(RITA) treatment for prostate cancer - Nature

Prostate Cancer and Prostatic Diseases (2006) 9, 266–269 & 2006 Nature Publishing Group All rights reserved 1365-7852/06 $30.00

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ORIGINAL ARTICLE

Histopathological findings after radiofrequency (RITA) treatment for prostate cancer C Patriarca1, F Bergamaschi2, G Gazzano3, P Corrada2, G Ordesi2, L Zanitzer2, M Di Pasquale1, P Giunta1 and B Campo2 1

Pathology Department, Azienda Ospedaliera di Melegnano, Milan, Italy; 2Urology Department, Azienda Ospedaliera di Melegnano, Milan, Italy and 3II Department of Pathology, S Paolo Hospital, University of Milan School of Medicine, Milan, Italy

Radiofrequency interstitial tumor ablation (RITA) is a thermal ablation method that uses needles and low radiofrequency (RF) energy. The aim of our study was to evaluate the histopathology of thermal lesions induced by RF energy delivered interstitially in prostate cancer patients who subsequently underwent prostatectomy, and to determine the feasibility, effectiveness and safety of this new method in a pilot study. Prostate Cancer and Prostatic Diseases (2006) 9, 266–269. doi:10.1038/sj.pcan.4500877; published online 9 May 2006

Keywords: radiofrequency; histopathology; necrosis

Introduction Hyperthermia has been amply studied and used in clinical applications in the past 10 years. 1–3 Temperatures above 601C have a rapid cytotoxic effect due to protein coagulation.1 The amount of heat energy produced and the subsequent thermal effect are determined by the amount of tissue contact (the length of the needle) and the wattage.4 These physical properties enable radiofrequency (RF) energy to be used for targeted, precise and customized tissue ablation, preserving adjacent tissue and organs, and producing necrotic lesions that are controllable in size and extension.4 In urology, treatment based on the delivery of low-level RF energy at a high temperature, has been claimed to be a good alternative to classic surgery in the treatment of benign prostatic hyperplasia 4–6 and carcinoma.7–10 The aim of our pilot study was to evaluate the histopathology of thermal lesions induced by RF energy delivered interstitially (radiofrequency interstitial tumor ablation, RITA) in prostate cancer patients scheduled for radical prostatectomy, and to comment on the feasibility and the safety of this method.

Materials and methods RITA instrumentation and procedure Radiofrequency interstitial tumor ablation is a thermal ablation method that uses needles and low RF energy. The system consists of a number of needle electrodes, all Correspondence: Dr F Bergamaschi, Department of Urology, Ospedale Vizzolo Predabissi, Via Pandina 1, Vizzolo Predabissi, Milan 20077, Italy. E-mail: [email protected] Received 3 January 2006; revised 27 March 2006; accepted 27 March 2006; published online 9 May 2006

of which deliver the RF energy, each needle electrode carrying an array of deployable hooks supporting separate thermocouples (Figure 1). The distal centimeter of the needle shaft is also an active electrode, as are all the hooks deployed from the tip. The remainder of the needle shaft is insulated both thermally and electrically. The generator is a 50 W monopolar RF generator operating at a frequency of 460 kHz. The generator displays real-time impedance measurements, total delivered energy measurements in Joules, and individual temperature readings for each electrode hook. The treatment is monitored and guided by transrectal ultrasound, which also guides the positioning of the electrodes. The thermocouples and needle electrodes are highly echogenic and clearly visible at ultrasound. A separate thermocouple is also used to monitor the temperature of selected periprostatic structures, such as the rectum and neurovascular bundles. Finally, a threeway urethral catheter is used for continuous irrigation with a chilled fluid to cool and protect the urethra from thermal injury. As for the procedure, the patient is placed in the lithotomy position, the scrotum is lifted and the patient is prepared and draped in the same sterile fashion as for transurethral surgery. The transrectal ultrasound transducer is inserted and the prostate is scanned in both the transverse and the sagittal planes. The volumes are measured and the prostate is mapped to establish the treatment plan in terms of the number and location of the ablations. The separate thermocouple is placed on Denonvillier’s fascia, reached transperineally, under the left or right lobe of the prostate (depending on the sequence of ablations established in the treatment plan). The treatment begins with the passage of the RITA needle electrode transperineally, under ultrasound guidance, to the first location to treat in the prostate. The power of the generator is then increased as necessary to

Histopathological findings after RF C Patriarca et al

discharged within a mean 24 h. No oedema major complications occurred. Urinary retention due to oedema induced by the thermal lesions was observed in 60% of patients between 24 h and 7 days after the treatment. After prostatectomy, formalin-fixed surgical specimens were routinely embedded. Transversal sections 0.5 cm thick were taken macroscopically from all 10 prostates,11 then coronal sections were routinely embedded and histological sections 3 mm thick were stained with hematoxylin and eosin. Step sections of each case also underwent immunohistochemical staining for bcl-2 antiapoptotic protein (124 clone monoclonal antibody) using standard immunohistochemical procedures (ABC perox).12 Figure 1 Needle electrode for radiofrequency interstitial tumor ablation (RITA) treatment.

120

°c watt ohm

100

T1 T2 T3 Power Rectal temp Impedance

80 60 40 20 0 1

2

3

4

5

6

7

8

9

minutes Figure 2 Hook temperatures, rectal temperatures, impedence and power employed. The temperatures were maintained for 5 min in eight cases, 4 min in one and 3 min in one. Table 1 Clinical data Patient no.

1 2 3 4 5 6 7 8 9 10

Interval between RITA and prostatectomy (days)

No. of lesions

Treatment time (min)

Size of ablation lesions (cm)

6 15 15 10 8 30 13 30 10 20

2 5 2 2 1 2 2 1 2 5

3’ 5’ 5’ 5’ 4’ 5’ 5’ 5’ 5’ 5’

2 2 1.5 2.5 0.9 2 2 2 2 2

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Results Histopathological findings The outer surface of the prostates showed no macroscopic signs of the treatment or histological evidence of necrosis or inflammation. Macroscopic examination of the cut surface of the prostate revealed the presence of sharply defined, rounded areas of the prostates of the in one (one case) or both lobes (nine cases). The tissues of these treated areas had a gray-white crumbly appearance with a well-defined dark red peripheral ring (Figure 3). The major diameters of the lesions ranged from 9 to 25 mm. Histological examination showed a precise compartmentalization of the lesions. Massive, homogeneous coagulative necrosis was evident in all cases. Shadows of neoplastic glands and nests were barely visible, intermingled with stromal necrotic tissue (Figure 4). ‘Pink’ homogenized coagulative necrosis encompassed the neoplastic tissue, as well as the non-neoplastic epithelial, smooth muscle, vascular and fibroblastic tissues. The previously mentioned ring was produced by a well-defined area of hemorrhagic extravasation and capillary ectasia. Squamous metaplasia of the ducts was always evident at the periphery of the necrotic area (Figure 5) and scattered foci of squamous metaplasia were detectable in the untreated tissue close to the hemorrhagic ring. Only two of the 10 cases revealed small foci of non-necrotic neoplastic tissue (with a maximum diameter of 3–6 mm) (Figure 6): these two cases coincided with the shorter time treated patients; the

Abbreviation: RITA, radiofrequency interstitial tumor ablation.

arrive at a hook temperature of 1001C (Figure 2) and different times are set in order to evaluate the results.

Patients and histopathological methods (Table 1) We performed RITA in 10 patients with histologically confirmed acinar adenocarcinoma. The Gleason score of the diagnostic needle biopsies ranges from 6 (3 þ 3) to 7 (4 þ 3 or 3 þ 4) and 8 (4 þ 4). The patients’ ages ranged from 58 to 69 years, and they all harbored a neoplasm clinically confined to the organ. Radical prostatectomy was performed 1 to 4 weeks after the RITA treatment (see Table 1). Two ablations were performed per prostate (one for each lobe) in seven cases; a single lobe was treated in one case; and five ablations were performed in two cases. All treatments were carried out under local perineal anesthesia and mild leptoanalgesia. Patients were

Figure 3 Macroscopic examination of the prostate: hemorrhagic ring surrounding necrotic areas, bilaterally. Prostate Cancer and Prostatic Diseases


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Figure 4 Massive coagulative ‘pink’ necrosis, encompassing both neoplastic acinar structures and fibromuscolar stroma in a patient treated for 5 min (H&E 400 ).

Figure 6 Small focus of vital acinar adenocarcinoma (right side) fusing with neoplastic necrotic areas (left side) in a patient treated for 3 min (H&E 200 ).

Figure 5 Squamous metaplasia within the hemorrhagic areas at the periphery of the necrotic tissue (H&E 400 ).

non-necrotic foci had a Gleason score of 6 and 8, respectively; and these foci were located respectively in the middle and at the periphery of the necrotic areas. bcl-2 immunostaining was lacking in the shadows of neoplastic nuclei in coagulative necrotic areas. There was no inflammatory reaction in all but three cases, where confined microfoci of lymphoplasmacellular reaction were seen around the necrotic areas. A giant cell granulomatous reaction was also evident in one case. No macroscopic changes in the normal and neoplastic tissue were apparent in any of the untreated prostatic tissue and resected lymph nodes, which had the classic appearance of conventional acinar adenocarcinoma. Finally, no correlations were found between the type of necrosis and the interval between RITA treatment and prostatectomy.

Clinical data The treatment took an average 10 to 12 min to complete. Temperatures higher than 1001C were reached within about 2 min and maintained for 5 min in eight patients, Prostate Cancer and Prostatic Diseases

4 min in one, and 3 min in one to establish how long it took to necrotize all the cells in the treatment area. No signs of damage to the urethral sphincter, bladder or rectal wall emerged at radical prostatectomy, and no greater difficulties were encountered in separating cleavage surfaces, apart from the presence of mild reactive fibrosis in the connective tissue of the pelvis and Denonvillier’s fascia in a few cases. Macroscopically, the prostates showed an almost perfect consistency between the areas where the hooks were deployed and the lesions obtained. The largest diameter of the necrotic volumes ranged from 0.9 to 2.5 cm, whereas the treated areas ranged in diameter from 1 to 2.5 cm. The two cases with small residual foci of non-necrotic neoplastic tissue coincided with the two patients treated for less than 5 minutes.

Discussion Our pilot study demonstrated that an effective necrosis, that is, a massive and homogeneous coagulative necrosis, can easily be achieved within 5 min of RITA treatment, making it a valid system for the safe, reproducible and controlled induction of necrotic lesions in prostate cancer. Radiofrequency thermal ablation has already been used in the field of cardiology for the precise ablation of aberrant pathways in cases of Wolff–Parkinson–White syndrome,13 and in the neurosurgical field for the


stereotactic ablation of abnormal neural tissue (glioma excision, cordotomy).14 Radiofrequency interstitial tumor ablation has been used to treat primary or metastatic liver neoplasms in patients unsuitable for surgery, with encouraging results,15–18 and has recently been proposed for use the treatment of prostate cancer.7–10 The histopathological effects of RITA treatments have received little attention so far, however. Some authors8 have reported finding sharply defined margins of necrosis, although they also found two cases with a patchy pattern of necrosis, with an inadequate cooling phase. The question of whether RITA-induced tissue lesions are truly necrotic in nature also remains to be clarified. Indeed, as Dr S Nahun Goldberg said in the opening comments of a recent article 2 ‘there is no question that one can achieve (y) mummification of the cells that are in fact dead, but because they don’t show signs of coagulative necrosis or the absence of nuclei, many pathologists have originally called these cells live’. The author is referring to liver neoplasms, like much of the available data on RF treatments. In prostate carcinoma, on the other hand, we documented an extensive and homogeneous coagulative necrosis, that is, a ‘pink’ transformation of both the nucleus and the cytoplasm of the neoplastic population, as well as the stroma intermingled with acinar carcinoma structures. We also documented the necrotic nature of such features that did not stain for bcl-2 protein, an antiapoptotic antigen often expressed by live conventional acinar adenocarcinoma cells.19 The two vital foci found in our series had neither Gleason score nor topography in common, suggesting an independent heat resistant mechanism. In our experience, the size of the ablation lesion depends on three factors: the length of the needles, the wattage and the duration of the treatment session. A maximum size of 25 mm is achieved with a needle 20 mm long and 20 W (Figure 2) for 5 min. Shorter needles and treatment times reduce the extent of tissue ablation, as reported in the literature,4 whereas a higher wattage 4 adversely affects the amount of tissue ablated because the tissue is heated to temperatures in excess of 1001C, leading to water evaporation and tissue charring. The precise compartmentalization of the lesions induced by RITA preserves from damages the untreated surrounding tissues. Accordingly, a sparing of the urinary sphincter and the nerve bundles can be achieved. Our study has shown that RITA treatment induces necrotic lesions of the planned shape and size in prostatic tissues, and we found no necrotic areas harboring residual vital tumor after a standard delivery of RF energy for 5 min. Such a satisfactory consistency between the expected ablation and the lesions actually obtained might provide the foundations for the decision process of a complete prostate ablation. As for possible future developments, we might expect: (1) adjustments to and new assessments of the RF delivery technology; (2) a retreatment modality to virtually ensure extensive prostatic tissue ablation; nevertheless, as a first step it seems more relevant to document the full necrosis of the treated areas.

(3) the treatment of limited foci of adenocarcinoma confined to the prostate using new imaging technology more effective in detecting cancer.

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