Immunohistochemical Evaluation of the Safety of Transurethral Electrovaporization of the Prostate and Its Clinical Results

Prostate Cancer and Prostatic Diseases (1999) 2, 16±20 ß 1999 Stockton Press All rights reserved 1365±7852/99 $12.00 http://www.stockton-press.co.uk/pc Immunohistochemical evaluation of the safety of transurethral electrovaporization of the prostate and its clinical results

A Tizzani1, P Gontero*3, G Casetta1, P Piana1, C Baima1, A de Zan1, G Bodo1 and D Pacchioni2 Departments of 1Pathologic Urology and 2Pathology, University of Torino, Torino, Italy; and 3Department of Urology, King's College Hospital, London, UK

Short term follow up studies on transurethral electrovaporization (TUEVP) have shown a relative low morbidity over TURP. The use of high power current has been claimed as a source of possible damage on the neuronal structures surrounding the prostate. The aims of our study were to assess longer follow up results as well as the safety of this technique. Over an 18 month mean follow up period symptom relief remained relatively stable. Postoperative dysuria was detected in a higher percentage of patients and was seen for a longer period in comparison with previous reports. Immunohistochemical staining performed using S-100 and NF monoclonal antibodies showed anatomical integrity of the prostatic neuronal ®bres surrounding the vaporization edge. In conclusion, although the effectiveness and safety of TUEVP are con®rmed by the present study, the occurrence of a signi®cant rate of long-lasting postoperative irritative symptoms must be taken into account.

Keywords: prostate electrovaporization; side effects; safety; neuronal damage; immunohistochemistry

Introduction advantage over TURP is a reduction of the morbidity associated with the procedure.7 The technique employs a Transurethral resection of the prostate (TURP) is generally special resectoscope `loop' (Vaportrode) that uses existing recognized as the `gold standard' treatment of benign electrosurgical generator sources.8 By using high-fre- prostatic hyperplasia (BPH) because, in spite of numerous quency cutting current, synchronous vaporization and other treatment options available, it can achieve better, coagulation of the prostatic tissue are obtained.9 The use more durable results at a more cost-effective rate.1 How- of high power levels has raised concerns about the ever, about a quarter of men selected on the basis of possible damage to adjacent tissues due to elevated symptoms and ¯ow rates fail to do well after TURP2 and tissue temperatures in proximity to the electrode. Inter- in the long term, about a ®fth undergo a second opera- stitial temperature changes during the use of Vaportrode tion.3 Causes of early morbidity include peri- and post- are transient and highly localized.8 However no clear operative bleeding requiring blood transfusion in 2 ± 5% demonstration of the anatomical integrity of periprostatic of patients4 and clinical manifestations of ¯uid absorption neuronal bundles has been reported so far. Short term occurring in 2% of cases.5,6 follow up studies have shown clinical improvements in Transurethral electrovaporization of the prostate symptoms and ¯ow rates close to those obtained with (TUEVP) is a modi®cation of TURP. The main potential standard TURP.10,11 The aims of our study were to assess relief of obstruc- tive symptoms durability in a longer follow up period Correspondence: *Dr P Gontero, Urology Research Registrar, (more than one year) and complication rate after TUEVP. Urology Of®ce, King's College Hospital, Denmark Hill, SE5 9RS London, UK. At the same time an immunohistochemical study was Received 28 May 1998; revised 27 August 1998; accepted performed in order to demonstrate histological integrity 23 September 1998 in nerve ®bers surrounding the vaporized prostatic tissue. Complications and safety of prostate electrovaporization A Tizzani et al 17 Patients and methods that they had provided informed consent. To de®ne long term results, all patients were interviewed at a minimum follow-up period of 1 y on IPSS, and asked speci®cally One hundred and seventy-seven TUEVP procedures were about side effects and complaints or satisfaction with the performed between January and December 1996 in our operation. institution, and assessed at the Department of Pathologic Urology, University of Torino. Selection criteria included all patients with moderate to severe symptoms as de®ned Immunohistochemistry by the International Symptoms Score (IPSS), a peak ¯ow Immunohistochemical evaluation of nervous structures rate less than 15 ml/s and a prostatic adenoma weight was carried out on 12 patients' tissue samples obtained usually not exceeding 40 gm. Patients with prostatic intraoperatively by resecting the prostatic capsule cancer, proven neurogenic bladder, urethral stricture beneath the vaporization edge with a TURP loop. and previous prostate surgery were excluded from the Biopsy specimens from the re-epithelized prostatic cap- study. Preoperative evaluation included digital rectal sule were obtained from the same patients at one month examination (DRE), the completion of a standard IPSS and studied as well. Two patients from this group under- questionnaire, uro¯owmetry using a Oynatec uro¯ow went a cystoprostatectomy six months later for bladder machine, transrectal ultrasound (TRUS) and abdominal cancer and prostatic nerves in these cases were also ultrasound, urinalysis, urine culture as well as all blood evaluated by immunohistochemistry. investigations required for spinal anesthesia. Patients Histological sections of paraf®n-embedded tissue were showing a PSA in the `grey zone' (4 ± 10 ng/ml range) stained with haematoxylin-eosin (HE). Immunohisto- and over the age-related limit in spite of normal DRE and chemical reaction was performed using monoclonal anti- TRUS, underwent free-total PSA determination and sub- body anti-neuro®lament (DAKO-NF, 2F11, 1:50 dilution) sequent systematic sextant biopsies when PSA free ratio 12 which reacts with the 200 KD and the 70 KD component was < 20%. of the three major polypeptide subunits generally present All vaporization procedures were performed by one of in neuro®laments. We also employed monoclonal anti- four operators after a learning curve of at least 10 patients body anti-S100 protein (DAKO; 1:100 dilution) which has prior to entering the study. The Circom ACMI grooved shown to be strictly S-100 speci®c. Vapor Trode vaporization electrode was used for the ®rst The staining were developed by streptavidin-biotin- 120 procedures, while the Circon ACMI ¯uted Vapor peroxidase complex. Neuro®laments are present in neu- Trode was used for the remaining 57 patients. The elec- ronal processes and peripheral nerves as well as sympa- trosurgical unit was set at pure cutting current at 300 W, thetic ganglion cells of normal tissues. S-100 is a nuclear higher than the 250 W value generally regarded as the and cytoplasmatic protein present in Schwann cells of the standard level. The vaporization process was begun at the peripheral nervous system. Detection of both these struc- six o'clock position of the bladder neck, advancing the tures enables a morphological evaluation of nervous electrode to the level of the verumontanum after all tissue structures integrity, whose identi®cation is not possible between 5 o'clock and 7 o'clock at the bladder neck had with conventional methods.13,14 been vaporized. Lateral lobes were then vaporized with successive passes from the bladder neck to the veru montanum, gradually advancing to 12 o'clock of the Statistical methods ipsilateral lobe. This process was repeated until the char- acteristic white ®bres of the surgical capsule were Student's t-test analysis was employed, to compare IPSS revealed with minimal bleeding. The vaporization on and peak ¯ow velocity (PFV) distribution, before the the roof (12 o'clock) was minimal since very little tissue vaporization and during follow up. was usually present. The procedure was completed by using gentle retrograde and also anterograde movements to remove as much residual apical tissue as possible at the veru montanum level. Mean operative time was 50 min. Results By exercising slow movements and medium pressure with the electrode on the prostatic tissue a 2 ± 3 mm deep The 177 participants enrolled in the study demonstrated furrow of vaporization could be created. Maximal effects the following preoperative features: median age 66 y of TUEVP were sometimes limited by the increased (s.d. 9; range 47 ± 91), mean PSA 2.44 ng/ml resistance due to formation of charred tissue. After com- (s.d. 2.14; range 0.1 ± 11.6), prostatic weight mean plete coagulation obtained with several passes by mean of value of 36.4 gm (s.d. 17.3). Only 142 patients were the vaporizing loop, tissue was not removed when it was evaluated in a long-term follow-up (range 12 ± 33 situated adjacent to the pericapsular zone. A standard 22 months, mean 18.8 months, s.d. 7.15). The drop out Ch, 3-way catheter was placed at the end of procedure. rate was 20% (35 cases) while six patients were with- Saline irrigation was usually discontinued after a few drawn from the study (two deaths, one permanent cathe- hours since only slight haematuria was noted in the terization following the procedure, the urodynamic majority of cases. Soon after the vaporization blood ®nding of detrusor atony in one case, and a radical samples were taken for serum electrolytes and haemaglo- cystectomy performed at six months follow-up in two bin. IPSS and peak ¯ow rate were reassessed at one patients owing to the worsening of an histologically month post-operatively. The follow-up protocol included super®cial bladder cancer). Symptom scores improved transrectal ultrasound in 67 patients and cystoscopy with signi®cantly from the baseline value at one month biopsy of the prostatic capsule in 12 patients, provided (P < 0.001) and remained signi®cantly low at the time of Complications and safety of prostate electrovaporization A Tizzani et al 18 Table 1 lists the main adverse events which occurred in the early or delayed follow-up in 140 patients

Adverse events N (%)

Ematuria early (lasting few days) 10 (7.2) delayed (starting 10 ± 15d postoperatively) 56 (40) Recatheterization rate (overall) 31 (22) after 1d removal 11 (35.5) after 2d removal 14 (45.2) after 3 or > d removal 6 (19.3) Urethrotomy 3 (2.2) Redo TURP/TUEVP 5 (3.6) Irritative symptoms duration < 7 days 20 (14.3) 1 month 84 (50.3) 2 months 28 (20) 3 or > months 8 (5.7) Occurrence of delayed dysuria after 7d from TUEVP 29 (21) after 15d from TUEVP 17 (12.3) Subjective LUTS deterioration post operatively after 3 months 23 (16.5) after 6 months 0 (0) after 1y 5 (3.6) Urinary incontinence terminal dribbling 37 (26.6) urge-incontinence 1 (0.7) stress-incontinence 3 (2.2) Retrograde ejaculation 115 (84) Impotence occurred after TUEVP 12 (8.7) Patient unsatisfactory rate of the procedure 22 (16)

underwent a subsequent endoscopic procedure (TURP Figure 1 (a) IPSS values variability at the baseline, at one month follow- in two cases and TUEVP in three cases) owing to persis- up and in the long term follow up (> 1 y) in all patients, and in the tent lower urinary tract symptoms (LUTS) attributable to subgroup of patients respectively with (TRUS) or without (TRUS7) bladder outlet obstruction con®rmed by urodynamic sonographic appearance of residual adenoma at one month follow up. ®ndings. 83.9% of sexually active men reported the Improvement in symptom score was highly signi®cant at one month (P < 0.0001) and maintained in the long term follow up (P < 0.0001); (b) occurrence of retrograde ejaculation, while 12 patients Mann ± Whitney test showed an overall signi®cant improved ¯ow rate at complained of postoperative impotence. Overall patient's one month follow up (P < 0.001). The difference in ¯ow rate observed in satisfaction rate for the procedure was 85%. patients respectively with or without sonographic ®nding of residual adenoma at one month was not signi®cant (P 0.21).

Immunohistochemistry last follow-up (P < 0.001), although a worsening trend in comparison to early results could be seen (Figure 1a). PFV Seven out of 13 tissue samples taken intraoperatively measured at one month (mean 19.1; s.d. 8.1) signi®- corresponded to the surgical capsule and four of them cantly increased when compared with the baseline (mean were positively stained for either S 100 and NF. Five out 9.63; s.d. 5.09) (P < 0.0001). of six of the remainder showed a positive reaction for In twenty-six out of 67 patients (38%) undergoing both monoclonal antibodies and were histologically TRUS one month postoperatively revealed a sonographic de®ned as residual adenomatous tissue. Microscopic pattern consistent with a signi®cant amount of residual examination showed in all cases a well preserved nervous adenomatous tissue. However these patients were not structure. Anti-S100 and anti-NF revealed in all cases the found to differ signi®cantly both in terms of IPSS and PFV integrity of nervous ®bers (Figure 2a,b). This immunohis- from the ones where only a thin BPH layer surrounded an tochemical pattern was comparable to that observed in otherwise open bladder neck (Figure 1). Overall mean TURP specimens obtained as control cases (Figure 2c). catheterization time was only of 1.8 d. IHC reactions conducted on 12 biopsy samples taken at In Table 1 early and later complications occurring both one month during cystoscopic evaluation stained nega- peri- and postoperatively are listed. No appreciable dif- tively for both markers in all cases. On the contrary, IHC ferences in serum sodium and haemoglobin levels were staining revealed a normal expression of neuronal anti- found in the ®rst hours following the procedure. None of gens in capsular tissue samples surrounding the vapor- the patients required a blood transfusion or experienced ization edge in two patients submitted to symptoms related to ¯uid absorption. Five patients cystoprostatectomy 6 months after TUEVP. Complications and safety of prostate electrovaporization A Tizzani et al

water above boiling point to induce steam production 19 and consequently cell explosion. This process is depen- dent upon several variables such as higher peak voltages, blended wave form and high power current generator. A particular electrode design, with larger surface areas than the TURP loop and several thin ridges on it, allows the combination of two electro-surgical effects: tissue vaporization with the development of a zone of desiccation below the vaporized zone and coagulation.16,17 As a result haemostasis and water reabsorption prevention can be achieved. In our series, the lack of bleeding requiring transfusion and the absence of symptoms related to ¯uid absorption con®rmed the well documented safety of TUEVP.7,10,15,18 Because of the relative decrease in bleeding during the procedure and the immediate postoperative period, catheterization time and length of hospital stay were signi®cantly reduced. However in our experience catheter removal occurred signi®cantly later and was associated with a signi®cant high recatheterization rate following early removal (1 ± 2 postoperative days) in comparison with previous reports from Kaplan.9,10 In the majority of cases urinary retention was not due to blood clots. Urethral oedema following thermal damage may explain this early complication. Gallucci et al. have raised concerns about the higher incidence of incontinence post TUEVP compared with TURP.19 Although sporadic cases of stress incontinence have occurred several comparative studies have been reported in which no difference over TURP was noted.7,20 During vaporization, electrical energy is converted in the tissue to high thermal energy. The extent of the lesion induced is proportionately greater with increasing power output of the electrosurgical unit. The most widely used power setting is 250 W, which allows the maximal depth of vaporization.21 One of the main concerns of the use of higher electrical energy is the possible effect on adjacent structures to the prostate, for example the neurovascular bundle or the bladder neck. Studies utilizing thermal mapping have demonstrated that interstitial sensors placed at the neurovascular bundles did not record any temperature change,22 and at one cm from the area of vaporization the temperature rise was slight and transient.23 The coagulation depth beyond the vaporized cavity is reported not to exceed 2 ± 3 mm. No microscopical heat- induced alterations were detected on histological evaluation of rectal serosa and bladder trigone in the canine Figure 2 (a) Prostatic capsular layer adjacent to the adenoma following 24 TUEVP. Sample taken by resecting a prostatic capsular chip with a TURP model. However using HE histopathological samples, loop. Immunohistochemical staining with anti-S100 monoclonal antibody structural abnormalities of the nerves cannot be detected. shows well preserved nervous structures (spindle cells arranged in parallel Our immunohistochemical study seemed to demonstrate bulbe. Black arrow) and mature ganglion cell (white arrow). Magni®cation the anatomical integrity of prostatic nerve ®bres sur- 400 (b) The same picture as A at 250 magni®cation. The black arrow points rounding the vaporization edge. These data con®rm the a well preserved nerve structure; (c) Control case. Immunohistochemical reaction with anti S-100 shows well preserved nervous structures (black lack of immunohistochemically demonstrable neuronal arrows) in a sample including also prostatic capsule following TURP. thermal damage, such as neuronal disruption occurring Magni®cation 250. after prostate heat delivery during thermotherapy.25 However speci®c antibodies on nervous structures may not reveal alterations in the functional properties of neuronal transmission. The lack of erectile dysfunction Discussion following TUEVP has been claimed as proof of the lack of effect of this procedure on the periprostatic neurovascular A seldom discussed bene®t of TUEVP over TURP is the bundle.10 A number of patients from our series, however, lower intraoperative morbidity reported by several com- complained of onset of erectile dysfunction after TUEVP. parative studies.7,9,15 In TUEVP prostatic tissue is vapor- No further diagnostic procedures were done in these ized by rapidly raising the temperature of intracellular patients to better de®ne the possible organic cause of Complications and safety of prostate electrovaporization A Tizzani et al

20 sexual failure, therefore the possibility of neuronal 4 Thorpe AC et al. Deaths and complications following prostatect- damage could not be ruled out. omy in 1400 men in the northern region. Br J Urol 1994; 74: 559 ± Improvement in symptoms and ¯ow rates following 565. 5 Olsson J, Nlsson A, Hahn RG. Symptom of the transurethral TUEVP are consistent and durable. This is not surprising resection syndrome using glycine as the irrigant. J Urol 1995; 154: since a complete ablation of the obstructing adenoma can 123 ± 128. easily be achieved. In our experience a signi®cant residual 6 Mebust WK et al. Transurethral prostatectomy: immediate and adenomatous tissue detected by means of TRUS was postoperative complications. A cooperative study of 13 partici- correlated to a decreased PFV, and although not statisti- pating institutions evaluating 3885 patients. J Urol 1989; 141: cally signi®cant, was able to compromise long term ben- 243 ± 247. e®ts. Large prostate volumes and technical errors 7 Ekengren J, Hahn RG. Complications during transurethral vaporization of the prostate. Urology 1996; 48: 424 ± 427. (advancing the vaportrode at a too high speed or exerting 8 Larson TR, Religo WM, Collins JM, Novieki D. Detailed prostatic a too heavy pressure on urethral surface) can decrease the interstitial thermal mapping during transurethral grooved roller- maximal effects of TUEVP with the formation of charred ball electrovaporization and loop electrosurgery for benign pro- tissue. As a result completed vaporization is prevented by static hyperplasia. Urology 1996; 48: 501 ± 507. an increased electrical resistance.22 The incidence of post- 9 Kaplan SA, Te AE. Transurethral electrovaporization of the operative dysuria has varied among published reports. prostate: a novel method for treating men with benign prostatic hyperplasia. Urology 1995; 45: 566 ± 572. Irritative symptoms have been reported as rare events. 10 Kaplan SA, Santarosa RP, Te AE. Electrovaporization of the Kaplan found a 5 ± 10% rate of dysuria usually resolving prostate for symptomatic benign prostatic hyperplasia: the 1 spontaneously after an average of 7 d.10 By contrast the year experience (Abstract). J Urol 1996; 155: 405A. majority of our patients complained of irritative symp- 11 Hamawy KJ, Siroky MB, Krane RJ, Babayan RK. Transurethral toms usually lasting one month postoperatively. The vaporization of the prostate (TUVP): an electrosurgical alterna- explanation of such a variability between different authors tive for BPH (abstract). J Endourol 1995; 9 (Suppl 1): 5124. 12 Catalona W et al. Increased speci®city of PSA screening through remains a mater of controversy. One of the main com- measurement of percentage free PSA in serum. J Urol 1995; 153: plaints of a signi®cant number of patients from our group 312A, Abstract 336. was troublesome dysuria occurring 5 ± 15 d after the pro- 13 Kindblam LG et al. S-100 protein in melanocytic tumours. Acta cedure. The symptom, usually self-limiting, had a variable Path Microbiol Immunol Scand. Sect A 1984; 92: 219 ± 230. degree of duration and no relief could be obtained despite 14 Miettinen M, Lehto VP, Virtanen I. Antibodies to intermediate antibiotic or FANS therapy. The new minimally invasive ®lament proteins in the diagnosis and classi®cation of human BPH ablation techniques, such as laser prostatectomy and tumours. Ultrastruct Pathol 1984; 7: 83 ± 107. 15 Narayan P et al. Transurethral vaportrode electrovaporization of microwave thermotherapy are more likely to induce pro- the prostate: physical principles, technique and results. Urology 26,27 longed irritative symptoms. These symptoms have 1996; 47: 505 ± 510. been related to an in¯ammatory process caused by a 16 Patel A, Fuchs GJ. Basic principles, discussion of variables and coagulative necrosis which is the pathological process operative techniques of TUEVP. Urotrends 1996; 1: 1 ± 8. underlying these techniques. It is therefore possible to 17 Piana P, Giammo' A, De Zan A, Tizzani A. Biophysical principles hypothesize that an excessive electrodissection carried of tissue vaporization. Min Urol Nephrol 1997; 49: 151 ± 156. 18 Hamawy KJ et al. Transurethral vaporization of the prostate out in order to attain a more complete prostatic tissue (TUVP): clinical follow-up at one year (Abstract). J Urol 1996 vaporization could produce a similar symptomatic pattern Suppl; 155: 404A. toward a necrotic process below the coagulated tissue.28 19 Gallucci M et al. Transurethral electrovaporizaton of the prostate (T.V.P.) vs TURP: A multicentric randomized comparative study (Abstract). Eur Urol 1996; 30: 398. Conclusions 20 Evans RM, Bernhard PH, Reddy PK. A randomized study of In three years of experience many enthusiastic reports transurethral resection of the prostate gland and transurethral vaporization of the prostate gland. (Abstract). J Urol 1997; 157 have claimed the safety and ef®cacy of TUEVP. This novel (Suppl): 556. technique, developed as a modi®cation of the standard 21 Narayan P et al. Factors affecting size and con®guration of endoscopic method for prostate ablation, appears to electrovaporization lesions in the prostate. Urology 1995; 47: decrease morbidity over TURP with comparable out- 679 ± 688. come. Our experience with a follow up of more than 22 Larson TR, Religo WM, Collins JM, Novicki D. Detailed prostatic one year seems to con®rm these results. Nevertheless interstitial thermal mapping during transurethral grooved roller- ball electrovaporization and loop electrosurgery for benign pro- some doubts regarding postoperative symptoms remain static hyperplasia. Urology 1996; 48: 501 ± 507. to be elucidated. Although the learning curve is minimal, 23 Reis RB et al. Interstitial thermometry in men undergoing electro- haemostasis excellent and ¯uid absorption negligible, it is vaporization: is it safe? (Abstract). J Urol 1996; 155 (Suppl) 707A, technically important to avoid tissue charred formation. 1585. Finally further randomized controlled studies are man- 24 Permutter AP, Muschter R, Rarvi HA. Electrosurgical vaporiza- datory to assess further the symptom free durability over tion of the prostate in the canine model. Urology 1995; 46: 518 ± 526. TURP in a longer follow up. 25 Perachino M et al. Does transurethral thermotherapy induce a long-term alpha blockade? Eur Urol 1993; 23: 299 ± 301. References 26 Kabalin JN. Laser prostatectomy performed with a right angle ®ring neodynium: YAG laser ®ber at 40 W power setting. J Urol 1 Neal DE. The morbidity of transurethral resection of the prostate. 1993; 150: 95 ± 99. Curr Op Urol 1996; 6: 147 ± 150. 27 De la Rosette JJMCH et al. High energy thermotherapy in treat- 2 Fowler FJ Jr et al. Symptom status and quality of life following ment of benign prostatic hyperplasia: results of European Benign prostatectomy. JAMA 1988; 259: 3018 ± 3022. Prostatic Hyperplasia Study Group. J Urol 1996; 156: 97 ± 102. 3 Wennberg JE et al. An assessment of prostatectomy for benign 28 Kaplan SA. Electrovaporization of the prostate. Durable modality urinary tract obstruction. JAMA 1988; 259: 3027 ± 3030. or passing fad? Urology 1997; 49: 157 ± 159.