Archivio Italiano di Urologia e Andrologia 2017; 89, 2106 ORIGINAL PAPER Safety of transrectal ultrasound-guided prostate biopsy in patients affected by Crohn’s disease Lucio Dell’Atti, Andrea Benedetto Galosi Department of Urology, University Hospital “Ospedali Riuniti”, Ancona, Italy. Purpose: Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointesti- nal tract. It is usually considered a contraindication to tran- srectal ultrasound-guided prostate biopsy (TRUSBx). The aim of this study was to investigate the safety of TRUSBx in a small cohort of patients with CD. Methods: We queried our institutional database clinical data of patients with a diagnosis of CD undergoing TRUSBx, and a retrospective prospective study of 5 patients was planned. All patients enrolled were in the remission phase of CD and asymptomatic. They received the same antibiotic prophylaxis and a povidone-iodine aqueous solution enema before the pro- cedure. A standardized reproducible technique was used with using a ultrasound machine equipped with a 5-9 MHz multi- frequency convex probe “end-fire”. The patients were treated under local anaesthesia, and a 14-core biopsy scheme was performed in each patient as first intention. After the proce- dure each patient was given a verbal numeric pain scale to evaluate tolerability of TRUSBx. Results: TRUSBx was successfully completed in all patients. The number of biopsy cores was 14 (12-16). Of the 5 biopsy procedures performed 40% revealed prostatic carcinoma (PCa) with a Gleason score 6 (3+3). No patients required catheterization or admission to the hospital for adverse events after the procedure. The most frequent adverse event was hematospermia (60%), while hematuria was present in 20% of patients and a minimal rectal bleeding in 20% of the patients. No patients reported severe or unbearable pain (score ≥ 8). Conclusions: This study suggests that CD may not be an absolute contraindication to TRUSBx for prostate cancer detection, but still requires a careful patients selection. KEY WORDS: Crohn’s disease; Inflammatory bowel disease; Prostate biopsy; Ultrasonography; Prostate cancer; Complications. Submitted 8 March 2017; Accepted 23 April 2017 Summary No conflict of interest declared. including genetic factors, immune-regulatory defects, microbial exposure and sex hormones such as androgens (3, 4). Recent studies reported that androgens may regu- late aspects of human immunity and also be associated with a statistically significant increased risk of inflamma- tory bowel disease (IBD) (5, 6). Prostate cancer (PCa) is an androgen-dependent pathologic condition whose anatomical location requires careful consideration in patients with CD (7). However, the detection of PCa is reliant on prostate biopsy for histological confirmation (8). Therefore, approximately 20-30% of men with CD will require a prostate biopsy within their lifetime, and compared with men non affected, they are at increased risk of developing complications following this proce- dure (7, 8). Although cancer detection rates or the com- plication rates between transrectal (TR) biopsy and transperineal (TP) biopsy are greatly debated (9, 10), in this retrospective study we analysed the use and the safe- ty of transrectal ultrasound-guided prostate biopsy (TRUSBx) in a small cohort of five patients with CD. MATERIALS AND METHODS Between August 2007 and January 2017, we performed a retrospective review of 5 patients affected by CD who underwent TRUSBx for abnormal digital rectal examina- tion (DRE), high prostate-specific antigen (PSA) levels (≥ 4 ng/ml), or both. Patients with a history of biopsy, surgical treatment for prostatic disease and incomplete clinical data were excluded from our study. All patients enrolled in the study were in the remission phase of CD and asymptomatic. All patients signed a consent form for TRUSBx. None of the patients was receiving anticoagu- lants or antiplatelet agents before the procedure. All patients received the same antibiotic prophylaxis: 5 days of ciprofloxacin (500 mg twice daily) starting 24 h before the biopsy (11). Moreover, all patients received a povidone-iodine aqueous solution enema starting fifteen minutes before the TRUSBx (12). All procedures were performed in order to empty the bladder, since we believe that even the state of bladder repletion may be an element of discomfort during the performance of map- ping biopsy. TRUSBx was performed with the patient in the left lateral decubitus using a General Electric Logiq 7 machine equipped with a 5-9MHz multi-frequency con- vex probe “end-fire”. The patients were treated under DOI: 10.4081/aiua.2017.2.106 INTRODUCTION Crohn’s disease (CD) is a chronic inflammatory condi- tion of the gastrointestinal tract characterized by a relapsing-remitting clinical behaviour, which may involve the whole digestive tract from the oral cavity to the anus (1). Incidence of CD is highest during last decades in high income countries as United States and Europe with rates ranging between 10-20/100.000 (2). The aetiology of this disease remains unknown; howev- er, it is supposed that a number of causes are implicated, Dell'Atti_Stesura Seveso 20/06/17 09:32 Pagina 106 107Archivio Italiano di Urologia e Andrologia 2017; 89, 2 Prostate biopsy and Crohn’s disease local anaesthesia with Lidocaine Spray 10 gr/100 ml applied two minutes before the procedure (13). After having images of the prostate and measurement of the volume, sampling was carried out with a 18-Gauge Tru-Cut needle pow- ered by an automatic spring-loaded biopsy disposable gun. A 14-core biop- sy scheme was performed in each patient, as first intention, including 2 basal samples (lateral and medial), 2 parasagittal samples (lateral and medi- al), 2 apical samples (lateral and medi- al), and 1 transitional zone sample on each side. After the procedure each patient was given a verbal numeric pain scale (VNS), which was designed with 0 representing absence of pain and 10 the maximum pain they perceived in life. Patients were discharged after a short period of observation (typically 60 min- utes) and once urinated. Patients were seen for follow-up 2 weeks after the biopsy and a full clinical outcomes of all cases were available. Descriptive statistics for variables with a normal distribution, non-normal distri- bution, and categorical variables were evaluated using mean and interquartile range, according to their distribution. Statistical analyses were performed using Microsoft Excel 2010 platform. A p < 0.05 was considered to indicate statistical significance. RESULTS Over the study period on 3,470 men underwent TRUSBx, 5 patients affected by CD in clinical and endo- scopic remission were retrospectively enrolled in the study. The mean age of enrolled patients was 63 years (range 56-71), with a prostate volume of 51 ml (range 39-60), initial PSA levels of 7.3 ng/ml (range 4.9-10.2). The clinical characteristics of the patients are shown in Table 1. TRUSBx was successfully completed in all patients. The number of biopsy cores was 14 (range 12-16). Of the 5 biopsy procedures performed 2 (40%) revealed PCa with a Gleason score 6 (3 + 3). In the remain 3 patients 2 biopsies showed prostatitis, while 1 reported benign tissue. Patients with higher serum PSA appeared more likely to have cancer on TRUSBx (p < 0.001). No patients required catheterization or admission to the hospital for adverse events after the procedure. The most fre- quent adverse event was hematospermia (60%), which had also the longest dura- tion (24.6 days). Hematuria was present in 20% of patients and a minimal rectal bleeding was observed in 20% of the patients after the biopsy (Figure 1). There were no serious infectious compli- cations in this study. The mean pain in the visual numer- ical scale in patients was 3.4 (2-7). No patients reported severe or unbearable pain (score ≥ 8). DISCUSSION Crohn’s disease is a IBD characterised by recurrent and destructive inflammation of the gastrointestinal tract (2, 3). Approximately 35% of IBD are diagnosed with an extra-intestinal manifestation of the disease, including uveitis, erythema nodosum, peripheral arthritis and scle- rosing cholangitis (14). Inflammation is known to play an important role in car- cinogenesis, and there is also a growing evidence that patients with CD have an increased risk for intestinal Table 1. Demographic and clinicopathologic features of patients with Crohn’s disease undergoing transrectal ultrasound prostate biopsy. Patients 1 2 3 4 5 Age (yrs) 56 62 59 67 71 Age at diagnosis (yrs) 29 35 32 44 52 BMI (Kg/m2) 27.2 31 28.4 32.5 33 Race Caucasian Caucasian Caucasian Caucasian Caucasian Smoking Current Past Yes Never Past Positive family history PCa No No Yes No No Localisation of CD Ileum-colon Colon Ileum-colon Colon Ileum Prior surgery for CD No No No No Yes Prostate volume (ml) 46 58 39 60 52 PSA level (ng/ml) 5.6 4.9 10.2 6.9 8.5 N° biopsy cores 14 14 12 16 14 Abnormal DRE, (n) No Yes Yes No No Prostate cancer, (n) No No Yes No Yes Biopsy Gleason score, (n) ≤ 6 0 0 1 0 1 7 0 0 0 0 0 ≥ 8 0 0 0 0 0 Pain in VNS 3 2 7 2 3 BMI = body mass index; CD = Crohn’s disease; PCa = prostate cancer; PSA = prostate-specific antigen; DRE= digital rectal examination; VNS = verbal numeric scale Figure 1. The prevalence of adverse events in patients with Crohn’s disease undergoing transrectal ultrasound prostate biopsy. Dell'Atti_Stesura Seveso 20/06/17 09:32 Pagina 107 Archivio Italiano di Urologia e Andrologia 2017; 89, 2 L. Dell’Atti, A.B. Galosi 108 cancers secondary to long-standing intestinal inflamma- tion or secondary to immunosuppressive therapies (15, 16). While it is well established that androgens play a role in PCa development, there are new evidences that androgens may also regulate aspects of human immuni- ty (6). Moreover, Klil-Dori et al. reported that the suppression of androgens to castration levels in a large population cohort of patients affected by PCa was associated with a decreased risk of IBD (7). In line with this study, the androgen deprivation through surgical castration has been shown to protect the intestinal permeability in a porcine model (17) and influence the composition of murine gut microbiota (18). Prostate biopsy plays an important role in diagnosing PCa, confirming the grade of cancer and stratifying cancer aggressiveness (8). In 20- 30% of patients with CD, a prostate biopsy will be require within their lifetime, and compared with patients with other benign intestinal conditions, they are at increased risk of developing postoperative complications following prostate biopsy (19). Some studies reported several risk factors in patients with CD following intes- tinal surgery for postoperative morbidities, including the presence of perforating disease, prolonged duration of symptoms, weight loss, anaemia, malnutrition and sev- eral acute flares of CD (19-21). Patients with rectal dis- ease such as CD represent a population in which the standard technique of TRUSBx may not be feasible for postoperative morbidities listed above. However, in liter- ature, the comparisons between the TR and TP prostate biopsy approaches showed no significant difference in the overall cancer detection rate and in the incidence of major or minor complications (10, 22). To our knowl- edge, this is the first study that report the largest series to date of TRUSBx in patients affected by CD. Fergany and Angermeier described the technique of TP prostate biop- sy using the ultrasound grid and a stabilizing platform employed for prostate brachytherapy in patient with ulcerative colitis and an ileal pouch. In their case study multiple cores of prostatic tissue were successfully obtained without major complications (23). Compared with TR biopsy, TP approach may offer a more aseptic method, with fewer infective complications in light of evidence of fluoroquinolone-resistant bacteria in bowel. However, TP biopsy is a more costly alternative, with longer procedural times and higher risks of acute reten- tion postoperatively (9, 10, 22, 24). In our Department we usually employ a TR approach using an end-fire probe, because we believe that to perform prostate biop- sy in the anterior area of the gland it is the most appro- priate technique. The end-fire probe permits biopsy cores to be taken more transversely (oriented along an anterior-posterior axis), has a more oblique-angled trajectory, and more flexibility in manoeuvring the biopsy direction than side- fire probes (25). In this population of patients TRUSBx provided a good visualization of the gland and facilitated multiple random needle biopsies under local anaesthesia without major complications. The most frequent adverse event was hematospermia (60%), hematuria and a rectal bleeding were observed in 20% of patients after the pro- cedure, respectively. However, in this study several limi- tations need to be acknowledged such as the use of a ret- rospective analysis, enrolling a small patient population, and omitting the preoperative evaluation of clinical symptoms. Therefore, the present study is not sufficient- ly powered to assess the impact of improved prostate biopsy technique on outcomes in patients with CD. CONCLUSIONS In conclusion, our study suggests that that CD may not be an absolute contraindication to TRUSBx for PCa detection, but still requires a careful patients selection. This case series is a unique, highly selected group of patients affected by CD in clinical remission, further studies to elucidate the best biopsy practices and share decision-making are required. REFERENCES 1. Leighton JA, Pasha SF. Inflammatory Disorders of the Small Bowel. Gastrointest Endosc Clin N Am. 2017; 27:63-77. 2. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012; 142:46-54. 3. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflam- matory bowel disease. Nature. 2007; 448:427-34. 4. Loftus EV Jr. Clinical epidemiology of inflammatory bowel dis- ease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004; 126:1504-17. 5. Fijak M, Meinhardt A. The testis in immune privilege. Immunol Rev. 2006; 213:66-81. 6. Morse MD, McNeel DG. Prostate cancer patients on androgen deprivation therapy develop persistent changes in adaptive immune responses. Hum Immunol. 2010; 71:496-504. 7. Klil-Drori AJ, Tascilar K, Yin H, et al. Androgen Deprivation Therapy and the Incidence of Inflammatory Bowel Disease in Patients With Prostate Cancer. Am J Epidemiol. 2016; 184:15-22. 8. Epstein JI, Sanderson H, Carter HB et al. Utility of saturation biopsy to predict insignificant cancer at radical prostatectomy. Urology. 2005;66:356-60. 9. Scott S, Samaratunga H, Chabert C, et al. Is transperineal prostate biopsy more accurate than transrectal biopsy in determin- ing final Gleason score and clinical risk category? A comparative analysis. BJU Int. 2015; 116:26-30. 10. Shen PF, Zhu YC, Wei WR, et al. The results of transperineal versus transrectal prostate biopsy: a systematic review and meta- analysis. Asian J Androl. 2012; 14:310-5. 11. Wu XW, Ji HZ, Wang FY. Meta-analysis of ciprofloxacin in treat- ment of Crohn's disease. Biomed Rep. 2015; 3:70-4. 12. Hay JM, Boussougant Y, Lacaine F, et al. Povidone-iodine enema as a preoperative bowel preparation for colorectal surgery. A bacte- riologic study. Dis Colon Rectum. 1989; 32:9-13. 13. Dell’Atti L. Lidocaine spray administration in transrectal ultra- sound-guided prostate biopsy: five years of experience. Arch Ital Urol Androl. 2014; 86:340-3. 14. Feuerstein JD, Flier SN, Yee EU, et al. A rare case series of con- comitant inflammatory bowel disease, sporadic adenomas, and ser- rated polyposis syndrome. J Crohns Colitis. 2014; 8:1735-9. Dell'Atti_Stesura Seveso 20/06/17 09:32 Pagina 108 109Archivio Italiano di Urologia e Andrologia 2017; 89, 2 Prostate biopsy and Crohn’s disease 15. Axelrad JE, Lichtiger S, Yajnik V. Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and can- cer treatment. World J Gastroenterol. 2016; 22:4794-801. 16. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011; 140:1807-16. 17. Deitch EA, Senthil M, Brown M, et al. rauma-shock-induced gut injury and the production of biologically active intestinal lymph is abrogated by castration in a large animal porcine model. Shock. 2008; 30:135-41. 18. Markle JG, Frank DN, Mortin-Toth S, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoim- munity. Science. 2013; 339:1084-8. 19. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and recurrence in 907 patients with primary ileocaecal Crohn's disease. Br J Surg. 2000; 87:1697-701. 20. Iesalnieks I, Kilger A, Glass H, et al. Intraabdominal septic com- plications following bowel resection for Crohn's disease: detrimental influence on long-term outcome. Int J Colorectal Dis. 2008; 23:1167-74. 21. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-13. 22. Shida Y, Hakariya T, Takehara K, et al. Comparison Between a Combined Transrectal and Transperineal Approach and a Transrectal Approach for Prostate Rebiopsy. Anticancer Res. 2016; 36:4685-90. 23. Fergany AF, Angermeier KW. A technique of transrectal ultra- sound guided transperineal random prostate biopsy in patients with ulcerative colitis and an ileal pouch. J Urol. 2000; 163:205-6. 24. Abdollah F, Novara G, Briganti A, et al. Trans-rectal versus trans-perineal saturation rebiopsy of the prostate: is there a differ- ence in cancer detection rate? Urology. 2011; 77:921-5. 25. Galosi AB, Tiroli M, Cantoro D, et al. Biopsy of the anterior prostate gland: technique with end-fire transrectal ultrasound. Arch Ital Urol Androl. 2010; 82:248-52. Correspondence Lucio Dell’Atti, MD, PhD (Correspondant Author) dellatti@hotmail.com Andrea Benedetto Galosi, MD Department of Urology - Marche Polytechnic University University Hospital “Ospedali Riuniti” 71 Conca Street - 60126 Torrette, Ancona, Italy Dell'Atti_Stesura Seveso 20/06/17 09:32 Pagina 109