ENDOUROLOGY AND STONE DISEASE Calculi in the Prostatic Surgical Bed as a complication after Holmium Laser Enucleation of the Prostate Young Ju Lee1, Seung-June Oh2* Purpose: To report de novo calculi in the prostatic surgical bed as a complication of Holmium laser enucleation of the prostate (HoLEP). Materials and Methods: Patients who underwent HoLEP and were enrolled in our Benign Prostatic Hyperplasia (BPH) Database Registry from July 2008 to December 2015 were reviewed. Cases of calculi removal in the pros- tatic surgical bed were identified. Clinical data, including preoperative evaluation, postoperative symptoms with a detailed history, urinalysis, pathology, cystourethroscopy, and stone analysis were collected and described. Results: Eight patients were identified including one patient who underwent HoLEP at another hospital. Among the 877 patients in our BPH database, 7 (0.8%) underwent calculi removal in the prostatic surgical bed. Median age was 67.0 years. Median prostatic volume was 75.5mL. The most common symptom was severe stabbing urethral pain (n = 4), with a median of 13 months after HoLEP. Calculi were pedunculated in the prostatic surgical bed or in the bladder neck with a small mucosal connection. Pathology of the resected tissue showed granulation tissue formation and dystrophic calcification. Conclusion: Calculi in the prostatic surgical bed or the bladder neck after HoLEP have never been reported previ- ously. Although it is very rare, recurrent urethral pain, persistent pyuria, and recurrent gross haematuria are signs for further investigation. Cystourethroscopy should be performed to rule out the presence of stones. Careful history taking and having an index of suspicion are important for the diagnosis. Keywords: prostatic hyperplasia; urinary calculi; transurethral resection of prostate; complication. INTRODUCTION Open prostatectomy or transurethral resection of the prostate (TURP) has been the standard of care in the treatment of benign prostatic hyperplasia (BPH). Laser prostatectomy was initially described in 1986 and became popular in 1990s(1). The use of this method has increased in the last decade in the treatment of BPH(2). Holmium laser enucleation of the prostate (HoLEP) is an effective and less invasive alternative to open prosta- tectomy for the surgical treatment of BPH. This method is associated with more favourable outcomes than mo- nopolar TURP(3). The coagulative property of holmium laser provides a relatively bloodless field with no risk of systemic fluid absorption resulting in transurethral resection syndrome. Overall, the complications after HoLEP are fewer than those after TURP(4). However, we discovered patients with de novo calculi in the prostatic surgical bed or bladder neck after HoLEP, which has never been re- ported previously. The purpose of this study is to report this as a complication and the characteristics of its clin- ical presentation. 1Department of Urology, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea. 2Department of Urology, Seoul National University Hospital, Seoul National University School of Medicine, Seoul, Republic of Korea. *Correspondence: Department of Urology, Seoul National University Hospital, Seoul National University School of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea. Phone: +82-2-2072-2406. Fax: +82-2-742-4665. E-mail: sjo@snu.ac.kr. Received May 2017 & Accepted December 2017 PATIENTS AND METHODS Patients We reviewed a patient cohort who had undergone HoLEP at our institution by a single surgeon (SJO) from July 2008 to December 2015. After the approval of institutional review board, we identified patients who also underwent urethral stone removal after HoLEP and reviewed their clinical presentation. In the course of re- search, additional 1 patient was identified who under- went HoLEP at another hospital and included for the analysis. Patients who underwent transurethral surgery due to de novo calculi were included. Patients who had previous urinary calculi were excluded. HoLEP was performed as we have previously described (5). For the enucleation, the three-lobe or four-lobe tech- nique was used with 26Fr resectoscope. After careful haemostasis by using Holmium laser, morcellation was performed with a tissue morcellator (Versacut; Lumenis Ltd.) through the guidance of a 26-Fr nephroscope. After the operation, the patients were discharged on postoperative day 1 after a voiding trial. When consid- erable haematuria existed, the discharge was deferred for 1 or 2 days. Follow-up was done at postoperative 2 weeks, 3 months, 6 months, and 12 months. Careful Endourology and Stone Diseases 238 Vol 15 No 05 September-October 2018 239 history taking, physical examination, and workups in- cluding urinalysis and uroflowmetry were performed at every follow-up visit. Cystoscopic examination was performed when the patient complained of severe ure- thral pain, gross haematuria or persistent microscopic haematuria. Computed tomography was performed for gross haematuria and persistent pyuria. Data analysis Data on preoperative evaluation, HoLEP procedures, the date of calculi removal in the prostatic surgical bed, the main presenting symptom, symptom onset after HoLEP, the interval from symptom onset to the diagno- sis, cystoscopic findings, pathology if present, and the result of stone analysis were obtained. The pathological images were examined by a pathologist. Physical stone analysis was performed using infrared absorption spec- trometry. The results were expressed as a true value or median, which was calculated by using Microsoft Excel software. RESULT A total of 8 patients who underwent calculi removal in the prostatic surgical after HoLEP were identified, in- cluding one patient who underwent HoLEP at another hospital. In our prospective BPH database, 7 (0.8%) patients were identified among 877 patients who under- went HoLEP between July 2008 and December 2015. The characteristics of the patients are presented in Ta- ble 1. Their median age was 67 years. All patients un- derwent HoLEP without immediate complications and were discharged at postoperative day 1 after a success- ful voiding trial. Severe urethral stabbing pain (n = 4) was the most com- mon presenting symptom followed by gross haematuria (n = 2), pyuria (n = 2), and microscopic haematuria (n=1). The urethral pain was typically very unpleasant, burning sensation after voiding or during voiding. The median duration from HoLEP to symptom onset was 13 months (range, 3–44 months). The median interval from the initial onset of symptoms to the diagnosis was 2 month (range, 0.7–12 months). After the diagnosis of calculi in the prostatic surgical bed, calculi removal was performed. All patients had calculi at the bladder neck and/or the prostatic surgical bed. The cystoscopic images of five patients are pre- sented in Figure 1. The largest one was 1.7 cm sized (Case 3). Most calculi were less than 1 cm and spicu- late in shape. The stones were hanging and/or impact- ed in the prostatic surgical bed in a scattered pattern. Calculi in the bladder neck dangled from the bladder neck, connected to the mucosa. Transurethral resection of the surgical bed was performed in one patient, and the pathological examination revealed urothelial den- udation, granulation tissue formation, and dystrophic calcification (Figure 2). The symptoms were resolved after the surgery. However, 1 patient (case 5) had a tur- bid urine and microscopic haematuria after 8 months and underwent the same surgery again for recurred Table 1. Characteristics of the patients. Clinical characteristics at the time of HoLEP Case 1 Case 2 Case 3 Case 4b Case 5c Case 6 Case 7 Case 8 Age (years) 61 61 67 62 71 77 73 67 Total prostate volume (mL)a 121 39 68 N.A. 85 56 83 N.A. Prostatic calcificationa No No No N.A. No No No N.A. Main presenting symptom New onset Severe Gross Severe Severe Gross Urethral pain New onset persistent urethral haematuria, urethral urethral haematuria, at the end of microscopic Pyuria pain after postvoid stabbing pain during UUI voiding, haematuria voiding urethral pain, and after new onset discomfort urgency voiding, persistent UUI pyuria Symptom onset after HoLEP (months) 3 13 19 13 11 6 44 26 Symptom onset to diagnosis (months) 3 1 0.7 1 6 12 3 1 Stone analysis 90% CA, 65% 80% 60% 60% 65% 80% 95% 10% CaOxD, Brushite, CaOxM, CaOxM, CaOxD, CaOxM, CaOxD, CaOxD 35% CA 20% 30% 30% 35% CA 20% 5% CaOxM CaOxD, CaOxD, Struvite CaOxM 10% CA 10% CA Abbreviations: CA, carbonate apatite; CaOxM, calcium oxalate monohydrate; CaOxD, calcium oxalate dihydrate; N.A., not available; PSA, prostate-specific antigen; PVR, postvoid residual volume; Qmax, maximal flow rate; UUI, Urge urinary incontinence. a) Measured with transrectal ultrasonography. b) Referred from another hospital. c) Had a recurrence after 8 months. Figure 1. Cystoscopic images. (a) Small stellated stones are im- pacted in the mucosa of the prostatic surgical bed (Case 1). (b) Numerous stones were identified in the prostatic surgical bed and the bladder neck (Case 4). (c) Transurethral resection of the prostatic surgical bed in case 4 after clearing the stones from the surgical bed. (d) Stones dangled from the bladder neck (Case 5). (e) Recurred stone hanging in the bladder neck (Case 5). (f) Stone dangled from the bladder neck connected to the bladder mucosa (Case 6). Calculi in the prostatic surgical bed after HoLEP-Lee et al. bladder neck stone. Stone analysis for the 2nd opera- tion revealed 95% Calcium oxalate dihydrate and 5% Calcium oxalate monohydrate. There were no evidence of urinary tract infection before the diagnosis, except 1 patient (Case 1) who complained of left testicular dis- comfort. DISCUSSION Long-term complications of HoLEP include retreat- ment, urethral stricture, bladder neck contracture, and meatal stenosis. To our knowledge, this is the first case series on calculi in the prostatic surgical bed after HoLEP. The occurrence of calculi in the surgical bed after laser prostatectomy is rare but possible. Previous reports include a case of urethral stone formation after potassium-titanyl-phosphate (KTP) laser ablation of the prostate(6). These stones can form even 5 years postop- eratively(7). Many etiologic factors have been postulated to explain calculi formation after photoselective vaporization of the prostate with a KTP laser. First, stasis of urine at the prostatic fossa can form urethral calculi, provided that no concurrent urethral strictures exist(6). Second, the presence of debris or foreign bodies after the sur- gery can serve as a nidus for stone formation, which can grow with time(7). Finally, the coagulative necrosis caused by the laser energy itself can induce dystrophic calcification as a reaction to tissue damage, leading to calculi formation. A holmium laser operates at a wavelength of 2,140 nm in a pulsed mode(8). This high-power energy can be used for incision, ablation, resection, and enucleation of prostatic tissues. Diffusion of thermal energy into the surrounding tissue is minimal when using a holmium laser. The thermal energy is absorbed by water, and the safety of the tissue is not compromised, unless direct contact occurs(9). A holmium laser can be used for su- perficial tissue ablation and adequate haemostasis for vessels with a < 1 mm diameter. Substantial tissue co- agulation can be accomplished at a depth of 3–4 mm(10). Although the holmium-YAG laser can penetrate tissues to a depth of only 0.4 mm, a 1–2-mm rim of surround- ing tissue coagulation was observed after holmium ablation of the prostate in a canine model(11). Because we use cutting, ablation, and coagulation freely during surgery, coagulative necrosis may occur, which can in- duce dystrophic calcification as a postoperative reactive change. In addition, threads of mucosa can serve as a nidus for stone formation during the wound-healing process, as fluttering mucosal flags are observed imme- diately after surgery. Unlike in radical prostatectomy, mucosa-to-mucosa anastomosis is not possible during an endoscopic procedure. The wound-healing process is essential for the recovery process. During the recovery, chronic inflammatory infiltrates and granulation tissues replace the necrotic coagulum from the base at 7 weeks after thermal laser injury(12). Until 12 weeks after the laser surgery, a few fragments of necrotic tissues or es- chars adhere to the prostatic urethra. During the resto- ration of mucosal injury, mucosal flags can serve as a nidus for calculi formation. During the healing process, crystal deposition can occur on the de-epithelialized surface, resulting in subsequent stone growth. The presence of pyuria and microscopic haematuria after prostatic surgery is not always a pathological finding(13). Persistent pyuria is one of the most com- mon complications after transurethral prostatectomy(14). Previous reports have noted that pyuria persisted longer than microscopic haematuria regardless of the type of the surgery (monopolar TURP vs. bipolar TURP vs. open prostatectomy). Persistent pyuria lasted a median of 274 days, which was significantly longer than the du- ration of persistent microscopic haematuria (176 days). Therefore, postoperative pyuria can be underestimated, and even ignored, if the patient does not have the com- patible symptoms. However, as one patient in this study showed persistent pyuria after treatment with antibiot- ics, further evaluation is necessary. As noted in our cas- es, a high degree of suspicion for urethral stones should be adopted in patients with recurrent gross haematuria and unexplained severe urethral pain at any time after HoLEP. Early and careful history taking and cystoure- throscopy can be helpful in such cases. A large intake of water might prevent urine stasis and urethral calculi formation, especially during the early postoperative re- covery period. Our study has a few limitations. This study was ret- rospective in nature, involving a cohort of patients operated by a single surgeon. However, the data were prospectively collected. Although this is a very rare complication, the surgeon’s preference for the use of Figure 2. Pathology of the specimen from the transurethral resection described in Fig. 1C (Case 4). (a) Haematoxylin and eosin staining of the resected tissue showing granulation tissue formation (× 40) and dystrophic calcification. (b) A magnified view of the rectangled area of Fig. 2a showing dystrophic calcification (× 100). The urethral luminal side is marked with an arrow. Calculi in the prostatic surgical bed after HoLEP-Lee et al. Endourology and Stone Diseases 240 Vol 15 No 05 September-October 2018 241 laser power and the haemostatic pattern can be factors affecting the incidence of urethral stones after HoLEP. CONCLUSIONS In conclusions, urinary calculi formation in the pros- tatic fossa or the bladder neck after HoLEP is a rare but possible complication. Unexplained urethral pain or discomfort, persistent pyuria, and recurrent gross hae- maturia require further investigation. Cystourethros- copy should be performed to rule out the presence of stones. A focused history taking and having an index of suspicion are essential to the diagnosis. ACKNOWLEDGEMENT Ye-Young Rhee provided photos of pathology. CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Floratos DL, de la Rosette JJ. Lasers in urology. BJU Int. 1999;84:204-11. 2. Schroeck FR, Hollingsworth JM, Kaufman SR, Hollenbeck BK, Wei JT. Population based trends in the surgical treatment of benign prostatic hyperplasia. J Urol. 2012;188:1837- 41. 3. Cornu JN, Ahyai S, Bachmann A, et al. A Systematic Review and Meta-analysis of Functional Outcomes and Complications Following Transurethral Procedures for Lower Urinary Tract Symptoms Resulting from Benign Prostatic Obstruction: An Update. Eur Urol. 2015;67:1066-96. 4. Vincent MW, Gilling PJ. HoLEP has come of age. World J Urol. 2015;33:487-93. 5. Kim M, Lee HE, Oh SJ. Technical aspects of holmium laser enucleation of the prostate for benign prostatic hyperplasia. Korean J Urol. 2013;54:570-9. 6. Tasci AI, Tugcu V, Ozbay B, Mutlu B, Cicekler O. Stone formation in prostatic urethra after potassium-titanyl-phosphate laser ablation of the prostate for benign prostatic hyperplasia. J Endourol. 2009;23:1879-81. 7. Malde S, Rajagopalan A, Koslowski M, Simoes AD, Choi WH, Shrotri NC. Potassium-titanyl- phosphate laser vaporization of the prostate: a case series of an unusual complication. J Endourol. 2012;26:682-5. 8. Le Duc A, Gilling PJ. Holmium laser resection of the prostate. Eur Urol. 1999;35:155-60. 9. van Rij S, Gilling PJ. In 2013, holmium laser enucleation of the prostate (HoLEP) may be the new 'gold standard'. Curr Urol Rep. 2012;13:427-32. 10. Tooher R, Sutherland P, Costello A, Gilling P, Rees G, Maddern G. A systematic review of holmium laser prostatectomy for benign prostatic hyperplasia. J Urol. 2004;171:1773- 81. 11. Kabalin JN. Holmium: YAG laser prostatectomy canine feasibility study. Lasers Surg Med. 1996;18:221-4. 12. Orihuela E, Pow-Sang M, Motamedi M, Cowan DF, Warren MM. Mechanism of healing of the human prostatic urethra following thermal injury. Urology. 1996;48:600-8. 13. Olvera-Posada D, Villeda-Sandoval C, Ramirez-Bonilla M, et al. Natural history of pyuria and microhematuria after prostate surgery. Actas Urol Esp. 2013;37:625-9. 14. Cho KH, Song KH, Chang YS. Study of the Duration of Pyuria after Transurethral Prostatectomy. Korean J Urol. 2007;48:199- 205. Calculi in the prostatic surgical bed after HoLEP-Lee et al.