Lymphatic drainage in renal cell carcinoma: back to the basics Riaz J. Karmali, Hiroo Suami, Christopher G. Wood* and Jose A. Karam* Departments of Plastic Surgery and *Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Lymphatic drainage in renal cell carcinoma (RCC) is unpredictable, however, basic patterns can be observed in cadaveric and sentinel lymph node mapping studies in patients with RCC. The existence of peripheral lymphovenous communications at the level of the renal vein has been shown in mammals but remains unknown in humans. The sentinel lymph node biopsy technique can be safely applied to map lymphatic drainage patterns in patients with RCC. Further standardisation of sentinel node biopsy techniques is required
Introduction Our understanding of the lymphatic drainage of the kidney has evolved with advances in experimental technique in cadaveric dissections. After Nuck [1] introduced the mercury injection technique, anatomists were able to investigate the lymphatic system in detail through cadaveric dissection experiments (Fig. 1A,B) [2]. Sappey [3] laid the foundation of lymphatic anatomy with his series of mercury injection studies on specific organ systems. After mercury injection techniques were dropped because of their toxicity, they were replaced by oil-based dye injection techniques developed by Gerota [4]. Stahr [5] adapted Gerota’s injection method to investigate the superficial and deep lymphatic system in the kidney. Poirier and Cuneo [6] traced efferent drainage pathways to the para-aortic, paracaval and interaortocaval lymph nodes (Fig. 1C). Ssysganow [7] then studied the interconnections of these retroperitoneal nodes. Parker [8] conducted perhaps the most detailed injection experiments on the kidney. The efferent vessels were mapped from the kidney to the thoracic duct. Based on these findings, Kubik [9] proposed an anatomical lymphatic drainage map from the intrarenal lymphatic system to the para-aortic,
to improve the clinical significance of mapping studies. Understanding lymphatic drainage in RCC may lead to an evidence-based consensus on the surgical management of retroperitoneal lymph nodes.
Keywords renal cell cancer, lymphatic drainage, sentinel lymph node, anatomy, lymphovenous communication, lymphadenectomy
preaortic, retroaortic, paracaval, precaval, retrocaval and interaortocaval lymph nodes (Fig. 1D). Autopsy studies have been used to investigate the lymphatics of tumour-bearing kidneys in RCC. Observed patterns of nodal metastasis are varied and have confirmed the unpredictability of lymphatic drainage in RCC. Modern imaging and surgical techniques have enabled surgeons to map sentinel lymph nodes safely in live patients with RCC. This strategy is in the early stages of development, but shows the experimental sophistication involved in the surgical treatment of RCC.
Anatomy The intrarenal lymphatic system originates from the superficial network [6],which runs immediately underneath the fibrous capsule. It drains either directly to the hilum or connects to the deeper cortical lymph capillaries along the capsular arterial branches [9,10]. These lymph vessels do not connect with those in the surrounding adipose capsule, although they may share a common draining node [9]. The lymphatic vessels in the renal parenchyma travel from the cortex and medulla toward the base of the medullary pyramid [9,10]. At the corticomedullary junction, valvular collecting
Fig. 1 (A) Nuck's findings on lymphatic drainage of the kidney through Mercury dissection experiments [1]. (B) Mascagni's findings on lymphatic
▶
drainage of the kidney through Mercury dissection experiments [2]. (C) Poirier and Cuneo's findings on lymphatic drainage of the kidney using an adapted version of Gerota's injection method [6]. (D) Anatomical organisation of the para-aortic, interaortocaval, paracaval lymph nodes based on Kubik [9]. [Kubik S. Foldi's Textbook of Lymphology, 2nd edn, 2006, Chapter 1, p. 106; Figure 1.92. Reproduced with permission from Elsevier GmbH Urban & Fischer Verlag].
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lymph vessels take up fluid from the connective tissue. This occurs along the entire length of the intrarenal lymphatic vessels [10]. The collecting lymph vessels, which emerge from the columns of Bertin, travel in the renal sinus along blood vessels to the hilum [9]. From the right kidney, efferent lymphatic vessels running anterior to the renal vein (anterior bundles) can drain into paracaval, precaval, retrocaval and interaortocaval nodes [8–10]. Retrocaval nodes are located close to the right crus of the diaphragm and connect with the thoracic duct [8–10]. Lymphatics from the hilum running posterior to the renal vein but anterior to the pelvis of the kidney and the renal artery (intravascular bundles) are few in number [8,11]. Their drainage is not well described [8]. Lymphatic vessels travelling posterior to the renal artery (posterior bundles) drain to the paracaval, retrocaval and interaortocaval nodes [8,9]. In some cases, posterior efferent lymphatic vessels have been observed curving superiorly through the right crus of the diaphragm and connecting directly to the thoracic duct without passing through any lymph nodes [8,11]. From the left kidney, efferent lymphatic vessels running anterior to the renal vein can drain into the para-aortic and preaortic nodes [8–10]. These vessels have also been observed to give off branches that run superiorly and connect with posterior draining efferent vessels [8–10]. Intravascular bundles from the left kidney, like the right kidney, are few in number and not clearly described. Posterior efferent lymphatic vessels can drain to the para-aortic and retroaortic nodes [8]. They can also curve superiorly through the left crus of the diaphragm and connect directly to the thoracic duct without passing through any lymph node [8,11,12]. We summarise these anatomical findings on lymphatic drainage of the kidneys in Figure 2. The retroperitoneal lymph nodes are an extensive network of lymphatics between the first and fifth lumbar vertebrae. They serve as the primary landing sites of renal lymph and have unpredictable interconnections before reaching the thoracic duct. In addition to draining the kidney, they also drain the sacrum, mesocolon, testicle, uterus, ovaries, adrenal glands, deep muscles of the dorsal region and the diaphragm [8,13]. Their study in non-tumour-bearing cadavers has revealed potential locoregional and efferent lymphogenous pathways. In a pilot study in patients with RCC in a clinical setting, Bex et al. [14] used preoperative lymphoscintgraphy and single-photon emission CT (SPECT) combined with low-dose CT and intra-operative radio-guided gamma probe sampling to map tumour draining lymph nodes (Fig. 3). In their interim analysis of 14 patients, lymphatic drainage was found to be localised to the para-aortic, paracaval, retrocaval and interaortocaval lymph nodes, with two patients having additional extra-abdominal nodes [15]. Sherif et al. [16] conducted a similar study and reported that right-sided
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tumours drained only to the paracaval and interaortocaval nodes and left-sided tumours drained to the para-aortic nodes (Table 1 [15,16]). Cadaveric injection studies in non-tumour-bearing kidneys have provided a foundational knowledge of renal lymphatic drainage; however, to better understand the movement of lymph within para-aortic, paracaval and interaortocaval nodes and toward the thoracic duct, future anatomical studies should be carried out in clinical and cadaveric settings.
Lymphovenous Communication Further complicating the study of lymphatic drainage in RCC, is the existence of peripheral lymphovenous communication sites. These sites may be located in the inferior vena cava at the level of the renal veins or in renal veins themselves. It has been suggested that haematogenous metastasis in RCC originates from lymphovenous anastomoses between the primary tumour and sentinel lymph nodes [17,18]. A competing theory has suggested that RCC undergoes haematogenous spread with lymph node involvement occurring afterwards [19]. Although metastasis in RCC has been studied extensively, the precise mechanism is still unknown. Silvester [20] injected 25 New World South-American primates with coloured gelatin solutions in the mesenteric or inguinal lymphatic nodes. He observed that the solution never passed through the lumbar or intestinal lymphatic trunks into the thoracic duct or anterior regions of the body, but passed directly into the vena cava at the level of the renal veins (the same was not found in his previous experiment in 16 different species of Old World primates [Fig. 4]). Job [21] extensively investigated these communications in a single species of common rat. He injected 100 specimens with a Berlin blue gelatin mass and India ink and reported inferior vena cava communications in 48 of these cases, iliolumbar communications in two cases, renal vein communications in eight cases and portal vein communications in 27 cases [21]. To confirm these findings, Engeset [22] injected 22 laboratory rats and five wild rats with metallic mercury under the experimental conditions laid out by Job [21], but found no evidence of abdominal lymphovenous communication (Fig. 5). To follow on from that study, Roddenberry and Allen [23] observed abdominal lymphovenous communications at the renal vein and inferior vena cava in two out of eight squirrel primates studied by injection of India ink and radiopaque medium (Fig. 6). Evidence of peripheral lymphovenous communications at the renal vein in certain primates and rodents suggests
Lymphatic drainage in RCC
Fig. 2 Summary of anatomical review of the lymphatic drainage of the kidney: anterior view (top) and posterior view (bottom).
Right Kidney
Left Kidney
this is probably a subspecies characteristic [23]; however, no autopsy series has been published that investigates their existence in humans. It is plausible that peripheral lymphovenous connections arise or disappear at birth, through aging or under pathological conditions. Revisiting
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
this subject, which was once studied in mammals [20–23], may provide insight into the temporality of haematogenous and lymphogenous metastasis in RCC. Most importantly, it would establish a paradigm for the understanding of the pathogenesis of the disease. © 2014 The Authors BJU International © 2014 BJU International
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Fig. 3 Sentinel lymph nodes detected in patients with RCC using lymphoscintigraphy and single-photon emission CT/CT imaging in a pilot study (n = 8) by Bex et al. [14]. [Eur J Nucl Med 2010; 37: 1120; Figure 1. Reproduced with permission from Springer Science+Business Media.]
Table 1 A comparison of patient selection and outcomes in lymphatic mapping attempts in patients with RCC by Bex et al. [15]] and Sherif et al. [16]]. Total Age, patients years (male: female)
Stage
RCC subtype
16 clear-cell 1 papillary 1 papillary/clear-cell 1 chromophobe
Bex et al [15]
20 (6:14)
44–79
pT1a–pT2, pN0, cM0
Sherif et al [16]
11 (6:7)
51–76
T1b–T3b, 11 clear-cell pN0/ + , cM0
Preoperative Total Falsevisualisation no. SNs positive, (right-sided: detected n left-sided primary tumour) 14/20 (10:4)
26
0
10/11 (6:4)
32
0
Distribution of SNs in patients with right-sided tumours
1 para-aortic 0 retroaortic 0 preaortic 6 interaortocaval 1 paracaval 4 retrocaval 0 precaval 1 internal mammary 1 mediastinal 1 right pleural 0 para-aortic 0 retroaortic 0 preaortic 4 interaortocaval 5 paracaval 0 retrocaval 0 precaval
Distribution Complications of SNs in related to SN patients with excision left-sided tumours
4 para-aortic 0 retroaortic 0 preaortic 1 interaortocaval 0 paracaval 0 retrocaval 0 precaval
0
4 para-aortic 0 retroaortic 0 preaortic 0 interaortocaval 0 paracaval 0 retrocaval 0 precaval
0
SN, sentinel node.
Another important venue of lymphovenous communication is through the thoracic duct. Assouad et al. [11] described direct lymphatic drainage into the thoracic duct (without passing through any lymph nodes) in several patients (from both right and left kidneys). As noted by the authors, this has tremendous implications in the field of metastasis in RCC. This direct drainage into the thoracic duct could explain how
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distant metastases can frequently occur without concurrent retroperitoneal lymph node involvement per se. In addition, what we normally consider as ‘haematogenous’ spread could simply be related to this direct lymphatic drainage into the thoracic duct, and then into the bloodstream through drainage into the left subclavian vein; in this fashion, this spread is truly lymphogenous, at least at its beginning. Brouwer et al. [24]
Lymphatic drainage in RCC
Fig. 4 The position and number of the reno-caval communications reported by Silvester [20] in 25 New World South American primates injected with coloured gelatin solutions in the mesenteric or inguinal lymphatic nodes. Circles indicate the positions of the communications and the figures in the circles indicate the number of communications found in each position. [Am J Anat 1912; 12: 451; Figure 1. Reproduced with permission from John Wiley & Sons, Inc.]
confirmed this important phenomenon of direct lymphatic drainage into the thoracic duct for the first time in vivo in humans.
prognostic factor and should ideally be accurately assessed for disease staging. The sentinel lymph node biopsy technique has recently been applied in patients with RCC to collect clinical data on the patterns of tumour-draining lymph nodes.
Sentinel Lymph Node Mapping
Intra-operative sentinel lymph node mapping in the kidney was first described in a live porcine model [31]. Since then, Bex et al. [14,15] and Sharif et al. [16] have safely applied lymphoscintigraphy and SPECT/CT followed by intraoperative sampling in patients undergoing nephrectomy to map lymphatic drainage. In their study design, tumours >4 cm (range 3.5–10 cm) received more than one injection of radioactive tracer and lymphoscintigraphy was performed at
The sentinel lymph node concept is based on the idea that a primary tumour drains directly to one or more sentinel nodes before travelling to secondary and tertiary nodes [25,26]. The location and number of these sentinel nodes is influenced by tumour morphology and physiology [27]. In RCC, lymph node metastasis leads to a dramatic decrease in 5-year survival [28–30]; therefore, sentinel lymph nodes can be an important
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Fig. 5 Images from albino rats (A)–(C) showing results from Engeset's bilateral mercury lumbar injections with the thoracic duct ligated. (A) Sacral lymphatics distended with mercury and anastamoses between lymph vessels evident but no mercury is seen outside the lymphatic system. (B) Note the retrograde filling in the chylus vessels but no mercury is seen outside the lymphatic system. (C) Note mercury outside the lymphatic system in a proximal abdominal vein. (D) Engeset's magnified radiogram of the right lumbar node with most of the node and efferent and afferent lymph vessels filled with mercury. He notes that large amounts of mercury entered the inferior vena cava and common iliac vein. An arrow points to small veins through which the mercury entered vena cava [22]. [Am J Anat 1959; 93: 383; Plate 1. Reproduced with permission from John Wiley & Sons, Inc.]
20 min and 2–4 h followed by SPECT/CT [14]. In a study of 20 patients with RCC with pT1a–pT2 pN0 cM0 disease of papillary or clear-cell subtype, Bex et al. [15] reported visualisation of at least one sentinel node in 14/20 patients (60%). The sensitivity and specificity of their imaging protocol was not evaluable given the small sample size. More recently, Brouwer et al. [24] reported on four patients where early lymphatic drainage was visualised along the
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course of the thoracic duct using lymphoscintigraphy and SPECT/CT. Interestingly, in one of these patients, this phenomenon was noted in the absence of retroperitoneal metastases. Sherif et al. [16] conducted a feasibility study in 11 patients with RCC with T1b–T3b disease of clear-cell subtype. They reported visualisation of at least one sentinel node in 10/11 patients [16]. Unlike that of Bex et al., their protocol consisted
Lymphatic drainage in RCC
Fig. 6 Allen and Roddenberry [23] discovered abdominal lymphovenous communications in two out of eight squirrel primates by injection of India ink and radiopaque medium. Left: a cross-section of the left renal vein (R.V.) and artery (L.R.A.) and longitudinal section of lumbar lymphatic (L.) which enters the renal vein behind a cresentric venous fold (C.V.F.). Note the unusually long lymphatic valve (L.V.), which projects into the renal vein. Note the thinness of the vein wall above and to the right of the mouth of lymphatic valve. Right: details of the terminal lymphatic valve projecting into the left renal vein. Between the valve cusps are erythrocytes which entered from the vein and masses of ink from an injected lumbar node.
of four peripheral injections of radioactive tracer, regardless of tumour size. Lymphoscintigraphy was performed immediately afterwards and anywhere between 3 and 18 h after injection followed by SPECT/CT [16]. Their study highlighted the need to standardise the timing and location of radioactive intratumoural injections (Table 2 [15,16]). It has previously been reported that tumours can undergo different levels of lymphangiogenesis (with most occurring in the periphery), causing significant variations in lymphatic remodelling [32]. This has the potential to limit the reliability of sentinel lymph node mapping altogether. In addition to their experimental approaches, Bex et al. and Sherif et al. also had different patient selection criteria and intra-operative sampling approaches (Table 2 [15,16]). Because of small sample sizes, the effects of these differences are unclear; however, it can be agreed that a standardised protocol would facilitate the collection of more clinically significant data.
Lymph Node Dissection The role of lymph node dissection (LND) in RCC is still under debate, even after the recent results of a phase III randomised clinical trial, the European Organisation for the Research and Treatment of Cancer (EORTC) 30881 trial [33]. Although the EORTC 30811 trial is the only prospective randomised study studying the role of LND in RCC, it has been heavily criticised, as the majority of the patients in the study had low-stage disease with a very low risk of harbouring lymph node metastases. Despite major advances in the treatment of renal malignancies, the timing and extent of LND remains controversial. On the one hand, several studies have shown that LND confers no survival benefit when performed
with radical nephrectomy [33,34]. On the other hand, some studies suggest that the detection and removal of early metastatic nodes may improve survival [35,36]. Given the conflicting evidence regarding the role of LND in RCC, it is clear that a better understanding of the basics of lymphatic drainage of the kidney would be particularly beneficial for patients with RCC. The European Association of Urology guidelines consider LND as a staging procedure, and recommend hilar LND in selected patients with clinically node-negative disease, and resection of grossly positive nodes in others [37], while the AUA calls for more studies on survival outcomes [38]. What is generally agreed on is that LND improves the accuracy of staging, and helps stratify patients for adjuvant clinical trials. In addition, LND can potentially prolong survival in carefully selected patients, especially in patients with papillary type II RCC, low-volume nodal disease and lack of sarcomatoid dedifferentiation [39]. Nevertheless, the potential risks and complications associated with extensive LND need to be considered and discussed with the patient during preoperative counselling. The goal of mapping studies in patients with RCC is to generate an evidence-based surgical template that can be used to guide LND. This remains a challenge, as lymphogenous metastasis frequently occurs outside the expected retroperitoneal basins. In an autopsy series of 554 cases of RCC, Johnsen et al. [40] reported 80 cases of lymph node metastasis with only 21 of these being restricted to the retroperitoneal nodes (mediastinal or pulmonary nodes in 52 cases). The heterogeneity of lymphatic metastasis in patients with RCC is underscored by the variability of drainage patterns reported in autopsy studies. Unfortunately, © 2014 The Authors BJU International © 2014 BJU International
813
814
No
Yes – nodal scintigraphy
No
Yes
to date, these investigations have provided limited clinical evidence for defining a clinically relevant surgical dissection template. Assouad et al. [11] conducted a dissection series and showed that hilar nodes have minimal involvement in lymphatic drainage of the kidney, and therefore, their excision would be of minimal clinical benefit. Rather, they note that the para-aortic, paracaval and interaortocaval nodes are the primary landing sites in patients with RCC. More recently, in a retrospective series of 28 patients found to have lymph node metastasis, Hadley et al. [41] reported that 29% skipped the renal hilar nodes. In addition, only 18% had lymph nodes confined to the ipsilateral (para-aortic or paracaval) nodes, which would be easily accessible during nephrectomy [41]. Forty-two percent of patients had lymph node metastasis in the interaortocaval region, 46% in the retroaortic and retrocaval region and 30% in the suprahilar region [41]. This group also noted that left kidney tumours had a higher frequency of enlarged lymph nodes in the ipsilateral suprahilar region [41].
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MBq, megabecquerel; tc, technetium. SPECT, single-photon emission CT.
60–80 MBq 99 m Tc-labelled albumin colloid Sherif et al. [16]
Four injections in the periphery of the tumour (1.0–2.0 mL)
(1) Immediately (2) 3–18h
64 angles with 30 s of data in each angle
Open nephrectomy only
(1) Gamma probe with 125-I seed (2) All nodes examined ex situ (3) Only sentinel nodes sampled that could be approached through access for specific renal surgery (1) Gamma probe (2) Both in situ and in separate detection of excised nodes (3) Minimum for a positive detection set level of 10 counts per min Open or laparoscopic nephrectomy (total and partial) 225 MBq 99m Tc-nanocolloid Bex et al. [15]
Tumours < 4 cm injected centrally (1 × 0.4 mL) Tumours 4–10 cm injected around the centre into solid parts avoiding areas of necrosis (2–3 × 0.4 mL)
(1) 20 min (2) 2–4 h
Axial 5-mm slices
Intraoperative sampling procedure Scheduled procedure Preoperative SPECT/CT Preoperative planar lymphoscintigraphy Ultrasound-guided primary tumour injection criteria Radioactive tracer
Table 2 A comparison of sentinel lymph node mapping approaches in patients with RCC carried out by Bex et al. [15]] and Sherif et al. [16]].
Patent blue
Postoperative procedures
Review
In the original modern description of radical nephrectomy, Robson et al. [42] proposed removal of the para-aortic and paracaval lymph nodes from the bifurcation of the aorta to the crus of the diaphragm whenever radical nephrectomy is performed. Palapattu et al. [43] suggested that extensive LND should start from the crus of the ipsilateral diaphragm superiorly to the medial border of the contralateral great vessel (including interaortocaval nodes) and medially to the bifurcation of the ipsilateral great vessel inferiorly. They proposed that limited LND should begin at the level of the renal hilum superiorly to the anterior, posterior and lateral aspects of the ipsilateral great vessels down to the level of the inferior mesenteric artery [43]. In a large retrospective series, Crispen et al. [44] proposed a template based on five previously defined pathological features of the primary tumour in patients with high-risk disease at the time of radical nephrectomy (with eligible patients having two of the five features). These include the presence of Fuhrman grade 3 or 4 disease, the presence of a sarcomatoid component, tumour size ≥ 10 cm, tumour stage pT3 or pT4 and the presence of coagulative tumour necrosis. In right-sided tumours, they recommend that the paracaval and interaortocaval lymph nodes should be removed, whereas in left-sided tumours, the para-aortic and interaortocaval lymph nodes should be removed from the crus of the diaphragm to the ipsilateral common iliac artery. They determined that the location of lymph node metastases was related to the side of the primary tumour. No right-sided tumours were found to have para-aortic involvement and no left-sided tumours had involvement of the paracaval lymph nodes without prior involvement of para-aortic and interaortocaval nodes, respectively [44].
Lymphatic drainage in RCC
Table 3 Proposed surgical approaches to lymph node dissection in the management of retroperitoneal nodes in RCC. Timing of LND
Extent of LND
Robson et al. [42]
Whenever undergoing radical nephrectomy
Palapattu et al. [43]
‘Extensive’: T1/T2 or T3/T4 disease with clinical nodes and no diffuse metastasis ‘Limited’: T1/T2 disease with clinical nodes and diffuse metastasis; T3/T4 disease with no clinical nodes and no diffuse metastasis; T3/T4 disease with clinical nodes and diffuse metastasis
Crispen et al. [44]
Two or more high risk pathological features: (1) presence of nuclear grade 3 or 4 (2) presence of a sarcomatoid component (3) tumour size ≥ 10 cm (4) tumour stage pT3 or pT4 (5) presence of coagulative tumour necrosis
Para-aortic and paracaval lymph nodes from the crus of the diaphragm to the bifurcation of the aorta ‘Extensive’: crus of the ipsilateral diaphragm superiorly to the medial border of the contralateral great vessel (including interaortocaval nodes) and medially to the bifurcation of the ipsilateral great vessel inferiorly ‘Limited’: level of the renal hilum superiorly to the anterior, posterior, and lateral aspects of the ipsilateral great vessels down to the level of the inferior mesenteric artery Right-sided tumours: paracaval and interaortocaval lymph nodes from the crus of the diaphragm to the common iliac artery Left-sided tumours: para-aortic and interaortocaval lymph nodes be removed in patients with left-sided tumours from the crus of the diaphragm to the common iliac artery
LND, lymph node dissection.
It has been an ongoing challenge to interpret collectively the results of studies that seek to define LND dissection templates. Heterogeneity in both the patient populations selected and disease stage make it difficult to clearly define when LND will be of value and in which patients (Table 3 [42–44]). Furthermore, there are substantial differences among current studies in the definitions of radiographic lymphadenopathy, the number of lymph nodes sampled and the techniques used in resecting and testing nodes. This challenges the applicability of proposed templates. A standardised lymphatic mapping protocol for patients with RCC could initiate the collection of more clinically meaningful data. This could be used to build an evidence-based consensus on the surgical management of retroperitoneal nodes; however, the complexities of renal anatomy, sentinel lymph node mapping and RCC pathogenesis have so far made this a particularly challenging goal.
Future Directions Basic patterns of lymphatic drainage from the kidney can be gleaned from past cadaveric dissection studies. It is important that future dissection studies be carried out on pathological specimens. Live mapping studies in patients with RCC are underway and promising but require significant refinement before the data can be applied clinically; therefore, there still exists a need for cadaveric injection experiments to build on our knowledge of renal lymphatic anatomy. Indocyanine green fluorescent lymphography is an emerging technique that has been successfully applied in lymphatic mapping studies in both patients with breast cancer and those with melanoma [45,46]. It has the advantages of lower costs and does not alter the surgical field. Currently, it is being investigated in preclinical studies for use in mapping lymphatic drainage in lung cancer [47]. The sentinel lymph
node biopsy technique is resource-intensive and this can be a limiting factor for many research groups. Looking forward, indocyanine green lymphography may be a more accessible and standardised technique for lymphatic mapping in RCC. Moreover, advanced multimodality imaging studies that are currently being investigated present a non-invasive alternative to the sentinel lymph node biopsy technique. Results of flourodeoxyglucose F 18 positron-emission tomography showed it has a high specificity (100%) but low sensitivity (75%) for detecting lymph node metastasis [48]. Futhermore, a pilot study was carried out using lymphotrophic nanoparticle-enhanced MRI imaging for assessing lymph nodes in patients with RCC, which was found to have both high specificity (100%) and sensitivity (95.5%) [49]. These preliminary results should be further investigated in a larger prospective study. More recently, high-resolution mapping of deep-tissue lymph nodes in preclinical animal models was carried out in live animals using 89 Zr-furmoxytol with positron-emission tomography/MRI [50]. Advances in imaging technology have the potential to improve the detection of sentinel lymph nodes and the overall process of preoperative planning before LND. If developed further, these multimodal techniques could provide a non-invasive alternative to sentinel lymph node mapping in patients with RCC.
Conclusion Lymphatic drainage in RCC is quite unpredictable. Data from past cadaveric dissections studies have defined much of our understanding of the basic anatomical layout of draining retroperitoneal lymph nodes. Furthermore, the existence of peripheral lymphovenous communications in humans should be studied in more detail. These data may shed more light © 2014 The Authors BJU International © 2014 BJU International
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on the mechanisms of lymphogenous and haematogenous metastasis. Sentinel lymph node mapping techniques have been successfully applied to study lymphatic drainage in RCC, albeit in a small number of patients. Continued refinement and standardisation of the experimental approach is needed to generate valid clinical data from such studies. The goal of lymphatic mapping in RCC is to better predict where early lymphatic metastases may occur. For now, it would be prudent to continue performing LND in carefully selected patients with a high risk of nodal metastasis based on preoperative clinical features. Ultimately, the hope is to build an evidence-based consensus on the role and extent of LND in patients with RCC.
Conflict of Interest None declared.
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Nuck A. Adenographia curiosa et uteri foeminei anatome nova. P. vander Aa: Lugduni Betavorum, 1692 Mascagni P. Vasorum lymphaticorum corporis humani historic et ichnographia. Siena: Pazzini Carli, 1787 Sappey M. Anatomie, Physiologie, Pathologie des vaisseaux Lymphatiques consideres chez L’homme at les Vertebres. Paris: A. Delahaye and E. Lecrosnier, 1874 Gerota D. Zur technik der Lymphgefassinjection. Eine neue Injectionmasse fur Lymphgefasse. Polychrom Injection. Anat Anz. 1896 Stahr H. Der Lymphapparat der Niere. Arch. f. Atuit. u. Phys., Anat. Abth. 1900. p. 40 Poirier P, Cuneo B. Lymphatics of the pelvis and abdomen. In Delamere G, Poirier P, Cuneo B eds, The Lymphatics, Chicago: W.T. Keener and Co., 1904: 129–207 Ssysganow AN. Ueber das Lymphsystem der Nieren und Nierenhüllen beim Menschen. Zeitsch F. D. Getsamt. Anat., Bd. 1930; 91 (S.): 771–831 Parker AE. Studies on the main posterior lymph channels of the abdomen. Am J Anat 1935; 56: 409–43 Kubik S. Anatomy of the lymphatic system. In Foldi M, Foldi E eds, Foldi’s Textbook of Lymphology, 2nd edn. Munich: Urban and Fischer, 2006: 1–149 Harrison DA, Clouse ME. Normal anatomy. In Clouse M, Wallace S eds, Lymphatic Imaging, Baltimore: Williams and Wilkins, 1985: 15–94 Assouad J, Riquet M, Berna P, Danel C. Intrapulmonary lymph node metastasis and renal cell carcinoma. Eur J Cardiothorac Surg 2007; 31: 132–4 Assouad J, Riquet M, Foucault C, Hidden G, Delmas V. Renal lymphatic drainage and thoracic duct connections: implications for cancer spread. Lymphology 2006; 39: 26–32 Battezzati M, Ippolito D. The Lymphatic System. New York: John Wiley & Sons, 1973: 292–304 Bex A, Vermeeren L, de Windt G, Prevoo W, Horenblas S, Olmos RA. Feasibility of sentinel node detection in renal cell carcinoma: a pilot study. Eur J Nucl Med Mol Imaging 2010; 37: 1117–23 Bex A, Vermeeren L, Meinhardt W et al. Intraoperative sentinel node identification and sampling in clinically node-negative renal cell carcinoma: initial experience in 20 patients. World J Urol 2011; 29: 793–9 Sherif AM, Eriksson E, Thörn M et al. Sentinel node detection in renal cell carcinoma. A feasibility study for detection of tumour-draining lymph nodes. BJU Int 2012; 109: 1134–9
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17 Qian CN, Berghuis B, Tsarfaty G et al. Preparing the ‘soil’: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res 2006; 66: 10365–76 18 Roozendaal R, Mebius RE, Kraal G. The conduit system of the lymph node. Int Immunol 2008; 20: 1483–7 19 Baldewijns MM, Roskams T, Ballet V et al. A low frequency of lymph node metastasis in clear-cell renal cell carcinoma is related to low lymphangiogenic activity. BJU Int 2009; 103: 1626–31 20 Silvester CF. On the presence of permanent communications between the lymphatic and the venous system at the level of the renal veins in adult South American monkeys. Am J Anat 1912; 12: 447–71 21 Job TT. Lymphatico-venous communications in the common rat and their significance. Am J Anat 1918; 24: 467–91 22 Engeset TA. Lymphatico-venous communications in the albino rat. J Anat 1959; 93: 380–3 23 Roddenberry H, Allen L. Observations on the abdominal lymphaticovenous communications of the squirrel monkey. Anat Rec 1967; 159: 147–57 24 Brouwer OR, Noe A, Olmos RA, Bex A. Lymphatic drainage from renal cell carcinoma along the thoracic duct visualized with SPECT/CT. Lymphat Res Biol 2013; 11: 233–8 25 Nieweg OE, Tanis PJ, Kroon BB. The definition of a sentinel node. Ann Surg Oncol 2001; 8: 538–41 26 Dahl K, Karlsson M, Marits P, Hoffstedt A, Winqvist O, Thörn M. Metinel node–the first lymph node draining a metastasis–contains tumor-reactive lymphocytes. Ann Surg Oncol 2008; 15: 1454–63 27 Sherif A, Garske U, de la Torre M, Thörn M. Hybrid SPECT-CT: an additional technique for sentinel node detection of patients with invasive bladder cancer. Eur Urol 2006; 50: 83–91 28 Bassil B, Dosoretz DE, Prout GR. Validation of the tumor, nodes and metastasis classification of renal cell carcinoma. J Urol 1985; 134: 450–4 29 Phillips CK, Taneja SS. The role of lymphadenectomy in the surgical management of renal cell carcinoma. Urol Oncol 2004; 22: 214–23 30 Capitanio U, Jeldres C, Patard JJ et al. Stage-specific effect of nodal metastases on survival in patients with non-metastatic renal cell carcinoma. BJU Int 2009; 103: 33–7 31 Bernie JE, Zupkas P, Monga M. Intraoperative mapping of renal lymphatic drainage: technique and application in a porcine model. J Endourol 2003; 17: 235–7 32 Padera TP, Kadambi A, di Tomaso E et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002; 296: 1883–6 33 Blom JH, van Poppel H, MarÈchal JM et al. 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 2009; 55: 28–34 34 Sun M, Trinh QD, Bianchi M et al. Extent of lymphadenectomy does not improve the survival of patients with renal cell carcinoma and nodal metastases: biases associated with the handling of missing data. BJU Int 2014; 113: 36–42 35 Pantuck AJ, Zisman A, Dorey F et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003; 97: 2995–3002 36 Kates M, Lavery HJ, Brajtbord J, Samadi D, Palese MA. Decreasing rates of lymph node dissection during radical nephrectomy for renal cell carcinoma. Ann Surg Oncol 2012; 19: 2693–9 37 Ljungberg B, Cowan NC, Hanbury DC et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol 2010; 58: 398–406 38 Campbell SC, Novick AC, Belldegrun A et al. Guideline for management of the clinical T1 renal mass. J Urol 2009; 182: 1271–9
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39 Delacroix SE, Chapin BF, Chen JJ et al. Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? J Urol 2011; 186: 1236–41 40 Johnsen JA, Hellsten S. Lymphatogenous spread of renal cell carcinoma: an autopsy study. J Urol 1997; 157: 450–3 41 Hadley DA, Stephenson RA, Samlowski WE, Dechet CB. Patterns of enlarged lymph nodes in patients with metastatic renal cell carcinoma. Urol Oncol 2011; 29: 751–5 42 Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol 1969; 101: 297–301 43 Palapattu GS, Kim HL, Belldegrun AS. Lymph node dissection in patients with kidney cancer: when is it indicated? Rev Urol 2003; 5: 196–9 44 Crispen PL, Breau RH, Allmer C et al. 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 2011; 59: 18–23 45 Gilmore DM, Khullar OV, Gioux S et al. Effective low-dose escalation of indocyanine green for near-infrared fluorescent sentinel lymph node mapping in melanoma. Ann Surg Oncol 2013; 20: 2357–63 46 Sugie T, Sawada T, Tagaya N et al. Comparison of the indocyanine green fluorescence and blue dye methods in detection of sentinel lymph nodes in early-stage breast cancer. Ann Surg Oncol 2013; 20: 2213–8
47 Khullar OV, Gilmore DM, Matsui A, Ashitate Y, Colson YL. Preclinical study of near-infrared-guided sentinel lymph node mapping of the porcine lung. Ann Thorac Surg 2013; 95: 312–8 48 Kang DE, White RL, Zuger JH, Sasser HC, Teigland CM. Clinical use of fluorodeoxyglucose F 18 positron emission tomography for detection of renal cell carcinoma. J Urol 2004; 171: 1806–9 49 Guimaraes AR, Tabatabei S, Dahl D, McDougal WS, Weissleder R, Harisinghani MG. Pilot studyevaluating use of lymphotrophic nanoparticle-enhanced magnetic resonance imaging for assessing lymph nodes in renal cell cancer. Urology 2008; 71: 708–12 50 Thorek DL, Ulmert D, Diop NF et al. Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle. Nat Commun 2014; 5: 1–9
Correspondence: Jose A. Karam, The University of Texas MD Anderson Cancer Center, Department of Urology, 1515 Holcombe Blvd, Unit 1373, Houston, TX 77030, USA. e-mail: [email protected] Abbreviations: SPECT, single-photon emission CT; LND, lymph node dissection; EORTC, European Organisation for the Research and Treatment of Cancer.
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Lymphatic drainage in renal cell carcinoma (RCC) is unpredictable, however, basic patterns can be observed in cadaveric and sentinel lymph node mapping studies in patients with RCC. The existence of peripheral lymphovenous communications at the level of the renal vein has been shown in mammals but remains unknown in humans. The sentinel lymph node biopsy technique can be safely applied to map lymphatic drainage patterns in patients with RCC. Further standardisation of sentinel node biopsy techniques is required
Introduction Our understanding of the lymphatic drainage of the kidney has evolved with advances in experimental technique in cadaveric dissections. After Nuck [1] introduced the mercury injection technique, anatomists were able to investigate the lymphatic system in detail through cadaveric dissection experiments (Fig. 1A,B) [2]. Sappey [3] laid the foundation of lymphatic anatomy with his series of mercury injection studies on specific organ systems. After mercury injection techniques were dropped because of their toxicity, they were replaced by oil-based dye injection techniques developed by Gerota [4]. Stahr [5] adapted Gerota’s injection method to investigate the superficial and deep lymphatic system in the kidney. Poirier and Cuneo [6] traced efferent drainage pathways to the para-aortic, paracaval and interaortocaval lymph nodes (Fig. 1C). Ssysganow [7] then studied the interconnections of these retroperitoneal nodes. Parker [8] conducted perhaps the most detailed injection experiments on the kidney. The efferent vessels were mapped from the kidney to the thoracic duct. Based on these findings, Kubik [9] proposed an anatomical lymphatic drainage map from the intrarenal lymphatic system to the para-aortic,
to improve the clinical significance of mapping studies. Understanding lymphatic drainage in RCC may lead to an evidence-based consensus on the surgical management of retroperitoneal lymph nodes.
Keywords renal cell cancer, lymphatic drainage, sentinel lymph node, anatomy, lymphovenous communication, lymphadenectomy
preaortic, retroaortic, paracaval, precaval, retrocaval and interaortocaval lymph nodes (Fig. 1D). Autopsy studies have been used to investigate the lymphatics of tumour-bearing kidneys in RCC. Observed patterns of nodal metastasis are varied and have confirmed the unpredictability of lymphatic drainage in RCC. Modern imaging and surgical techniques have enabled surgeons to map sentinel lymph nodes safely in live patients with RCC. This strategy is in the early stages of development, but shows the experimental sophistication involved in the surgical treatment of RCC.
Anatomy The intrarenal lymphatic system originates from the superficial network [6],which runs immediately underneath the fibrous capsule. It drains either directly to the hilum or connects to the deeper cortical lymph capillaries along the capsular arterial branches [9,10]. These lymph vessels do not connect with those in the surrounding adipose capsule, although they may share a common draining node [9]. The lymphatic vessels in the renal parenchyma travel from the cortex and medulla toward the base of the medullary pyramid [9,10]. At the corticomedullary junction, valvular collecting
Fig. 1 (A) Nuck's findings on lymphatic drainage of the kidney through Mercury dissection experiments [1]. (B) Mascagni's findings on lymphatic
▶
drainage of the kidney through Mercury dissection experiments [2]. (C) Poirier and Cuneo's findings on lymphatic drainage of the kidney using an adapted version of Gerota's injection method [6]. (D) Anatomical organisation of the para-aortic, interaortocaval, paracaval lymph nodes based on Kubik [9]. [Kubik S. Foldi's Textbook of Lymphology, 2nd edn, 2006, Chapter 1, p. 106; Figure 1.92. Reproduced with permission from Elsevier GmbH Urban & Fischer Verlag].
BJU Int 2014; 114: 806–817 wileyonlinelibrary.com
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Lymphatic drainage in RCC
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lymph vessels take up fluid from the connective tissue. This occurs along the entire length of the intrarenal lymphatic vessels [10]. The collecting lymph vessels, which emerge from the columns of Bertin, travel in the renal sinus along blood vessels to the hilum [9]. From the right kidney, efferent lymphatic vessels running anterior to the renal vein (anterior bundles) can drain into paracaval, precaval, retrocaval and interaortocaval nodes [8–10]. Retrocaval nodes are located close to the right crus of the diaphragm and connect with the thoracic duct [8–10]. Lymphatics from the hilum running posterior to the renal vein but anterior to the pelvis of the kidney and the renal artery (intravascular bundles) are few in number [8,11]. Their drainage is not well described [8]. Lymphatic vessels travelling posterior to the renal artery (posterior bundles) drain to the paracaval, retrocaval and interaortocaval nodes [8,9]. In some cases, posterior efferent lymphatic vessels have been observed curving superiorly through the right crus of the diaphragm and connecting directly to the thoracic duct without passing through any lymph nodes [8,11]. From the left kidney, efferent lymphatic vessels running anterior to the renal vein can drain into the para-aortic and preaortic nodes [8–10]. These vessels have also been observed to give off branches that run superiorly and connect with posterior draining efferent vessels [8–10]. Intravascular bundles from the left kidney, like the right kidney, are few in number and not clearly described. Posterior efferent lymphatic vessels can drain to the para-aortic and retroaortic nodes [8]. They can also curve superiorly through the left crus of the diaphragm and connect directly to the thoracic duct without passing through any lymph node [8,11,12]. We summarise these anatomical findings on lymphatic drainage of the kidneys in Figure 2. The retroperitoneal lymph nodes are an extensive network of lymphatics between the first and fifth lumbar vertebrae. They serve as the primary landing sites of renal lymph and have unpredictable interconnections before reaching the thoracic duct. In addition to draining the kidney, they also drain the sacrum, mesocolon, testicle, uterus, ovaries, adrenal glands, deep muscles of the dorsal region and the diaphragm [8,13]. Their study in non-tumour-bearing cadavers has revealed potential locoregional and efferent lymphogenous pathways. In a pilot study in patients with RCC in a clinical setting, Bex et al. [14] used preoperative lymphoscintgraphy and single-photon emission CT (SPECT) combined with low-dose CT and intra-operative radio-guided gamma probe sampling to map tumour draining lymph nodes (Fig. 3). In their interim analysis of 14 patients, lymphatic drainage was found to be localised to the para-aortic, paracaval, retrocaval and interaortocaval lymph nodes, with two patients having additional extra-abdominal nodes [15]. Sherif et al. [16] conducted a similar study and reported that right-sided
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tumours drained only to the paracaval and interaortocaval nodes and left-sided tumours drained to the para-aortic nodes (Table 1 [15,16]). Cadaveric injection studies in non-tumour-bearing kidneys have provided a foundational knowledge of renal lymphatic drainage; however, to better understand the movement of lymph within para-aortic, paracaval and interaortocaval nodes and toward the thoracic duct, future anatomical studies should be carried out in clinical and cadaveric settings.
Lymphovenous Communication Further complicating the study of lymphatic drainage in RCC, is the existence of peripheral lymphovenous communication sites. These sites may be located in the inferior vena cava at the level of the renal veins or in renal veins themselves. It has been suggested that haematogenous metastasis in RCC originates from lymphovenous anastomoses between the primary tumour and sentinel lymph nodes [17,18]. A competing theory has suggested that RCC undergoes haematogenous spread with lymph node involvement occurring afterwards [19]. Although metastasis in RCC has been studied extensively, the precise mechanism is still unknown. Silvester [20] injected 25 New World South-American primates with coloured gelatin solutions in the mesenteric or inguinal lymphatic nodes. He observed that the solution never passed through the lumbar or intestinal lymphatic trunks into the thoracic duct or anterior regions of the body, but passed directly into the vena cava at the level of the renal veins (the same was not found in his previous experiment in 16 different species of Old World primates [Fig. 4]). Job [21] extensively investigated these communications in a single species of common rat. He injected 100 specimens with a Berlin blue gelatin mass and India ink and reported inferior vena cava communications in 48 of these cases, iliolumbar communications in two cases, renal vein communications in eight cases and portal vein communications in 27 cases [21]. To confirm these findings, Engeset [22] injected 22 laboratory rats and five wild rats with metallic mercury under the experimental conditions laid out by Job [21], but found no evidence of abdominal lymphovenous communication (Fig. 5). To follow on from that study, Roddenberry and Allen [23] observed abdominal lymphovenous communications at the renal vein and inferior vena cava in two out of eight squirrel primates studied by injection of India ink and radiopaque medium (Fig. 6). Evidence of peripheral lymphovenous communications at the renal vein in certain primates and rodents suggests
Lymphatic drainage in RCC
Fig. 2 Summary of anatomical review of the lymphatic drainage of the kidney: anterior view (top) and posterior view (bottom).
Right Kidney
Left Kidney
this is probably a subspecies characteristic [23]; however, no autopsy series has been published that investigates their existence in humans. It is plausible that peripheral lymphovenous connections arise or disappear at birth, through aging or under pathological conditions. Revisiting
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
this subject, which was once studied in mammals [20–23], may provide insight into the temporality of haematogenous and lymphogenous metastasis in RCC. Most importantly, it would establish a paradigm for the understanding of the pathogenesis of the disease. © 2014 The Authors BJU International © 2014 BJU International
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Fig. 3 Sentinel lymph nodes detected in patients with RCC using lymphoscintigraphy and single-photon emission CT/CT imaging in a pilot study (n = 8) by Bex et al. [14]. [Eur J Nucl Med 2010; 37: 1120; Figure 1. Reproduced with permission from Springer Science+Business Media.]
Table 1 A comparison of patient selection and outcomes in lymphatic mapping attempts in patients with RCC by Bex et al. [15]] and Sherif et al. [16]]. Total Age, patients years (male: female)
Stage
RCC subtype
16 clear-cell 1 papillary 1 papillary/clear-cell 1 chromophobe
Bex et al [15]
20 (6:14)
44–79
pT1a–pT2, pN0, cM0
Sherif et al [16]
11 (6:7)
51–76
T1b–T3b, 11 clear-cell pN0/ + , cM0
Preoperative Total Falsevisualisation no. SNs positive, (right-sided: detected n left-sided primary tumour) 14/20 (10:4)
26
0
10/11 (6:4)
32
0
Distribution of SNs in patients with right-sided tumours
1 para-aortic 0 retroaortic 0 preaortic 6 interaortocaval 1 paracaval 4 retrocaval 0 precaval 1 internal mammary 1 mediastinal 1 right pleural 0 para-aortic 0 retroaortic 0 preaortic 4 interaortocaval 5 paracaval 0 retrocaval 0 precaval
Distribution Complications of SNs in related to SN patients with excision left-sided tumours
4 para-aortic 0 retroaortic 0 preaortic 1 interaortocaval 0 paracaval 0 retrocaval 0 precaval
0
4 para-aortic 0 retroaortic 0 preaortic 0 interaortocaval 0 paracaval 0 retrocaval 0 precaval
0
SN, sentinel node.
Another important venue of lymphovenous communication is through the thoracic duct. Assouad et al. [11] described direct lymphatic drainage into the thoracic duct (without passing through any lymph nodes) in several patients (from both right and left kidneys). As noted by the authors, this has tremendous implications in the field of metastasis in RCC. This direct drainage into the thoracic duct could explain how
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distant metastases can frequently occur without concurrent retroperitoneal lymph node involvement per se. In addition, what we normally consider as ‘haematogenous’ spread could simply be related to this direct lymphatic drainage into the thoracic duct, and then into the bloodstream through drainage into the left subclavian vein; in this fashion, this spread is truly lymphogenous, at least at its beginning. Brouwer et al. [24]
Lymphatic drainage in RCC
Fig. 4 The position and number of the reno-caval communications reported by Silvester [20] in 25 New World South American primates injected with coloured gelatin solutions in the mesenteric or inguinal lymphatic nodes. Circles indicate the positions of the communications and the figures in the circles indicate the number of communications found in each position. [Am J Anat 1912; 12: 451; Figure 1. Reproduced with permission from John Wiley & Sons, Inc.]
confirmed this important phenomenon of direct lymphatic drainage into the thoracic duct for the first time in vivo in humans.
prognostic factor and should ideally be accurately assessed for disease staging. The sentinel lymph node biopsy technique has recently been applied in patients with RCC to collect clinical data on the patterns of tumour-draining lymph nodes.
Sentinel Lymph Node Mapping
Intra-operative sentinel lymph node mapping in the kidney was first described in a live porcine model [31]. Since then, Bex et al. [14,15] and Sharif et al. [16] have safely applied lymphoscintigraphy and SPECT/CT followed by intraoperative sampling in patients undergoing nephrectomy to map lymphatic drainage. In their study design, tumours >4 cm (range 3.5–10 cm) received more than one injection of radioactive tracer and lymphoscintigraphy was performed at
The sentinel lymph node concept is based on the idea that a primary tumour drains directly to one or more sentinel nodes before travelling to secondary and tertiary nodes [25,26]. The location and number of these sentinel nodes is influenced by tumour morphology and physiology [27]. In RCC, lymph node metastasis leads to a dramatic decrease in 5-year survival [28–30]; therefore, sentinel lymph nodes can be an important
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Fig. 5 Images from albino rats (A)–(C) showing results from Engeset's bilateral mercury lumbar injections with the thoracic duct ligated. (A) Sacral lymphatics distended with mercury and anastamoses between lymph vessels evident but no mercury is seen outside the lymphatic system. (B) Note the retrograde filling in the chylus vessels but no mercury is seen outside the lymphatic system. (C) Note mercury outside the lymphatic system in a proximal abdominal vein. (D) Engeset's magnified radiogram of the right lumbar node with most of the node and efferent and afferent lymph vessels filled with mercury. He notes that large amounts of mercury entered the inferior vena cava and common iliac vein. An arrow points to small veins through which the mercury entered vena cava [22]. [Am J Anat 1959; 93: 383; Plate 1. Reproduced with permission from John Wiley & Sons, Inc.]
20 min and 2–4 h followed by SPECT/CT [14]. In a study of 20 patients with RCC with pT1a–pT2 pN0 cM0 disease of papillary or clear-cell subtype, Bex et al. [15] reported visualisation of at least one sentinel node in 14/20 patients (60%). The sensitivity and specificity of their imaging protocol was not evaluable given the small sample size. More recently, Brouwer et al. [24] reported on four patients where early lymphatic drainage was visualised along the
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course of the thoracic duct using lymphoscintigraphy and SPECT/CT. Interestingly, in one of these patients, this phenomenon was noted in the absence of retroperitoneal metastases. Sherif et al. [16] conducted a feasibility study in 11 patients with RCC with T1b–T3b disease of clear-cell subtype. They reported visualisation of at least one sentinel node in 10/11 patients [16]. Unlike that of Bex et al., their protocol consisted
Lymphatic drainage in RCC
Fig. 6 Allen and Roddenberry [23] discovered abdominal lymphovenous communications in two out of eight squirrel primates by injection of India ink and radiopaque medium. Left: a cross-section of the left renal vein (R.V.) and artery (L.R.A.) and longitudinal section of lumbar lymphatic (L.) which enters the renal vein behind a cresentric venous fold (C.V.F.). Note the unusually long lymphatic valve (L.V.), which projects into the renal vein. Note the thinness of the vein wall above and to the right of the mouth of lymphatic valve. Right: details of the terminal lymphatic valve projecting into the left renal vein. Between the valve cusps are erythrocytes which entered from the vein and masses of ink from an injected lumbar node.
of four peripheral injections of radioactive tracer, regardless of tumour size. Lymphoscintigraphy was performed immediately afterwards and anywhere between 3 and 18 h after injection followed by SPECT/CT [16]. Their study highlighted the need to standardise the timing and location of radioactive intratumoural injections (Table 2 [15,16]). It has previously been reported that tumours can undergo different levels of lymphangiogenesis (with most occurring in the periphery), causing significant variations in lymphatic remodelling [32]. This has the potential to limit the reliability of sentinel lymph node mapping altogether. In addition to their experimental approaches, Bex et al. and Sherif et al. also had different patient selection criteria and intra-operative sampling approaches (Table 2 [15,16]). Because of small sample sizes, the effects of these differences are unclear; however, it can be agreed that a standardised protocol would facilitate the collection of more clinically significant data.
Lymph Node Dissection The role of lymph node dissection (LND) in RCC is still under debate, even after the recent results of a phase III randomised clinical trial, the European Organisation for the Research and Treatment of Cancer (EORTC) 30881 trial [33]. Although the EORTC 30811 trial is the only prospective randomised study studying the role of LND in RCC, it has been heavily criticised, as the majority of the patients in the study had low-stage disease with a very low risk of harbouring lymph node metastases. Despite major advances in the treatment of renal malignancies, the timing and extent of LND remains controversial. On the one hand, several studies have shown that LND confers no survival benefit when performed
with radical nephrectomy [33,34]. On the other hand, some studies suggest that the detection and removal of early metastatic nodes may improve survival [35,36]. Given the conflicting evidence regarding the role of LND in RCC, it is clear that a better understanding of the basics of lymphatic drainage of the kidney would be particularly beneficial for patients with RCC. The European Association of Urology guidelines consider LND as a staging procedure, and recommend hilar LND in selected patients with clinically node-negative disease, and resection of grossly positive nodes in others [37], while the AUA calls for more studies on survival outcomes [38]. What is generally agreed on is that LND improves the accuracy of staging, and helps stratify patients for adjuvant clinical trials. In addition, LND can potentially prolong survival in carefully selected patients, especially in patients with papillary type II RCC, low-volume nodal disease and lack of sarcomatoid dedifferentiation [39]. Nevertheless, the potential risks and complications associated with extensive LND need to be considered and discussed with the patient during preoperative counselling. The goal of mapping studies in patients with RCC is to generate an evidence-based surgical template that can be used to guide LND. This remains a challenge, as lymphogenous metastasis frequently occurs outside the expected retroperitoneal basins. In an autopsy series of 554 cases of RCC, Johnsen et al. [40] reported 80 cases of lymph node metastasis with only 21 of these being restricted to the retroperitoneal nodes (mediastinal or pulmonary nodes in 52 cases). The heterogeneity of lymphatic metastasis in patients with RCC is underscored by the variability of drainage patterns reported in autopsy studies. Unfortunately, © 2014 The Authors BJU International © 2014 BJU International
813
814
No
Yes – nodal scintigraphy
No
Yes
to date, these investigations have provided limited clinical evidence for defining a clinically relevant surgical dissection template. Assouad et al. [11] conducted a dissection series and showed that hilar nodes have minimal involvement in lymphatic drainage of the kidney, and therefore, their excision would be of minimal clinical benefit. Rather, they note that the para-aortic, paracaval and interaortocaval nodes are the primary landing sites in patients with RCC. More recently, in a retrospective series of 28 patients found to have lymph node metastasis, Hadley et al. [41] reported that 29% skipped the renal hilar nodes. In addition, only 18% had lymph nodes confined to the ipsilateral (para-aortic or paracaval) nodes, which would be easily accessible during nephrectomy [41]. Forty-two percent of patients had lymph node metastasis in the interaortocaval region, 46% in the retroaortic and retrocaval region and 30% in the suprahilar region [41]. This group also noted that left kidney tumours had a higher frequency of enlarged lymph nodes in the ipsilateral suprahilar region [41].
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MBq, megabecquerel; tc, technetium. SPECT, single-photon emission CT.
60–80 MBq 99 m Tc-labelled albumin colloid Sherif et al. [16]
Four injections in the periphery of the tumour (1.0–2.0 mL)
(1) Immediately (2) 3–18h
64 angles with 30 s of data in each angle
Open nephrectomy only
(1) Gamma probe with 125-I seed (2) All nodes examined ex situ (3) Only sentinel nodes sampled that could be approached through access for specific renal surgery (1) Gamma probe (2) Both in situ and in separate detection of excised nodes (3) Minimum for a positive detection set level of 10 counts per min Open or laparoscopic nephrectomy (total and partial) 225 MBq 99m Tc-nanocolloid Bex et al. [15]
Tumours < 4 cm injected centrally (1 × 0.4 mL) Tumours 4–10 cm injected around the centre into solid parts avoiding areas of necrosis (2–3 × 0.4 mL)
(1) 20 min (2) 2–4 h
Axial 5-mm slices
Intraoperative sampling procedure Scheduled procedure Preoperative SPECT/CT Preoperative planar lymphoscintigraphy Ultrasound-guided primary tumour injection criteria Radioactive tracer
Table 2 A comparison of sentinel lymph node mapping approaches in patients with RCC carried out by Bex et al. [15]] and Sherif et al. [16]].
Patent blue
Postoperative procedures
Review
In the original modern description of radical nephrectomy, Robson et al. [42] proposed removal of the para-aortic and paracaval lymph nodes from the bifurcation of the aorta to the crus of the diaphragm whenever radical nephrectomy is performed. Palapattu et al. [43] suggested that extensive LND should start from the crus of the ipsilateral diaphragm superiorly to the medial border of the contralateral great vessel (including interaortocaval nodes) and medially to the bifurcation of the ipsilateral great vessel inferiorly. They proposed that limited LND should begin at the level of the renal hilum superiorly to the anterior, posterior and lateral aspects of the ipsilateral great vessels down to the level of the inferior mesenteric artery [43]. In a large retrospective series, Crispen et al. [44] proposed a template based on five previously defined pathological features of the primary tumour in patients with high-risk disease at the time of radical nephrectomy (with eligible patients having two of the five features). These include the presence of Fuhrman grade 3 or 4 disease, the presence of a sarcomatoid component, tumour size ≥ 10 cm, tumour stage pT3 or pT4 and the presence of coagulative tumour necrosis. In right-sided tumours, they recommend that the paracaval and interaortocaval lymph nodes should be removed, whereas in left-sided tumours, the para-aortic and interaortocaval lymph nodes should be removed from the crus of the diaphragm to the ipsilateral common iliac artery. They determined that the location of lymph node metastases was related to the side of the primary tumour. No right-sided tumours were found to have para-aortic involvement and no left-sided tumours had involvement of the paracaval lymph nodes without prior involvement of para-aortic and interaortocaval nodes, respectively [44].
Lymphatic drainage in RCC
Table 3 Proposed surgical approaches to lymph node dissection in the management of retroperitoneal nodes in RCC. Timing of LND
Extent of LND
Robson et al. [42]
Whenever undergoing radical nephrectomy
Palapattu et al. [43]
‘Extensive’: T1/T2 or T3/T4 disease with clinical nodes and no diffuse metastasis ‘Limited’: T1/T2 disease with clinical nodes and diffuse metastasis; T3/T4 disease with no clinical nodes and no diffuse metastasis; T3/T4 disease with clinical nodes and diffuse metastasis
Crispen et al. [44]
Two or more high risk pathological features: (1) presence of nuclear grade 3 or 4 (2) presence of a sarcomatoid component (3) tumour size ≥ 10 cm (4) tumour stage pT3 or pT4 (5) presence of coagulative tumour necrosis
Para-aortic and paracaval lymph nodes from the crus of the diaphragm to the bifurcation of the aorta ‘Extensive’: crus of the ipsilateral diaphragm superiorly to the medial border of the contralateral great vessel (including interaortocaval nodes) and medially to the bifurcation of the ipsilateral great vessel inferiorly ‘Limited’: level of the renal hilum superiorly to the anterior, posterior, and lateral aspects of the ipsilateral great vessels down to the level of the inferior mesenteric artery Right-sided tumours: paracaval and interaortocaval lymph nodes from the crus of the diaphragm to the common iliac artery Left-sided tumours: para-aortic and interaortocaval lymph nodes be removed in patients with left-sided tumours from the crus of the diaphragm to the common iliac artery
LND, lymph node dissection.
It has been an ongoing challenge to interpret collectively the results of studies that seek to define LND dissection templates. Heterogeneity in both the patient populations selected and disease stage make it difficult to clearly define when LND will be of value and in which patients (Table 3 [42–44]). Furthermore, there are substantial differences among current studies in the definitions of radiographic lymphadenopathy, the number of lymph nodes sampled and the techniques used in resecting and testing nodes. This challenges the applicability of proposed templates. A standardised lymphatic mapping protocol for patients with RCC could initiate the collection of more clinically meaningful data. This could be used to build an evidence-based consensus on the surgical management of retroperitoneal nodes; however, the complexities of renal anatomy, sentinel lymph node mapping and RCC pathogenesis have so far made this a particularly challenging goal.
Future Directions Basic patterns of lymphatic drainage from the kidney can be gleaned from past cadaveric dissection studies. It is important that future dissection studies be carried out on pathological specimens. Live mapping studies in patients with RCC are underway and promising but require significant refinement before the data can be applied clinically; therefore, there still exists a need for cadaveric injection experiments to build on our knowledge of renal lymphatic anatomy. Indocyanine green fluorescent lymphography is an emerging technique that has been successfully applied in lymphatic mapping studies in both patients with breast cancer and those with melanoma [45,46]. It has the advantages of lower costs and does not alter the surgical field. Currently, it is being investigated in preclinical studies for use in mapping lymphatic drainage in lung cancer [47]. The sentinel lymph
node biopsy technique is resource-intensive and this can be a limiting factor for many research groups. Looking forward, indocyanine green lymphography may be a more accessible and standardised technique for lymphatic mapping in RCC. Moreover, advanced multimodality imaging studies that are currently being investigated present a non-invasive alternative to the sentinel lymph node biopsy technique. Results of flourodeoxyglucose F 18 positron-emission tomography showed it has a high specificity (100%) but low sensitivity (75%) for detecting lymph node metastasis [48]. Futhermore, a pilot study was carried out using lymphotrophic nanoparticle-enhanced MRI imaging for assessing lymph nodes in patients with RCC, which was found to have both high specificity (100%) and sensitivity (95.5%) [49]. These preliminary results should be further investigated in a larger prospective study. More recently, high-resolution mapping of deep-tissue lymph nodes in preclinical animal models was carried out in live animals using 89 Zr-furmoxytol with positron-emission tomography/MRI [50]. Advances in imaging technology have the potential to improve the detection of sentinel lymph nodes and the overall process of preoperative planning before LND. If developed further, these multimodal techniques could provide a non-invasive alternative to sentinel lymph node mapping in patients with RCC.
Conclusion Lymphatic drainage in RCC is quite unpredictable. Data from past cadaveric dissections studies have defined much of our understanding of the basic anatomical layout of draining retroperitoneal lymph nodes. Furthermore, the existence of peripheral lymphovenous communications in humans should be studied in more detail. These data may shed more light © 2014 The Authors BJU International © 2014 BJU International
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on the mechanisms of lymphogenous and haematogenous metastasis. Sentinel lymph node mapping techniques have been successfully applied to study lymphatic drainage in RCC, albeit in a small number of patients. Continued refinement and standardisation of the experimental approach is needed to generate valid clinical data from such studies. The goal of lymphatic mapping in RCC is to better predict where early lymphatic metastases may occur. For now, it would be prudent to continue performing LND in carefully selected patients with a high risk of nodal metastasis based on preoperative clinical features. Ultimately, the hope is to build an evidence-based consensus on the role and extent of LND in patients with RCC.
Conflict of Interest None declared.
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Correspondence: Jose A. Karam, The University of Texas MD Anderson Cancer Center, Department of Urology, 1515 Holcombe Blvd, Unit 1373, Houston, TX 77030, USA. e-mail: [email protected] Abbreviations: SPECT, single-photon emission CT; LND, lymph node dissection; EORTC, European Organisation for the Research and Treatment of Cancer.
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