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1 만성전립선염의 검사실진단 趙仁來 인제대일산백병원비뇨기과

2 CP/CPPS Magnitude of the Problem Overall prevalence: 2-6% Similar to ischemic heart disease and diabetes More common than asthma Previous or concurrent diagnosis: 11-14% 2-7 million office visits/year (USA) 8% of urology visits Most common diagnosis in men under 50 years

3 CP/CPPS Epidermiology Overall prevalence: 2-16%» Nickel % men suffer prostatitis Sxs» Nickel et al More 2 million office visits/year (USA, ) Most common diagnosis in men under 50 years Urologist Office visits» MacNaughton-Collins et al US 8% MacNaughton-Collins et al Italy 12% Rizzo et al Canada 3% Nickel et al. 2005

4 만성전립선염증후군의역학적특징 분류 전형적인임상양상 빈도 ( 전립선염증후군카테고리중 ) 카테고리 I 급성발병 1-5% 카테고리 II 재발성요로감염 5-10% 카테고리 IIIA 골반부위의불쾌감이나통증, 최소한 3개월이상 40-65% 카테고리 IIIB 골반부위의불쾌감이나통증, 최소한 3개월이상 20-40% 카테고리 IV 무증상, 전립선염증상이없는환자에서검사도중우연히발견모름

5 Cause of CPPS : unknown The principal purpose in evaluation of the patient : To exclude a treatable cause of symptoms

6 Possible pathogenesis of CPPS Initiation Response Propagation Outcome Infection Immunogen Toxin Trauma Inflammation Neurologic injury Immunologic Neurologic Pain Nickel, 2002

7 Possible Etiologies of Chronic Prostatitis/ CPPS Autoimmune Hormonal Bacterial Reflux of urate into prostatic duct Cytokine driven Leukotriene driven or influenced Viral Granulomatous Aberration of peptide growth factors Biochemical aberration possible role of citrate Mycoplasma, e.g. Mycoplasma genitalium

8 Etiology and Classification of Prostatitis Early 19C, Perineal trauma due to horse riding, excessive ejaculation Early 20C, Infection? , Bacterial organisms, eg Gono 1950, Bacterial organisms and WBC 1968, 3-glass test, Meares & Stamey 1978, Drash, et al. Classification

9 Evaluation of CPPS Objective Identification of specific & treatable causes of pelvic pain No generally accepted standard evaluation

10 전립선염의감별진단 비뇨기계종양 ( 방광암, 전립선암 ) 하부요로결석 간질성혹은방사선치료후의방광염 신경인성방광 감염질환즉요도염과부고환염등 위장관질환으로염증성장질환 직장이나항문주위질환 ( 농양, 치열, 치핵등 ) 서혜부탈장 요도협착등

11 Urological Work-up of Patients with Prostatitis Syndrome (EAU, 2009) 1. Clinical history and symptoms 2. Physical Examination 3. UA & UC (mid-stream urine) 4. R/O venereal diseases 5. Micturition chart, UFR, RU 6. 4 glass test (Meares & Stamey) 7. Antibacterial therapy in patients with proven or suspected infection 8. In case of no improvement (after 2 weeks) further evaluation is necessary e.g. video urodynamics

12 Evaluation of the Patient with Chronic Prostatitis/ CPPS Mandatory (Urol 2002, Nickel ) 1. History 2. P/E, including DRE 3. UA, UC Recommended 1. Lower urinary tract localization (4-glass or 2-glass test) 2. Symptom inventory or index (NIH CPSI) 3. Flow rate 4. Residual urine determination 5. Urine cytology Optional 1. Semen analysis and culture 2. Urethral swab for culture 3. Pressure flow studies 4. Video urodynamics (including flow-emg studies) 5. Cystoscopy 6. TRUS of prostate 7. Pelvic imaging (US, CT scan or MRI) 8. PSA (>50 yrs or >40 strong positive family history)

13 Evaluation of a Patient with CPPS (international consensus)(i) Schaeffer AJ, Int J Antimicrob Agents. 2004;24(Suppl 1):S49-52 Basic evaluation 1. History 2. P/E, including DRE 3. UA, UC - midstream Further evaluation 1. Symptom inventory or index (NIH CPSI) 2. Lower urinary tract localization (4-glass or 2-glass test) 3. Flow rate 4. Residual urine determination Evaluation in selected patients

14 Evaluation of a Patient with CPPS (international consensus)(ii) Schaeffer AJ, Int J Antimicrob Agents. 2004;24(Suppl 1):S49-52 Evaluation in selected patients Clinical 1. IPSS Laboratory 1. Urine cytology 2. Urethral evalution VB1 or swab for culture 3. Semen analysis and culture 4. PSA Interventional studies 1. Urodynamic evaluation 1. Pressure flow studies 2. Video urodynamics (including flow-emg studies) 2. Cystoscopy Imaging 1. TRUS of prostate 2. Abdominal/Pelvic US 3. CT scan 4. MRI

15 하부요로감염부위감별진단 (Meares & Stamey, 1968)

16 전립선염증후군진단을위한 4 배분뇨법 : 방법 시술전환자의방광충만을확인한다. 시술중포경수술을안한환자의경우포피를뒤로젖힌다. 귀두를비누와물또는포비돈 (povidone)- 요오드용액으로세척한다. 첫 10 ml 의소변을모은다 ( 첫뇨 ; VB1). 다음 100 ml 의소변은버리고중간뇨 10ml 를모은다 (VB2). 전립선마사지를시행하고전립선액 (EPS) 을모은다. 전립선마사지후첫 10ml 의소변을모은다 (VB3). 정량적배양을위해모든검체는검사실로즉시보낸다.

18 전립선염증후군진단을위한 4 배분뇨법 : 판독 10 3 colony forming unit/ml 보다적은집락수의모든검체는세균성전립선염음성으로판독한다. VB3 또는 EPS 가 VB1 보다더큰 1 이상의 log(s) 값의집락수를가질때는만성세균성전립선염이다. VB1 이다른검체보다많은집락수를가질때는요도염또는오염된검체로판독한다. 모든검체가 10 3 이상의집락수를보일때는해석이불가하다. 이경우환자에게 2~3 일간전립선을투과할수는없으나방광내소변을살균할수있는항생제 (ampicillin 이나 nitrofurantoin) 를사용한뒤검사를반복한다.

19 Chronic Bacterial Prostatitis cfu/ml in the 4-glass-specimen Pat VB1 VB2 EPS VB3 Pathogen ,000 4,400 E.coli , E.coli , E.coli , E.coli E.coli , P.aeruginosa E.cloacae Krieger JN 1998 J New Rem Clin 47: 4-15

20 Traditional Urology Classification Syndrome Symptoms EPS WBCs Bacteriuria PE Acute bacterial Chronic bacterial Nonbacterial + + Prostatodynia +

21 전립선액검사의문제점 정상치? Coverslip을이용한문제 Coverslip vs Hemocytometer : 23% vs 53% 위음성가능 개인적기술 몇번시행? 1회 vs 주3회 : 26% vs 97% 전립선관폐쇄

22 Diagnostic Criteria of EPS Prostatitis 10 WBC/hpf or 1,000 WBCs/mm 3 Clumping of PMNL (5+) and presence of lipid laden macrophages suggest prostatitis, although not diagnostic.

23 균배양검사의문제점 1. 특수한배지가필요 혐기성세균 Coryneform 세균의 miss 가능 2. 전립선조직의세균배양 3. 항생제의복용 4. PCR 검사

24 비세균성전립선염 ( 만성골반통증증후군, NIH Category III) 환자들에서의 16S rrna 의 PCR 을이용한분자생물학적인균검출 1. JN Krieger, DE Riley, et al. Prokaryotic DNA sequences in patients with chronic idiopathic prostatitis. J Clin Microbiology, 1996: 34; DE Riley, JN Krieger, et al. Diverse and related 16S rrna-encoding DNA sequences in prostate tissues of men with chronic prostatitis. J Clin Microbiology, 1998: 36;

25 결과 Chronic non-bacterial prostatitis & Prostatodynia - NIH Category III, CPPS - 16S rrna (+) : 73%

26 문제점. 세균성전립선염으로진단하기위하여정액이나소변, 전립선액을가지고 PCR을하는방법은오염의가능성이거의 100% 이다. False positive율이높다. 이방법으로채취된검체의PCR은신뢰가떨어진다. 균이이미사별되었다하더라도 PCR 방법의진단으로는양성으로나온다.

27 PCR 의기술적인문제점 위음성 검사자의실수, 검체체취의문제점 기술적인문제 환자의검체내에목적으로하는핵산의양이적을때 목적으로하는핵산의변이 (Mutation) 억제물질 (inhibitor) 의존재 위양성 검사자의실수, 검체체취의문제점 목적으로하지않은핵산의증폭 오염 (Contamination)

28 핵산의변이 (Mutation) Sexually Transmitted Diseases, May 2007, Vol. 34, No. 5, p 만약핵산의변이가일어난원인균에감염되었다면, 기존의 primer 에의한 PCR 로증폭되지않아위음성이결과가발생할수있다.

29 377 bp Marker Wild Mutant bp

30 Inhibitor 로인한위음성 Inhibitors of nucleic acid amplification Range from 1 to 7% 검체의종류 (urine > swab) 나환자군에따라발생정도가다름 Inhibition 을일으키는물질 검체내에존재하는생물학적물질 Beta-human chorionic gonadotropin (beta-hcg) Crystals Nitrates Hemoglobin heparin 검체조작에필요한 detergents 나 solvents

31 Inhibition 에의한위음성을극복하기 위한방법 Internal control 위음성이의심될때 PCR 의반복검사 검체의희석 (in the order of 1:5-1:20) Heat, cool, freeze or simply just let the specimen stand for a certain amount of time 핵산의 purification 을위해상품화된첨가물 High Pure TM (Roche) QIAamp (Qiagen)

32 오염에의한위양성 PCR 의가장큰문제 민감도가높다는것은 PCR 의가장큰장점인동시에그만큼검체의오염에의한위양성가능성이높아짐을의미

33 검체 contamination 의경로 Product carryover 이전의검체에서증폭된산물에의한오염 Cross-contamination Positive controls 또는 positive specimens 에의한오염 Exogenous sources 검체를체취하는의사나검사자에의한오염

34 Contamination 을극복하는방법 Meticulous laboratory techniques Strict physical separation of work areas and contaminant devices Environmental decontamination Avoidance of highly concentrated controls Use of negative controls

35 PCR product 의 decontaminations Contamination 중에가장심각한것은이전의검사에서증폭된산물이공기 (aerosols) 를통해오염되는것이다. Decontamination 방법 UV light Gamma ray irradiation Psoralen and isopsoralen derivatives DNase treatment Uracil N-Glycosylase (UNG) treatment

36 검사대행업체의정도관리 아직까지유전자검사기관에대한공인인증은없다. 학회차원의정도관리가필요

37 PCR 의임상적문제점

38 Dead organism PCR 은살아있는미생물과죽은미생물을구별할수없다. 항생제등의치료로인해세균이죽더라도그 DNA 는존재한다. 치료완료후즉각적인검사는 dead organism 을검출하여양성으로판정하는문제가발생할수있다. 따라서치료후 F/U PCR 검사는치료완료후최소 3 주이후에시행한다.

39 Not a quantitative test 보통의 PCR 검사는정량검사가아닌정성검사이다. 따라서 PCR 은미생물의 DNA 의존재여부만을확인하는것이지그미생물의양을측정하는것이아니다.

40 전립선염 15 종 요도염 6 종 Escherichia coli Multiplex PCR Pseudomonas aeruginosa Enterococcus faecalis Proteus spp Staphylococcus aureus Klebsiella spp Strepptpcoccus spp Enterobacter spp Veillonella spp 상기원인균들이실제전립선염원인균으로작용하고있는가?

41 Pathogens causing CBP Aetiollogically recognized Remaining controversial «Uropathogens» E. coli Coag.neg. Staphylococci Klebsiella spp. Streptococci P. mirabilis Corynebacterium spp P. aeruginosa C. trachomatis Other GNB Genital Mycoplasma E. faecalis Anaerobic bacteria S. aureus Yeasts / HSV 1 & 2 T.vaginalis Naber & Weidner, 2000

42 PCR 검사요약 PCR 은미생물을직접검출할수있는민감하고빠르고정확한검사이다. 하지만, 언제든지위양성과위음성과같은기술적인문제점이발생할수있다. 따라서엄격한정도관리 (strict quality control program) 가필요하다. 검사하는의사또는의료인 검사대행업체 또한이러한이유때문에임상적적용에도신중을요한다.

43 Diagnosing and Treating Chronic Prostatitis: Do Urologists use the Four-Glass Test? McNaughton M, et al Urol 2000;55:403-7 U.S.A. National Mail Survey Urologists responded (64%) How often perform 4-glass test (past 12 Mons) Never - 33%, Rarely - 47% : 80% < Half - 9%, Half - 4%, > Half - 3% : 16% Almost Always - 4% (cf. Canada 2%, Nickel et al, 1998)

44 Two Glass Tests (Nickel) TEST Pre and post massage test SPECIMEN Pre-M Post-M CAT II WBC +/- + Culture +/- + CAT IIIa WBC - + Culture - - CAT IIIb WBC - - Culture - -

45 Comparison of EPS with VB3: A Means to Diagnose Chronic Prostatitis/CPPS Ludwig M, Weidner W, et al. Urol 2000;55:175-7 < 10 WBCs in EPS < 10 WBCs in VB3 n=180 n=178 (98.9%) 10 WBCs in EPS 10 WBCs in VB3 n=148 n=136 (91.9%) Sensitivity : 91.9%, Specificity : 98.9%, Accuracy : 95.7% Predictive value : positive %, negative %

46 전립선통과전립선염환자에서정액검사가필요하다 ( 비뇨기과추계학술대회초록집, 1996) 전립선염환자에서정낭염의동반빈도? 전립선염이재발이잘되고치료가잘되지않는원인의하나 - 전립선염과정낭염이동반된환자에서정낭염을치료하지않은상태에서치료를종결하여요도염이나전립선염이재발

47 농정액증의진단 정액에서의 WBC 수 : 1 x 10 6 /ml 개 6 개 /100 개정자

48 미성숙정자와백혈구의감별 Bryan-Leishman 염색 Giemsa 염색

49 정낭염의진단을위한정액검사시기 처음내원시에전립선통으로진단시 전립선염으로진단된환자에는 EPS에서 WBC 수가 10개이하로최소한 2주이상지속시

50 전립선통과전립선염환자에서 정액검사가필요하다 대상 : 전립선통으로분류된 73명전립선염환자 74명 - 세균성 9명비세균성 65명 정낭염진단율 : 전립선통군 14% 전립선염군 32% ( 비뇨기과추계학술대회초록집, 1996)

51 Identification of unusual bacteria in the semen and urine of men with NIH type III prostatitis Jarvi, et al. JU 2001;165(suppl):27-31 Pts: IIIa 23, IIIb 8 - All semen and urine samples (VB1, VB2, VB3) : PCR using Universial Eubacterial primers - Unusual organisms were identified : Paenibacillus sp., Proteobacterium sp., Flavobacterium, uncultured eubacterium, Bradyrhizobium sp. - 1 st reported findings of Paenibacillus sp., Proteobacterium sp in human GU tract fields - Suggests that these bacteria are associated with prostatitis

52 Semen analysis Examination of EPS should not be replaced by that of ejaculate because It is difficult to differentiate spermatocytes and leucocytes The detection rate for positive culture is significantly reduced Krieger et al. J Androl 1996; Weidner et al. Arch Androl 1991; 26:173

53 성병검사 ( 조인래, 남성과학회지, 1999) 만성전립선염 정상 대상 : 326명 100명 요도염의기왕력 : 70% 6% p<0.01 요도염의기왕력이없는 30% 중에서요도염이생길가능성이있는여성과성관계있음 : 19% 없음 : 11%

54 STD and Chronic Prostatitis ( 조인래, 남성과학회지, 1999) 대상 : 만성전립선염 206 명 ( 병력 3 개월이상 ) 전립선염의만성화비율 : 요도염의병력이있는군 (148 명 ) - 75% 없는군 (58 명 ) - 72% 전립선염의병력기간과전립선초음파소견, 전립선증상들의비교 - 유의한차이없음 결론 : 요도염의병력이전립선염의만성화에영향을주지않는것으로사료

55 기타검사 PSA Zinc Cytokines

56 What is the Role/Value of Serum PSA in Evaluation of Prostatitis Useful as additional tool for diagnosis (only) of acute bacterial prostatitis (ABP) Minor elevations in PSA and free PSA are not clinically relevant and are not useful serum markers for diagnosis of CP/CPPS (Nadler et al) PSA levels are not helpful to differentiate between CBP and CPPS, because it heralds inflammation and infection Anderson & Weidner, WHO Consultation, Paris 2005

57 What is the Role/Value of Serum PSA in Evaluation of Prostatitis (cont.) Aggressiveness of inflammation is the most important morphological factor responsible for PSA elevation (Yaman et al, 2003) Elevated serum PSA correlates with content of WBC in EPS (Gu et al, 2004) In men with elevated PSA, screening for cat IV (asymptomatic prstatitis) should be done to reduce number of biopsies for cancer (Potts 2000) Anderson & Weidner, WHO Consultation, Paris 2005

58 PSA Prostatitis: Summary (1) 무증상의 PSA 가증가된환자의경우한달후 PSA 가정상화되는경우는대개문헌의경우 40-50% 정도로보고되고있다. 이러한 PSA 감소는항생제투여, Placebo, Observation 연구들에서각각비슷하게보고되고있다. 항생제치료가무증상의환자에서 PSA 감소에어느정도의도움을주는지는아직논란거리이다.

59 PSA Prostatitis: Summary (2) CP II, IIIa, IIIb 환자들에게서항생제치료는 PSA 를낮추는데효과적으로보이지만대조군의연구가아직없다. CP II, IIIa, IIIb 환자들에게서 PSA 가정상화된경우전립선암의배제가가능한지에대한조직학적연구결과가부족하다. 현재임상적으로전립선조직검사를바로시행하지못하는상황의환자들에게조직검사를유예하는것이어떤의미를가지는지, 또한항생제투여가도움이되는지에대한연구가필요하다.

60 Cytokines as Biochemical Markers of Inflammation in CP/CPPS The following were investigated: Il-1beta; Il-2; Il-6; Il-8; IL-10; TNF-alpha; INF-gamma; NGF. NGF and cytokines that regulate inflammation (Il-6 and Il-10) may play a role in the pain symptoms TNF-alpha and Il-1beta may be useful to identify man with CP with high WBC and asymptomatic prostatitis (Yanget al 2004) Overall conclusion: Cytokine plymosphisms are an area of research but is curently not developed to have clinical utility Anderson & Weidner, WHO Consultation, Paris 2005

61 전립선염의진단 : 맺는말 전립선염특히만성골반통증후군의원인을아직잘모름따라서치료가가능한원인과다른질환이있는지찾아서치료 한국의의료현실에서적절한진단기준과개원의와의연계적인진단모델에대한연구필요 ( 향후지침개발예정 )

슬라이드 1

슬라이드 1 Proposed Korean guideline for the diagnosis of BPH Hyun Woo Kim The Catholic University of Korea BPH Guideline AHCPR guideline on BPH (1994) AUA guideline on BPH (2003) EAU guideline on BPH (2004) International