What is urology? A surgical sub-specialty addressing the -urinary system -male reproductive system 1 Goals of this course Pediatric urology Urologic Oncology Voiding dysfunction Pediatric Urology Renal anomalies- number and position Ureteral abnormalities Hydronephrosis Hypospadius Cryptorchidism 2 Renal Anomalies Renal blastema originates at sacral segments Wolfian duct (mesonephros) normal contact to renal blastema necessary for normal renal development Final position is at upper lumbar vertebrae due to renal ascent Blood supply- develops arteries as it rises not uncommon to have multiple arteries Clinical Correlation Renal agenesisBilateral- “Potter’s “ – incompatible with life Unilateral- 1:1100 births -ipsilateral ureter – 50% absent, all abnormal -Wolfian structures (vas, SV,ampulla, ejac duct) often absent -If solitary absent vas 79% will have absent ipsilat kidney 3 Clinical Correlation Renal Ectopia- Failure or abnormal renal ascent -Incidence 1:1000 -Locations-pelvic, lumbar, abdominal, thoracic, crossed Ureteral Abnormalities Duplicated collecting system and ectopic ureters Ureter begins as branch off Wolfian duct = “ureteric bud” Timing is everything- improper branching or duplication leads to abnormal renal development 4 Clinical Correlation Weigert- Meyer Rule -upper pole ureter is distal and medial and obstructs -lower pole ureter is proximal lateral and refluxes May lead to female incontinence but never in the male 5 6 7 Hydronephrosis Common Causes: -UPJ obstruction -Ureteral obstruction -Ureteral reflux -Distal obstruction i.e. Posterior Urethral Valves UPJ Obstruction 80% of all cases of peri-natal hydronephrosis 2 males : 1female Bilateral in 10-40% of patients Causes- crossing vessels or intrinsic ureteral defect High incidence in contralateral renal anomalies 8 UPJ obstruction cont. Symptoms: Most commonly found on pre-natal US Most common cause of palpable abdominal mass in infant Rarer- failure to thrive, UTI/sepsis, pain, hematuria UTI common presenting symptom in children after the neonatal period UPJ obstruction cont. Diagnosis: Must be confirmed with post natal US Pitfalls: false negative- if US preformed too early no hydro secondary to relative dehydration (should be done after 2 -3 days) false positive- mistaken sonolucent renal pyramids ( until 3 months of age) IVU Lasix renal scan- T1/2 > 20 min VCUG to r/o reflux 9 UPJ obstruction cont. Treatment: Surgical repair generally saves most kidneys Timing of surgery controversial but w/in first 3 years of life probably best Hypospadias Caused by the incomplete closure of embryonic folds 1:300 live male births The more distal the more common: 50%-glanular, coronal 30% midshaft 20% peno-scrotal, scrotal, perineal 10 Hypospadias cont The more proximal evaluate for ambiguous genitalia, i.e. r/o Congenital Adrenal Hyperplasia Palpate gonads are they where they should be Look for dorsal hood – DO NOT CIRCUMCISE 11 Cryptorchidism Failure of testicular descent Nl. Internal testicular descent towards int. inguinal ring is caused by differential growth of lumbar vertebral column and pelvis Testicular passage through the ing.canal is mediated through gubernacular swelling Testis is in scrotum by 26 weeks gestatation (60%descend by 30 weeks 93% by 32 weeks 12 Cryptorchidism Types: abdominal- located inside internal inguinal ring canalicular- located b/w internal and external inguinal rings ectopic- located outside nl descent pathway retractile- moves freely in and out of scrotum Cryptorchidism When to repair? 90% of testis that descend will do so by 3 months Why repair? Tetsicular functionthe earlier the better, spermatogenic fct already impaired w/in first months of life Testicular cancerCryptorchidism increases risk of future cancer, correction does not decrease the risk but allows adequate follow-up Correction should be done by 12-18 months of age 13 Urologic Oncology Kidney Cancer Bladder Cancer Prostate Cancer Testicular Cancer Kidney Cancer Demographics 30,800 new cases diagnosed in 2001 3% of adult cancers in U.S. 2 Males : 1 Female Kidney cancer is on the rise All stages have been increasing 14 Kidney Cancer 4 Main Histologic Types: Clear Cell- most common 85% Papillary- 5-10% Chromophobe-nuclear halo, stain positive for Hales Colloidal Iron 5% Oncocytoma- likely benign “central scar”, “spoke wheel pattern” Medullary- highly aggressive –seen in pts. W SCD/T 15 Kidney Cancer Genetics Oncogene- single gene mutation results in cancer Tumor suppressor gene- 2 hit hypothesis Genotype – VHL: germline VHL tumor suppressor gene mutation (3p25) – HPRC: germline MET oncogene mutation (7q31) – HCRC: germline chromosome 3 translocation Diagnosis Classic Triad: Hematuria, Palpable mass, Flank pain Urinalysis Renal Ultrasound CT scan Enhancing mass = cancer (usually) MRI 16 17 Kidney Cancer Staging T1-Tumor in kidney less then 7cm T1a-<4cm : T1b 4-7cm T2-organ confined >7cm T3- T3a-invaded adrenal or perinephric fat but w/i. Gerota’s fascia T3b-extends into renal veins or IVC below diaphragm T3c-invades vena cava above diaphragm T4- invades beyond Gerota’s fascia Other staging system Stage Stage Stage Stage I = T1 N0M0 II =T2 N0M0 III = T3 or T1,2 N1 M0 IV = T4N0 or T1-3 N2 or any M+ 18 19 20 21 Treatment of localized disease Options: Radical Nephrectomyopen vs. laparoscopic Partial Nephrectomy Ablative techniques Watchful Waiting 22 “The best agent against RCC is Formalin” Surgery remains the best option for treating RCC Metastatic Renal Cancer Remains a grim picture 3yr. Survival is <5% 23 “Standard” Treatment for mRCC RCC is an immunologically responsive tumor RCC is not responsive to current chemotherapeutic regimens or radiation therapy RCC is known to express the MDR gene family Immunotherapy IFN- subQ- response rates range 3-12% few long term (>2 yr.) responses IL-2- 15-20% response rate few (~10%) long term responses (>11yrs) High dose IL-2 > low dose subQ re response High dose IL-2 > low dose subQ re morbidity 24 What about the primary? Better response rates after removal of the primary = “debulking” operations 25 Bladder Cancer EPIDEMIOLOGY 4th most common malignancy in U.S. males 7th most common malignancy in U.S. females 2-3Males: 1 Female Whites > Black ~54,300 new cases in 2001 ~12,400 deaths in 2001 26 RISK FACTORS Smoking Chemical exposure aniline dyes aromatic amines (2-naphthylamine, 4aminobiphenyl) acrolein Race whites > blacks Age Greater than 60 SITE OF DISEASE 5% Upper Tract Majority Renal Pelvis Then distal 1/3 of ureter 95% Bladder 23%- pts with upper tract TCC will have subsequent bladder TCC 5%- pts. with primary bladder cancer will have UT involvement 27 HISTOLOGY 95% -Transitional cell carcinoma 2-5%- Squamous cell carcinoma 2% - Adenocarcinoma (mostly urachal) 1%- Other I.e. small cell, rhabdo EVALUATION IVP/ RPG RUS Urine Cytology Cystoscopy Selective cytology Ureteroscopy TURBT 28 TNM STAGING Ta- non-invasive papillary carcinoma Tis- carcinoma-in-situ (flat tumor) T1- Lamina propria invasion ** T2- Invasion of muscularis propria T2a- superficial T2b- deep T3- Invasion of peri-vesical tissue T3a- microscopically T3b- macroscopically T4- Invasion of adjacent organs T4a- prostate, uterus, vagina T4b- pelvic wall, abdominal wall STAGING CONTINUED Superficial disease- Ta, Tis, T1 Invasive disease- > T2 29 Ta CIS BASEMENT T1a MEMBRANE T1b MM MM MM T C C MUSCULARIS PROPRIA BASEMENT MM MEMBRANE MM T2 T3a/b MUSCULARIS PROPRIA S U P E R F I C I A L MM I N V A S I V E T C C 30 Treatment Superficial disease: TURBT +/- Intravesical therapy Invasive disease: Cystectomy +/- chemotherapy Approximately 50% recurrence rate when cystectomy performed for invasive disease Intravesical Chemotherapy Thiotepa Doxorubicin Mitomycin C 31 Mitomycin C Antibiotic chemotherapy Not FDA approved for TCC 49% C.R. seen in Ta/ T1 disease 15% decrease in overall recurrence rate for prophylaxis best results with 1 pop dose specifically low grade, low stage, low risk* dose- 20-40mg/40ml H2O x 4-8 weeks S.E.- cystitis, skin rash , decreased capacity, myelosuppression *Solosna et al. JU April 1999 Chemo Conclusions All 3 have equal efficacy Short term reduction in recurrence rate is between 13-30% No benefit seen long term No reduction seen rate of progression seen Overall in 2011 pts. Enrolled in clinical trials: 6.9% progression seen in controls 7.5 %in treatment groups 32 Intravesical Immunotherapy BCG Alpha Interferon BCG Morales 1976 Non specific immune system stimulant Mean decrease in recurrence rate is 40% Decreases and prolongs progression rate and time to progression Overall progression rate decreased by 28% Most effective intravesical therapy - shown in multiple randomized trials 33 Bladder Cancer Treatment Invasive Disease- > T2 Disease Cystectomy with or without adjuvant Chemotherapy Chemo for invasive TCC MVAC vs. Gemcitabine and cis-platinum Cystectomy Outcomes Pelvic recurrence – 10-15% vs 50% with XRT 5 yr survival- 65-80% T2-T3a N0 30% with N+ disease 34 Testis Cancer Most common malignancy in males 15-35yrs old 3:1 ratio whites: AA Most curable solid malignancy Paradigm for multi-modal therapy 35 36 Tumor Markers Alpha –Fetoprotein (AFP)- ½ life 5-7 days elevated in pure embryonal , yolk sac, teratocarcinomas NOT in pure seminoma or choriocarcinoma B-HCG- ½ life 24-48 hrs produced by syntiotrophoblasts 100% of choriocarcinomas, 40-60% of embryonal , 10% pure seminoma OVERALL 90% of testis tumors WILL have an elevated marker Staging TNM Tumor- Tis T1- Tumor confined to testis T2- Tumor invades tunica or vasc and lymphatic invasion T3- invasion of spermatic cord T4- invades scrotum Nodes- N0 N1- single node <2cm N2-single node 2-5cm or >1LN none >5cm N3- LN > 5cm 37 Staging Stage I – tumor confined to testis Stage II- IIA- N1 IIB- N2 IIC- N3 Stage III- M+ Treatment Seminoma- Stage I orchiectomy +/- XRT Stage II- orchiectomy + chemo NSGCT- Stage I- orchiectomy +/- RPLND Stage IIA- orchiectomy + RPLND >StageIIB- orchiectomy + chemo Chemo – Etoposide + cis-platinum +/Bleomycin 38 Prostate Cancer Demographics Most commonly diagnosed non-skin malignancy diagnosed in men ~ 179,300 new cases diagnosed in 1999 Second most frequent cause of cancer related death among men ~ 34,800 men died of prostate cancer in 1999 39 Autopsy Studies Age in Years 20-29 30-39 40-49 50-59 60-69 % CaP 2 29 32 55 64 1994 Sakret al. In Vitro Tumors found by PSA screening Autopsy Cystoprost. PSA Tumor Vol.(cc) 0.05 – 0.15 0.02 – 0.17 0.5 – 2.4 Gleason score 4.8 % extra-capsular 0 % < 0.5 cc & GS < 4 94 5.1 6.8 2 20 – 48 78 5 - 15 40 Current Screening Recommendations American Cancer Society & American Urological Association – Annual PSA & DRE • From age 50 • From age 40 if high risk (AA or family history) American College of Physicians & American Academy of Family Physicians – Counsel men 50 to 65 regarding risk vs. benefit U.S. Preventive Services Task Force – routine screening not advocated Screening Men With a Family History First degree relatives: 1 relative increases the risk 2 x 2 relatives increases the risk 4.9 x 3 relatives increases the risk 10.9 x Younger age at presentation Comparable results with RRP (Bova et al, J Urol 1998) 41 Screening African American Men Younger age at presentation Larger tumors Higher PSA levels at time of diagnosis Greater failure for any given PSA strata Greater PPV for PSA > 4.0 ng/ml (38 -48% vs. 22 -34%) Moul et al, JAMA 1997 & Smith et al, J Urol 1997 & Powel J Urol 1997 Screening Schedule AUA Recommendations: Yearly in men > 50 Yearly in high risk patients from age 40 Other possible schedules: PSA < 2ng/ml every 2 years PSA < 1ng/ml at age 40 may wait 510years PSA < 2 and > 70yrs no further PSA 42 WHEN (To Stop) If life expectancy less than 10 yrs Age 70-80 Age 70 and PSA < 2ng/ml If the possiblity of prostate cancer is past #5 on his problem list Screening Tools PSA DRE PSA Velocity Age Specific PSA PSA density % Free PSA 43 PSA Glycoprotien that is secreted by epithelial cells into prostatic ducts and seminal fluid Specific for prostatic tissue but not for prostate cancer > 4ng/ml considered abnormal Limitations Only 70% pathologically organ confined 20% have PSA < 4.0 ng/ml PPV of PSA > 4.0 ng/ml only 20 30% 44 DRE 20% of patients with CaP will have nl. PSA PPV 16% Will detect up to 35% of cancers missed based solely on PSA Combined with PSA only 4-9% of CaP will be missed Diagnosis TRUS/Bx: Morbidity 1687 men undergoing sextant biopsies as outpatient – Hematospermia - 45.3% – Hematuria - 23.6% – Low grade fever - 4.2% – Sepsis - 0.4% Rietbergen et al, Urol 1997 45 Staging T1- non-palpable T1a—found in less than 5% of TURP chips T1b- found in more than 5% of TURP chip T1C- found on biopsy due to elevated PSA T2- palpable disease T2a- one lobe T2b- both lobes involved T3- extends thru capsule T3a-extra-capsular penetration T3b- seminal vesical invasion T4- ninvasion of adjacent structures Nodes N1 if involves regional lymph nodes 46 Prostate Cancer Incidence and mortality in the PSA Era Treatment Options Localized disease: Watchful waiting Radiation Radical Prostatectomy Metastatic Disease: Hormonal therapy (orchiectomy= medical vs. surgical) 47 Risk of death in men with conservatively managed prostate cancer followed for 15 years Grade 55 – 59 60 -64 65 - 69 2-4 0 - 74 4 / 27 5 / 40 6 / 56 7 / 73 5 6 / 27 8 / 39 10 / 55 11 / 71 6 18 / 25 23 / 36 27 / 48 30 / 59 7 70 / 15 62 / 24 53 / 36 42 / 51 8 - 10 87 / 10 81 / 16 72 / 25 60 / 38 Efficacy of RP: 2758 men from 8 University Medical Centers Category Disease-specific* Metastatasis-free* Grade 1 94% 87% Grade 2 80% 68% Grade 3 77% 52% Organ confined Not organ confined 91% 83% 77% 59% *10 year survival Gerber et al, JAMA 1996 48 Efficacy of XRT: 1765 men from 6 University Medical Centers Recurrence free survival* Low grade (2 – 4) 75% Mod grade (5 – 6) 73% High grade (7 – 10) 53% PSA < 10 81% PSA 10 - 20 68% PSA > 20 31 – 51% * 5 year survival, failure = 3 consecutive rises in PSA Shipley et al, JAMA 1999 Voiding Dysfunction 49 Normal voiding is a balance between an ability to store and ability to empty. All voiding dysfunction therefore can be characterized as an abnormality of one or a combination of these 2. Bladder anatomy and physiology Bladder muscle: 3 layers of muscle inner and outer longitudinal middle circular layers are best identified at the bladder neck Bladder innervation: bladder wall- parasympathetic nerve endings also a non adrenergic, non cholinergic component of autonomic nervous system bladder neck- alpha -1 adrenergic fibers 50 Voiding dysfunction Failure to store: Decreased compliancefibrosis, idiopathic Detrusor hyperactivityinvoluntary contractions (neuro dx., obstruction) sensory urgency- (inflam., infx) Decreased resistancestress incontinence, trrauma to BN, neurologic disease 51 Voiding dysfunction Failure to empty: Decreased bladder contractility vs. increased outlet resistance Decreased Contractilityneurologic, myogenic (DM), psychogenic, idiopathic Increased resistanceBPH, stricture, sphicnter dyssynergia Diagnosis HISTORY & PHYSICAL Urodynamics: cystometry + uroflow+ urethral pressure + ext sphincter CMG Normal bladder capacity 400-500cc Compliance (dV/dP) should be less then 15cm H20 4 phases of nl/ cystogram - initial pressure rise to resting pressure - tonus limb (visco elastic properties of bladder) dV/dP - limit is reached strong urge to void - voluntary voiding (increased bladder pressure decreased resistance 52 Uroflow: voiding rate depends on volume (min 150 cc for accuracy normal flow rate 15-25cc/sec normal pattern- rapid rise to max rate (w/in 1/3 of total voiding time) Abnormal Uroflow Interrupted Stream: abdominal straining- detrusor dysfct. bladder stone, BPH obstruction DSD flat elongated low max flow: typical BOO 53 Voiding dysfunction from neuro disaese Findings based on site of injury 54 CVA Leads to detrusor instability and impaired mobility >60% patients have UI 1 week post CVA ~20% patients have UI 6 months post CVA Acutely- retention Long term- detrusor hypereflexia (urgency) Suprasacral SCI Immediate- spinal shock -absent somatic reflex activity & flaccid muscle paralysis below lesion -suppression of autonomic activity: bladder is acontractile and areflexic -smoothe sphincter generally fct.= retention 55 SCI Cont. Later: ebbing of shock coincides with return of DTR detrusor hypereflexia, smoothe sphincter synergia and striated sphincter dyssenergia generally results in incomplete emptyng DSD- may lead to upper tract detrioration ( pressures > 40cm H2O Sacral SCI Detrusor areflexia Competent but non relaxing smoothe sphincter Leads to retention with large capacity atonic bladder 56 Peripheral nerve disease DM, tabes Dorsalis, Herpes Zoster, Disk Dis. Denervation – detrusor hypo-reflexia or areflexia increased bladder capacity decreased contractility decreased sensation Parkinson’s Decreased innervation to striated urethral sphincter Increased incidence of detrusor instability Often complicated by prostatic obstruction 57 Dementia Detrusor hyper-reflexia most common UDS finding Question function over detrusor pathology Normal Pressure Hydrocephallus Symptom triad: -Dementia -Gait abnormalities -UI Urge incontinence but lack of care 58 Incontinence is abnormal at any age Age increases risk of incontinence because: decreased bladder contractility decreased bladder capacity increased urgency increased PVR (50-100ml) increased involunary contractions increased urine output at night decreased maximal urethral closure pressure (females) poorer health decreased mobility At Any Age Urinary Tract Integrity + Mentation, Motivation and Dexterity Continence 59 Transient Incontinence D- delirium I – infection A – atrophic vaginitis P – pharmaceuticals E – excess urine output (lasix, intake) R – restricted mobility S – stool impaction Improve overall function alone may improve continence Lower Urinary Tract Functional incont 60 Female Incontinence 30% of women older than 60 Etiologies: trauma (obstetric, surgical) neurologic congenital hormonal Female Incontinence Classification: urge- physiologic (“warning”) stress- anatomic (“no warning”) overflow- analagous to male BPH total- non functional urethra combination 61 BPH Characterized by enlargement of prostate hyperplastic growth in peri-urethral area (transition zone) Gross appearance- nodular enlargement resulting from irregular mixture of glandular and stromal components Microscopic- hyperplastic glandular and/or stromal elements BPH Prostatic growth is androgen dependent:\ Testosterone produced by testicular Leydig cells Converted to DHT in the prostate by 5 alpha reductase DHT binds with high affinity to intracellular androgen receptor Prostatic innervation via alpha adrenergic fibers 62 Prostatism vs. BPH BPH is a pathalogic diagnosis Prostatism is a constellation of symptoms: urinary frequency, nocturia, decreased flow rate, incomplete emptying, intermittence, straining DD of prostatism: BPH, urethral stricture, prostatitis BPH Treatments Medical: pathology directed alpha 1 blockade- terazosin, doxazosin alpha 1c specific blockade- tamsulosin 5 alpha reductase inhib.- finesteride combination therapy may be most effective Surgical: ablative technology- laser, microwave resection- TURP, open prostatectomy 63