R, Mulders PF, Valeri A, Chautard D, Descotes JL, Rambeaud JJ, Mejean A, Karakiewicz PI. Patients with renal cell carcinoma nodal metastases can be accurately identified: external validation of a new nomogram.  Int J Cancer. 2007 Dec 1;121(11):2556-61.
[6] Studer UE, Scherz S, Scheidegger J et al (1990) Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 144:243–245.
[7] Terrone C, Guercio S, De Luca S, Poggio M, Castelli E, Scoffone C, Tarabuzzi R, Scarpa RM, Fontana D, Rocca Rossetti S. The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int. 2003 Jan;91(1):37-40.
[8] Freedland SJ, Dekernion JB. Role of lymphadenectomy for patients undergoing radical nephrectomy for renal cell carcinoma. Rev Urol. 2003 Summer;5(3):191-5.
[9]  Delacroix SE Jr, Chapin BF, Chen JJ et al (2011) Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? J Urol 186:1236–1241
[10] Herrlinger A, Schrott KM, Schott G, Sigel A.  What are the benefits of extended dissection of the regional renal lymph nodes in the therapy of renal cell carcinoma.J Urol. 1991 Nov;146(5):1224-7.
[11] Pantuck AJ, Zisman A, Dorey F et al (2003) Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 169:2076–2083
[12] Whitson JM, Harris CR, Reese AC et al (2011) Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol 185:1615–1620.
[13]  Terrone C, Cracco C, Porpiglia F et al (2006) Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 49:324–331
[14] Feuerstein MA, Kent M, Bazzi WM, Bernstein M, Russo P. Analysis of lymph node dissection in patients with ≥7-cm renal tumors. World J Urol. 2014 Jan 9.
[15] Blom JH, van Poppel H, Marechal JM et al (2009) Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 55:28–34
[16] Blute ML, Leibovich BC, Cheville JC et al (2004) A protocol for performing extended lymph node dissection using primary tumor pathological features for patients treated with radical nephrectomy for clear cell renal cell carcinoma. J Urol 172:465–469
[17] Capitanio U, Abdollah F, Matloob R et al (2013) When to perform lymph node dissection in patients with renal cell carcinoma: a novel approach to the preoperative assessment of risk of lymph node invasion at surgery and of lymph node progression during follow-up. BJU Int 112:E59–E66

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