Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer Caroline Eymerit-Morin, Merzouka Zidane, Souhil Lebdai, Stéphane Triau, Abdel Rahmene Azzouzi & Marie- Christine Rousselet Virchows Archiv The European Journal of Pathology ISSN 0945-6317 Volume 463 Number 4 Virchows Arch (2013) 463:547-552 DOI 10.1007/s00428-013-1454-9 1 23 Your article is protected by copyright and all rights are held exclusively by Springer- Verlag Berlin Heidelberg. This e-offprint is for personal use only and shall not be self- archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. 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The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy Virchows Arch (2013) 463:547–552 DOI 10.1007/s00428-013-1454-9 ORIGINAL ARTICLE Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer Caroline Eymerit-Morin & Merzouka Zidane & Souhil Lebdai & Stéphane Triau & Abdel Rahmene Azzouzi & Marie-Christine Rousselet Received: 5 February 2013 /Revised: 23 April 2013 /Accepted: 8 July 2013 /Published online: 16 August 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Low-risk prostate adenocarcinoma is classically Keywords Photodynamic therapy . Photosensitizer . managed either with active surveillance or radical therapy Targeted therapy . WST11 (such as external radiotherapy or radical prostatectomy), but both have significant side effects. Vascular-targeted photo- dynamic therapy (VTP) is a focal therapy proposed as an Introduction alternative approach for localized, low-volume, and low- Gleason score (≤6) carcinomas. We report histological mod- Prostate cancer (PCa) stage and Gleason grade are determi- ifications observed in prostate biopsies of 56 patients, nants of prognosis. With screening of PCa by PSA measure- performed 6 months after VTP using the photosensitizer ment having become the mainstream, many men are diag- TOOKAD® Soluble (WST11) and low-energy laser admin- nosed with low-risk, low-volume, and low-grade PCa. In this istered in the tumor area transperineally by optic fibers. In 53 context, current radical therapies are questioned in terms of patients, we observed sharply demarcated hyaline fibrotic benefit for survival and risk of cancer progression, in view of scars, with or without rare atrophic glands, sometimes re- their significant adverse side effects [1]. Another approach is duced to corpora amylacea surrounded by giant multinuclear active surveillance (AS) which, however, goes along with a macrophages. Mild chronic inflammation, hemosiderin, and significant risk of progression during the surveillance period. coagulative necrosis were also observed. When residual A new approach is the concept of focal therapy which is cancer was present in a treated lobe (17 patients), it was organ-sparing, as selective tumor ablation is the goal. Of the always located outside the scar, most often close to the focal therapy approaches, the most promising are high- prostate capsule, and it showed no therapy-related modifica- intensity-focused ultrasound (HIFU), cryotherapy, and tion. Histopathological interpretation of post-WST11 VTP vascular-targeted photodynamic therapy (VTP) [2–5]. VTP prostate biopsies was straightforward, in contrast with that of is intended for patients with localized PCa, as an alternative prostate biopsies after radio or hormonal therapy, which to AS, as it avoids the risks of morbidity inherent to radical introduces lesions difficult to interpret. VTP resulted in therapy but without compromising life expectancy of the complete ablation of cancer in the targeted area. treated patient [6]. In 1990, a letter to the Lancet reported the application of this minimally invasive procedure in PCa for the treatment of two patients [7]. VTP was further assessed for its tolerance and the dose determined in terms C. Eymerit-Morin : M. Zidane : S. Triau : M.<C. Rousselet of the time of laser illumination with the use of different Cellular and Tissue Pathology Department, LUNAM University, photosensitizers in phase I or phase II studies [8]. At present, CHU University Hospital, Angers, France the TOOKAD® Soluble WST11 (padeliporfin), a chloro- phyll derivative developed by Steba Biotech, is one of the S. Lebdai : A. R. Azzouzi Urology Department, LUNAM University, CHU University photosensitizers of choice [9]. Diagnosis, localization, and Hospital, Angers, France staging of Pca are determined through preoperative prostate biopsies. The photosensitizer is intravenously infused, ab- < * M. C. Rousselet ( ) sorbs light, and transfers energy to oxygen molecules creat- Département de Pathologie Cellulaire et Tissulaire, CHU Angers, 49933 Angers Cedex 9, France ing free oxygen species [10]. Light is introduced by e-mail: [email protected] transperineal optical fibers at the presumed location of the Author's personal copy 548 Virchows Arch (2013) 463:547–552 cancer in the prostate under ultrasound transrectal guidance. Table 1 Inclusion and exclusion criteria for enrollment in the study Damage to vascular endothelium leads to vascular occlusion Inclusion criteria by thrombosis followed by ischemia and necrosis of the Men over 18 years old targeted area. At the cellular level, in vitro studies showed Diagnosed PCa histologically proven on biopsies phototherapy-induced apoptosis [11]. Histological effects of Gleason score ≤3+3 WST11 VTP have been mainly reported in animal models TNM stage up to cT2b-N0/Nx-M0/Mx PSA<10 ng/ml using WST09, the precursor photosensitizer of WST11, or No prior treatment for PCa WST11; early effects such as hemorrhagic necrosis with Eligible for active surveillance inflammation, gland destruction, atrophy, and vascular Exclusion criteria thrombosis have been observed in the treated area, ultimately Contraindication for general anesthesia followed by dense fibrosis [12–14]. In human PCa, the History of viral or alcoholic hepatitis histological lesions induced by WST11 VTP have been History of inflammatory bowel disease or other risk factor for fistula briefly described in review articles focusing on new PCa formation Previous TURP therapies [15, 16]. They appeared similar to what had been Medication with photosensitizing effects reported for WST09: fibrosis without residual cancer cells Anticoagulant drugs but entrapped benign atrophic glands and a very clear de- History of sun hypersensitivity, porphyria marcation between treated areas and the adjacent normal History of renal, hepatic, hematological, or cardiovascular pathology tissue [17]. In the course of phase II trials using WST11 VTP to treat localized PCa, we had the opportunity to study the prostate performed on an automated device (Autostainer, with biopsies of 56 patients before and 6 months after VTP. The Envision-plus revelation kit, Dako) using the cocktail anti- primary aim of our report was to describe the remodeling p504S (monoclonal rabbit antihuman P504S, clone 13H4, effects in prostatic tissue induced by the procedure. The DaKo, 1:200 dilution) and anti p63 (monoclonal mouse anti- secondary aim was to evaluate at 6 months post therapy the human p63 protein, clone 4A4, Dako, 1:100 dilution) with presence of residual cancer and its grade and topography, prior antigen retrieval in EDTA buffer pH 8. notably in the targeted area and in its relation with the Magnetic resonance imaging (MRI) allowed the evalua- prostate capsule. tion of the prostate volume, of any extra-prostatic or nodal extension, and was also necessary to plan the treatment. Material and methods Treatment procedure Population The procedure was performed under general anesthesia The University Hospital of Angers included 56 patients by the same operator. Optical fibers were installed between December 2008 and July 2010 in two open multi- transperineally in the prostate by ultrasound guidance. center prospective phase II trials, with the primary aim to The location and number of fibers depended on the loca- assess tolerance and feasibility of Tookad® Soluble WST11 tion of the tumor according to the results of the biopsies VTP. Patient's consent was obtained, as well as the agree- and MRI. Then, the patients received a 10-min intravenous ment of the Committee of Protection of Persons and the infusion of TOOKAD® Soluble WST11. Subsequently, Ethical Committee. Inclusion and exclusion criteria are listed transillumination of the target zone began with a 753 nm in Table 1. wavelength laser at a fixed power of 150 mW/cm and a fixed energy of 200 J/cm during 22.2 min. This induced Initial diagnosis and staging necrosis of the targeted prostate area. For reasons of secu- rity, the minimal distance between the optical fibers and Initial diagnosis was based on transrectal ultrasound-guided the urethra or the capsule was kept at 5 mm. The patients prostate biopsies of at least 12 cores (six per lobe) performed at were protected from light during the entire procedure and the basis, the middle, and the apex of each hemi gland. for 24 h following treatment. Formalin-fixed paraffin-embedded tissue block of each biopsy