Lymphoceles: A Contemporary Review and an Approach for Prevention

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A lymphocele, in basic terms, is a cystic cavity containing lymphatic fluid, with a fibrous (not epithelial lined) capsule.
A lymphocele, in basic terms, is a cystic cavity containing lymphatic fluid, with a fibrous (not epithelial lined) capsule.

Most prostatectomies are now being done with concomitant lymphadenectomy. A few factors are responsible. First, urologists are increasingly comfortable offering active surveillance for very-low-risk and most low-risk prostate cancers, all but removing them from the surgical realm. In a National Cancer Database study, 70% of prostatectomies were accompanied by pelvic lymph node dissection (PLND) in 2010–2011,1 and we suspect this number has only risen since.  Second, mounting data indicate that staging is improved with extended PLND (ePLND). It stands to reason that we now have renewed interest in assessing why lymphoceles seem to be an almost inevitable consequence of lymph node removal, uncovering the putative risk factors, and determining how they can be prevented.

History and definitions

A lymphocele, in basic terms, is a cystic cavity containing lymphatic fluid, with a fibrous (not epithelial lined) capsule. It was first described using the term “lymphocyst” after a series of hysterectomies for cervical cancer by Mori in 19552. No official categorization system or severity grading system exists for post-surgical lymphoceles, but some people describe them by denoting how the diagnosis was made, either prompted by symptom-driven investigation (clinical) or incidental on abdominopelvic radiographic exam (radiographic/subclinical).

Pathophysiology, natural history

The exact mechanism of lymphocele formation after either transperitoneal or extraperitoneal prostatectomy with lymphadenectomy is largely speculative. Unsealed lymph channels allow for ongoing lymphorrhea that accumulates into a surgical space. Some collections ultimately resorb spontaneously. Peritoneum allows free absorption of lymph, so for persistent lymphoceles, the fluid cavity must be excluded or walled-off from the peritoneal cavity. In an extraperitoneal approach, exclusion from the peritoneum is easy to conceive, but is perhaps less obvious following a transperitoneal approach. Pelvic lymphoceles are rare following radical cystectomy with lymphadenectomy. This suggests the bladder plays a key role in walling off lymphocele cavities following prostatectomy. Indeed, the bladder usually forms the medial wall of a pelvic lymphocele cavity (figure 1).

The incidence of lymphoceles naturally depends on the rigor with which one searches for them. Since follow-up does not routinely include imaging, the true incidence is unknown.3 If routine imaging is done, radiographic lymphoceles are quite common. Two studies have included routine CT scans postoperatively, one by Orvieto et al, in which 51% had radiographic and 15.4% had clinical lymphoceles,4 and another by Solberg et al, which found a 54% incidence of radiographic lymphoceles.5

If lymphoceles become symptomatic they typically do so at approximately the third postoperative week.6 Symptoms are predominantly related to local compression. The patient may report generalized abdominal or pelvic pain and pressure. If the external iliac vein is compressed, leg edema or venous thrombosis may ensue. If the bladder is compressed, irritative urinary frequency occurs as the bladder is prevented from filling. Similarly, constipation can occur from rectal compression. When secondarily infected, fever, chills, and even night sweats are seen. When symptomatic, most patients will require intervention either with percutaneous drain placement or laparoscopic marsupialization.7

Risk factors

Standard vs extended lymphadenectomy. The impact of lymphadenectomy extent has been studied. Interestingly, even when lymphadenectomy is omitted, the lymphocele rate is not zero,8 perhaps because even by mobilizing the bladder and defatting the anterior surface of prostate, lymphatic channels may be disrupted, though this is pure speculation. A standard PLND (sPLND) includes nodes bounded by the common iliac artery superiorly, external iliac vein laterally, node of Cloquet inferiorly, and the obturator nerve posteriorly.9 An ePLND extends the lateral border to the genitofemoral nerve, medially to the bladder wall and ureter, and includes the internal iliac nodes, including tissue below the obturator nerve.9 One might expect that the more lymphatic channels transgressed over a larger lymphadenectomy template, the greater the likelihood of lymphocele formation. This remains controversial, however.

Naselli et al evaluated 359 patients undergoing PLND (98 sPLND, 249 ePLND) with a 12.6% lymphocele rate, 7.4% of which were symptomatic.9 On multivariate analysis, the number of nodes showed a significant linear association with symptomatic lymphocele formation. Lymphoceles developed in 2% of the sPLND group compared with 9.6% of the ePLND group. Similarly, Briganti et al found a higher incidence of lymphocele in ePLND (10.3%) vs sPLND (4.6%) in a series of 963 patients.10

Other groups have found no difference in lymphocele rates by lympadenectomy extent. In a study of 492 robotic prostatectomies, Liss et al found similar (~5%) rates of lymphocele for both templates; however, in this series lymph node yield was statistically similar in the sPLND and ePLND groups.11 Yuh et al compared obturator nodes only to ePLND in 406 patients, and symptomatic lymphocele rates were very similar (2.2% and 2.5%).12

Heparin. Chemoprophylaxis to prevent thromboembolic complications has become a standard feature in contemporary prostatectomy series. Since lymphatic fluid contains similar coagulation factors as plasma,3 it has been postulated that anticoagulation may prolong lymphorrhea by keeping lymphatic channels open longer, though this remains controversial. In a fairly small Swedish study in 1994, 24 patients with and without heparin were compared for degree of lymph fluid buildup postop. The lymph fluid buildup was markedly higher in the heparinized group.13 In a similar study in 1992, Biggs and Catalona looked at 68 patients. In the group receiving prophylactic heparin, prolonged suction drainage for high drain output was more common.14

Others have found no association of lymphoceles with prophylactic heparin. In a study of 579 men undergoing prostatectomy with and without heparin, Sieber et al found no difference in lymphocele rates.15 In a study of almost 1500 patients, lymphocele rates were also no different whether or not heparin prophylaxis was administered.16

Lymph node positivity. Whether node status at the time of prostatectomy influences the likelihood of lymphocele development is another arena in which the literature is split. The issue may be difficult to untangle from extent of lymphadenectomy, since patients at highest risk of lymph node positivity typically receive a more thorough dissection, which is more likely to reveal positive nodes. In the Orvieto Study,4 on multivariate analysis, nodal involvement was associated with twice the risk of lymphocele formation (p=0.03). Other studies have not supported this observation. In a study by Capitanio et al of 552 prostatectomies, only age and number of nodes, and not lymph node status, predicted lymphocele.17

Patient age. As mentioned above, Capitanio et al found an increased clinically significant lymphocele risk of 5% for every year of age.17 However, in the study by Orvieto and colleagues, patient age was not a factor on univariate or multivariate analysis.4

Trans vs extraperitoneal prostatectomy. A randomized trial comparing transperitoneal and extraperitoneal prostatectomy would be required to definitively settle the question as to which has a higher lymphocele rate. One intuitively expects the rate to be lower with a transperitoneal approach, but the lymphadenectomy cavity can still become walled off, typically by the bladder, as described earlier. Retrospective propensity matched analysis such as one by Horovitz and colleagues18 examined 3183 RARPs by a single surgeon, with 671 in each group. Symptomatic lymphocele rates between the group were statistically similar: 2.83% after extraperitoneal and 1.49% after transperitoneal. Low event rates may hamper definitive conclusions.

Potential preventative strategies

Investigators have explored various strategies to prevent lymphoceles from forming. Leaving a JP drain in longer to divert excess lymphorrhea rather than letting it accumulate makes intuitive sense. Like many factors in this arena, results have been conflicting. In a randomized study, Danuser demonstrated the lowest rate of symptomatic lymphoceles among patient in whom a JP was left in for 7 days compared with 1 day or no drain at all.19 However, in this study, the overall lymphocele rate was similar in all groups. In a study of 4173 prostatectomies with bilateral pelvic lymph node dissection, Gotto et al found no association with the number of pelvic drains (1 or 2) and development of symptomatic lymphocele, or laterality of the lymphocele when laterality of drain placement was known.20 It seems likely that pelvic drainage adds little value to prevent lymphocele formation, probably because the duration of drainage would have to be quite longer than the ranges studied, as lymphoceles present on average 3 weeks postop.21

One might expect that rigorous clip application during lymphadenectomy would decrease the incidence of lymphoceles. A prospective randomized trial comparing titanium clip application to bipolar cautery found no difference in overall or symptomatic lymphoceles between groups.22 In an accompanying editorial, the observation that clips were only applied at the femoral canal was cited as a major study limitation.23 They argued that clips should either be applied liberally in all locations or not at all. As such, systematic use of extensive clipping can achieve a near zero lymphocele rate as reported by others.24

For those favoring an extraperitoneal approach to prostatectomy, making a large fenestration in the peritoneum at the end of a case may reduce the incidence of lymphocele formation. Stolzenburg et al compared 50 patients with and without this technique and found a 32% lymphocele rate in patients without a fenestration compared with a 6% rate with fenestration.25 Why this linear fenestration does not rapidly seal over shortly postoperatively is difficult to conceptualize.

Virtually all types of hemostatic agents have been used in attempts to prevent lymphocele formation. In a study by Waldert et al, 32 patients had Floseal applied to the lymphadenectomy bed and 110 patients did not.26 The incidence of symptomatic lymphoceles decreased from 14.5% to 3.1% in favor of FloSeal®. Similarly lower lymphocele incidence has been found after TachoSil® application.27 Authors generally hypothesize that a fibrin clot may be formed, reducing lymphorrhea. We hypothesize some sort of local sclerosant effect, akin to sclerosing of the pleural cavity or hydrocele sac whereby a hemostatic agent inflames and subsequently obliterates the potential cystic cavity, thus preventing lymphocele formation.

Peritoneal advancement flap - The Lahey Lymphocele Stitch

Our institutional experience with lymphocele prevention began in 2012, when we began creating a peritoneal interposition flap using the visceral peritoneum of the bladder. Based on our observations that the bladder forms the medial wall of a pelvic lymphocele, and noting the scarcity of lymphoceles after cystectomy, the crucial role of the bladder in walling off a lymphocele was apparent. After transperitoneal robotic prostatectomy and pelvic lymphadenectomy, the available peritoneum folded around laterally and sutured to the bladder itself so that the bladder's lateral aspect is now covered with visceral peritoneum. This prevents the bladder from adhering to and walling off the pelvic lymphadenectomy bed, allowing continuous egress of lymphatic fluid into the peritoneal cavity. Another way to conceive of this is creation of a fenestration up front at the time of prostatectomy, notwithstanding that the approach is already transperitoneal. In a nonrandomized study of 78 patients with a flap and 77 patients without a flap, there were no lymphoceles in the peritoneal advancement flap group compared with an 11.6% baseline lymphocele rate.28 This strategic suture fixation of available peritoneum bilaterally can be accomplished in less than 5 minutes at the end of the case. A multi-institutional randomized trial using the Lahey lymphocele stitch is in preparation. For a video of the technique, please visit http://bit.ly/laheystitch

David Canes, MD

David Canes, MD, of the Lahey Institute of Urology at Lahey Hospital & Medical Center in Burlington, MA.








Alireza Moinzadeh, MD

Alireza Moinzadeh, MD, of the Lahey Institute of Urology at Lahey Hospital & Medical Center in Burlington, MA.







References

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2. Mori N. Clinical and experimental studies on the so-called lymphocyst which develops after radical hysterectomy in cancer of the uterine cervix. J Jpn Obstet Gynecol Soc. 1955;2:178-203.

3. Lee HJ, Kane CJ. How to minimize lymphoceles and treat clinically symptomatic lymphoceles after radical prostatectomy. Curr Urol Rep. 2014;15:445.

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5. Solberg A, Angelsen A, Bergan U, et al. Frequency of lymphoceles after open and laparoscopic pelvic lymph node dissection in patients with prostate cancer. Scand J Urol Nephrol. 2003;37:218-221.

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10. Briganti A, Chun FK, Salonia A, et al. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur Urol. 2006;50:1006-1013.

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12. Yuh BE, Ruel NH, Mejia R, et al. Standardized comparison of robot-assisted limited and extended pelvic lymphadenectomy for prostate cancer. BJU Int. 2013;112:81-88.

13. Tomic R, Granfors T, Sjödin JG, Ohberg L. Lymph leakage after staging pelvic lymphadenectomy for prostatic carcinoma with and without heparin prophylaxis. Scand J Urol Nephrol. 1994;28:273-275.

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15. Sieber PR, Rommel FM, Agusta VE, et al. Is heparin contraindicated in pelvic lymphadenectomy and radical prostatectomy? J Urol. 1997;158(3 Pt 1):869-871.

16. Chalmers DJ, Scarpato KR, Staff I, et al. Does heparin prophylaxis reduce the risk of venous thromboembolism in patients undergoing robot-assisted prostatectomy? J Endourol. 2013;27:800-803.

17. Capitanio U, Pellucchi F, Gallina A, et al. How can we predict lymphorrhoea and clinically significant lymphocoeles after radical prostatectomy and pelvic lymphadenectomy? Clinical implications. BJU Int. 2011;107:1095-1101.

18. Horovitz D, Lu X, Feng C, et al. Rate of symptomatic lymphocele formation after extraperitoneal vs transperitoneal robot-assisted radical prostatectomy and bilateral pelvic lymphadenectomy. J Endourol. 2017;31:1037-1043.

19. Danuser H, Di Pierro GB, Stucki P, Mattei A. Extended pelvic lymphadenectomy and various radical prostatectomy techniques: is pelvic drainage necessary? BJU Int. 2013;111:963-969.

20. Gotto GT, Yunis LH, Guillonneau B, et al. Predictors of symptomatic lymphocele after radical prostatectomy and bilateral pelvic lymph node dissection. Int J Urol. 2011;18:291-296.

21. Canes D, Cohen MS, Tuerk IA. Laparoscopic radical prostatectomy: omitting a pelvic drain. Int Braz J Urol. 2008;34:151-158.

22. Grande P, Di Pierro GB, Mordasini L, et al. Prospective randomized trial comparing titanium clips to bipolar coagulation in sealing lymphatic vessels during pelvic lymph node dissection at the time of robot-assisted radical prostatectomy. Eur Urol. 2017;71:155-158

23. Stolzenburg JU, Kyriazis I, Liatsikos E. Postoperative lymphocele formation after pelvic lymph node dissection at the time of radical prostatectomy should not be considered an inevitable consequence of the approach. Eur Urol. 2017;71:159-160.

24. Davis JW, Shah JB, Achim M. Robot-assisted extended pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP): a video-based illustration of technique, results, and unmet patient selection needs. BJU Int. 2011;108(6 Pt 2):993-998.

25. Stolzenburg JU, Wasserscheid J, Rabenalt R, et al. Reduction in incidence of lymphocele following extraperitoneal radical prostatectomy and pelvic lymph node dissection by bilateral peritoneal fenestration. World J Urol. 2008;26:581-586.

26. Waldert M, Remzi M, Klatte T, Klingler HC. FloSeal reduces the incidence of lymphoceles after lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy. J Endourol. 2011;25:969-973.

27. Simonato A, Varca V, Esposito M, et al. The use of a surgical patch in the prevention of lymphoceles after extraperitoneal pelvic lymphadenectomy for prostate cancer: a randomized prospective pilot study. J Urol. 2009;182:2285-2290.

28. Lebeis C, Canes D, Sorcini A, Moinzadeh A. Novel technique prevents lymphoceles after transperitoneal robotic-assisted pelvic lymph node dissection: Peritoneal flap interposition. Urology. 2015;85:1505-1509.

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