CONTENTS

1 2 Introduction Benign Prostatic Hypertrophy 2.1 Benign Prostatic Hypertrophy 2.2 Simple Prostatectomy 2.3 Transurethral Needle Ablation of the Prostate (TUNA) 2.4 Transurethral Resection of the Prostate 3 Cancer, Adrenals, Kidney, and Ureter 3.1 Urothelial Tumors of the Renal Pelvis and Ureters 4 Cancer, Bladder, Penis, and Urethra 4.1 Bacillus Calmette-Gu 4.2 Bladder Cancer 4.3 Cystoscopy 4.4 Extragonadal Germ Cell Tumors 4.5 Partial Cystectomy 4.6 Penile Cancer 4.7 Radical Cystectomy 4.8 Surveillance for Recurrent Bladder Cancer 4.9 Transurethral Resection of Bladder Tumors 4.10 Treatment of Carcinoma In Situ 4.11 Urethral Cancer 4.12 Urine Tumor Markers in Bladder Cancer Diagnosis 5 Cancer, Prostate 5.1 Metastatic and Advanced Prostate Cancer 5.2 Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer 5.3 Precancerous Lesions of the Prostate 5.4 Prostate Cancer

5.5 Prostate Cancer and Nutrition 5.6 Prostate Cancer Diagnosis and Staging 6 Cancer, Testicle 6.1 Leydig Cell Tumors 6.2 Nonseminomatous Testicular Tumors 6.3 Partial Orchiectomy 6.4 Radical Orchiectomy 6.5 Testicular Cancer 6.6 Testicular Choriocarcinoma 6.7 Testicular Seminoma 7 Cancer, Wilms Tumor and Neuroblastoma 7.1 Neuroblastoma 7.2 Wilms Tumor 8 Common Problems of the Penis 8.1 Balanitis Circumscripta Plasmacellularis 8.2 Balanitis in Emergency Medicine 8.3 Balanitis Xerotica Obliterans 8.4 Balanoposthitis 8.5 Dorsal Slit of the Foreskin 8.6 Paraphimosis 8.7 Pearly Penile Papules 8.8 Peyronie Disease 8.9 Phimosis, Adult Circumcision, and Buried Penis 8.10 Priapism 9 Common Problems of the Testicle 9.1 Cryptorchidism 9.2 Epididymitis

9.3 Epididymo-orchitis Empiric Therapy 9.4 Epididymo-orchitis Organism-Specific Therapy 9.5 Hydrocele 9.6 Manual Detorsion of the Testes 9.7 Spermatocele 9.8 Testicular Torsion 9.9 Torsion of the Appendices and Epididymis 9.10 Varicocele 10 Common Problems of the Urethra 10.1 Urethral Caruncle 10.2 Urethral Diverticula 10.3 Urethral Prolapse 10.4 Urethral Syndrome 10.5 Urethral Warts 10.6 Urethritis 10.7 Urethritis Empiric Therapy 10.8 Urethritis Organism-Specific Therapy 11 Congenital Urologic Conditions 11.1 Cystic Diseases of the Kidney 11.2 Horseshoe Kidney 11.3 Prune Belly Syndrome 12 Dermatological Disorders 12.1 Malignant Dermatologic Diseases of the Male Genitalia 12.2 Nonmalignant Dermatologic Diseases of the Male Genitalia 13 Erectile Dysfunction, Premature Ejaculation, and Sexual Disorders 13.1 Erectile Dysfunction 13.2 Hematospermia

13.3 History Taking in the Erectile Dysfunction Patient 13.4 Physiology of Erectile Dysfunction 13.5 Premature Ejaculation 14 Fistulas 14.1 Enterovesical Fistula 14.2 Renoalimentary Fistula 14.3 Vesicovaginal and Ureterovaginal Fistula 14.4 Vesicovaginal Fistula 15 Hydronephrosis and Ureter Disorders 15.1 Hydronephrosis and Hydroureter 15.2 Megaureter and Other Congenital Ureteral Anomalies 15.3 Obstructed Megaureter 15.4 Retroperitoneal Fibrosis 15.5 Ureterocele 15.6 Ureteropelvic Junction Obstruction 15.7 Urinary Tract Obstruction 15.8 Vesicoureteral Reflux 16 Incontinence 16.1 Cystoscopy and Urethroscopy in the Assessment of Urinary Incontinence 16.2 Urinary Incontinence 16.3 Urinary Incontinence Relevant Anatomy 16.4 Urodynamic Studies for Urinary Incontinence 17 Infections and Related Inflammatory Conditions 17.1 Acute Bacterial Prostatitis 17.2 Bacterial Prostatitis 17.3 Chronic Bacterial Prostatitis 17.4 Chronic Pelvic Pain Syndrome and Prostatodynia

17.5 Emphysematous Pyelonephritis 17.6 Emphysematous Pyelonephritis (EPN) 17.7 Filarial Hydrocele 17.8 Fournier Gangrene 17.9 Gonococcal Infections 17.10 Lymphogranuloma Venereum 17.11 Nonbacterial Cystitis 17.12 Nonbacterial Prostatitis 17.13 Noninfectious Hemorrhagic Cystitis 17.14 Orchitis 17.15 Papillary Necrosis 17.16 Papillomavirus 17.17 Perinephric Abscess 17.18 Pyonephrosis 17.19 Radiation Cystitis 17.20 Renal Corticomedullary Abscess 17.21 Syphilis 17.22 Trigonitis 17.23 Tuberculosis of the Genitourinary System 17.24 Ureaplasma Infection 17.25 Uric Acid Nephropathy 17.26 Urinary Tract Infection in Females 17.27 Urinary Tract Infection in Males 17.28 Urinary Tract Infections in Pregnancy 17.29 Xanthogranulomatous Pyelonephritis 18 Interstitial Cystitis 18.1 Interstitial Cystitis

19 Male Infertility 19.1 Male Infertility 19.2 Sertoli-Cell-Only Syndrome 19.3 Vasovasostomy and Vasoepididymostomy 20 Neurogenic Bladder and Overactive Bladder 20.1 Neurogenic Bladder 20.2 Overactive Bladder 20.3 Overactive Bladder - Etiology, Diagnosis, and Impact 20.4 Overactive Bladder in Children 21 Stones 21.1 Bladder Stones 21.2 Causes of Flank Pain 21.3 Cystinuria 21.4 Extracorporeal Shockwave Lithotripsy 21.5 Hypercalciuria 21.6 Hyperoxaluria 21.7 Hyperuricosuria and Gouty Diathesis 21.8 Hypocitraturia 21.9 Nephrocalcinosis 21.10 Nephrolithiasis 21.11 Pregnancy and Urolithiasis 21.12 Pyelolithotomy 21.13 Struvite and Staghorn Calculi 22 Strictures 22.1 Ureteral Stricture 22.2 Urethral Strictures in Males 23 Surgery

23.1 Adrenal Surgery 23.2 Augmentation Cystoplasty 23.3 Dorsal Penile Nerve Block 23.4 Laparoscopic Pelvic Lymph Node Dissection 23.5 Lasers in Urology 23.6 Nephroptosis 23.7 Nephrostomy 23.8 Nerve Block, Dorsal Penile, Neonatal 23.9 No Scalpel Vasectomy 23.10 Paraphimosis Reduction Procedures 23.11 Partial Nephrectomy 23.12 Pelvic Lymph Node Dissection 23.13 Penile Injection and Aspiration 23.14 Pyeloplasty 23.15 Radical Nephrectomy 23.16 Retroperitoneal Lymph Node Dissection 23.17 Suprapubic Catheterization 23.18 Techniques of Local Anesthesia for Prostate Procedures and Biopsies 23.19 Testicle and Epididymis Anesthesia 23.20 Transperitoneal Laparoscopic Radical Nephrectomy 23.21 Transureteroureterostomy 23.22 Ureterocalicostomy 23.23 Ureterolithotomy 23.24 Ureteroscopy 23.25 Urethral Catheterization in Men 23.26 Urinary Diversions and Neobladders 24 Trauma 24.1 Bladder Trauma

24.2 Penile Fracture and Trauma 24.3 Renal Trauma 24.4 Scrotal Trauma 24.5 Testicular Trauma 24.6 Ureteral Injury During Gynecologic Surgery 24.7 Ureteral Trauma 24.8 Urethral Trauma 24.9 Zipper Injuries 25 Urologic Imaging 25.1 Transrectal Ultrasonography of the Prostate 25.2 Urologic Imaging Without X-rays - Ultrasonography, MRI, and Nuclear Medicine

Introduction:Urology is the medical and surgical specialty that focuses on the urinary tracts of males and females, and on the reproductive system of males. Medical professionals specializing in the field of urology are called urologists and are trained to diagnose, treat, and manage patients with urological disorders. The organs covered by urology include the kidneys, adrenal glands, ureters, urinary bladder, urethra, and the male reproductive organs (testes, epididymis, vas deferens, seminal vesicles, prostate and penis). Urology is one of the most competitive specialties to enter for physicians. The urinary and reproductive tracts are closely linked, and disorders of one often affect the other, so a major part of the conditions managed in urology fall in the area of genitourinary disorders. Urology combines management of medical (i.e., non-surgical) problems such as urinary trac infections and benign prostatic hyperplasia, as well as surgical problems such as the surgical management of cancers, the correction of congenital abnormalities, and correcting stress incontinence. Urology is closely related to, and in some cases overlaps with, the medical fields of oncology, nephrology, gynecology, andrology, pediatric surgery, gastroenterology, and endocrinology.

Benign prostatic hyperplasia (BPH):also known as benign prostatic hypertrophy, is a histologic diagnosis characterized by proliferation of the cellular elements of the prostate. Cellular accumulation and gland enlargement may result from epithelial and stromal proliferation, impaired preprogrammed cell death (apoptosis), or both. BPH involves the stromal and epithelial elements of the prostate arising in the periurethral and transition zones of the gland (see Pathophysiology). The hyperplasia presumably results in enlargement of the prostate that may restrict the flow of urine from the bladder. BPH is considered a normal part of the aging process in men and is hormonally dependent on testosterone and dihydrotestosterone (DHT) production. An estimated 50% of men demonstrate histopathologic BPH by age 60 years. This number increases to 90% by age 85 years. The voiding dysfunction that results from prostate gland enlargement and bladder outlet obstruction (BOO) is termed lower urinary tract symptoms (LUTS). It has also been commonly referred to as prostatism, although this term has decreased in popularity. These entities overlap; not all men with BPH have LUTS, and likewise, not all men with LUTS have BPH. Approximately half of men diagnosed with histopathologic BPH demonstrate moderate-to-severe LUTS. Clinical manifestations of LUTS include urinary frequency, urgency, nocturia (awakening at night to urinate), decreased or intermittent force of stream, or a sensation of incomplete emptying. Complications occur less commonly but may include acute urinary retention (AUR), impaired bladder emptying, the need for corrective surgery, renal failure, recurrent urinary tract infections, bladder stones, or gross hematuria. (See Clinical Presentation.) Prostate volume may increase over time in men with BPH. In addition, peak urinary flow, voided volume, and symptoms may worsen over time in men with untreated BPH (see Workup). The risk of AUR and the need for corrective surgery increases with age. Patients who are not bothered by their symptoms and are not experiencing complications of BPH should be managed with a strategy of watchful waiting. Patients with mild LUTS can be treated initially with medical therapy. Transurethral resection of the prostate (TURP) is considered the criterion standard for relieving bladder outlet obstruction (BOO) secondary to BPH. However, there is considerable interest in the development of minimally invasive therapies to accomplish the goal of TURP while avoiding its adverse effects (see Treatment and Management).

Anatomy:The prostate is a walnut-sized gland that forms part of the male reproductive system. It is located anterior to the rectum and just distal to the urinary bladder. It is in continuum with the urinary tract and connects directly with the penile urethra. It is therefore a conduit between the bladder and the urethra. (See the image below.)

Normal prostate anatomy. The prostate is located at the apex of the bladder and surrounds the proximal urethra. The gland is composed of several zones or lobes that are enclosed by an outer layer of tissue (capsule). These include the peripheral, central, anterior fibromuscular stroma, and transition zones. BPH originates in the transition zone, which surrounds the urethra.

Pathophysiology:Prostatic enlargement depends on the potent androgen dihydrotestosterone (DHT). In the prostate gland, type II 5-alpha-reductase metabolizes circulating testosterone into DHT, which works locally, not systemically. DHT binds to androgen receptors in the cell nuclei, potentially resulting in BPH. In vitro studies have shown that large numbers of alpha-1-adrenergic receptors are located in the smooth muscle of the stroma and capsule of the prostate, as well as in the bladder neck. Stimulation of these receptors causes an increase in smooth-muscle tone, which can worsen LUTS. Conversely, blockade of these receptors (see Treatment and Management) can reversibly relax these muscles, with subsequent relief of LUTS. Microscopically, BPH is characterized as a hyperplastic process. The hyperplasia results in enlargement of the prostate that may restrict the flow of urine from the bladder, resulting in clinical manifestations of BPH. The prostate enlarges with age in a hormonally dependent manner. Notably, castrated males (ie, who are unable to make testosterone) do not develop BPH. The traditional theory behind BPH is that, as the prostate enlarges, the surrounding capsule prevents it from radially expanding, potentially resulting in urethral compression. However, obstruction-induced bladder dysfunction contributes significantly to LUTS. The bladder wall becomes thickened, trabeculated, and irritable when it is forced to hypertrophy and increase its own contractile force. This increased sensitivity (detrusor overactivity [DO]), even with small volumes of urine in the bladder, is believed to contribute to urinary frequency and LUTS. The bladder may gradually weaken and lose the ability to empty completely, leading to increased residual urine volume and, possibly, acute or chronic urinary retention.

In the bladder, obstruction leads to smooth-muscle-cell hypertrophy. Biopsy specimens of trabeculated bladders demonstrate evidence of scarce smooth-muscle fibers with an increase in collagen. The collagen fibers limit compliance, leading to higher bladder pressures upon filling. In addition, their presence limits shortening of adjacent smooth muscle cells, leading to impaired emptying and the development of residual urine. The main function of the prostate gland is to secrete an alkaline fluid that comprises approximately 70% of the seminal volume. The secretions produce lubrication and nutrition for the sperm. The alkaline fluid in the ejaculate results in liquefaction of the seminal plug and helps to neutralize the acidic vaginal environment. The prostatic urethra is a conduit for semen and prevents retrograde ejaculation (ie, ejaculation resulting in semen being forced backwards into the bladder) by closing off the bladder neck during sexual climax. Ejaculation involves a coordinated contraction of many different components, including the smooth muscles of the seminal vesicles, vasa deferentia, ejaculatory ducts, and the ischiocavernosus and bulbocavernosus muscles.

Epidemiology:BPH is a common problem that affects the quality of life in approximately one third of men older than 50 years. BPH is histologically evident in up to 90% of men by age 85 years. As many as 14 million men in the United States have symptoms of BPH. Worldwide, approximately 30 million men have symptoms related to BPH. The prevalence of BPH in white and African-American men is similar. However, BPH tends to be more severe and progressive in African-American men, possibly because of the higher testosterone levels, 5-alphareductase activity, androgen receptor expression, and growth factor activity in this population. The increased activity leads to an increased rate of prostatic hyperplasia and subsequent enlargement and its sequelae.

Prognosis:In the past, chronic end-stage BOO often led to renal failure and uremia. Although this complication has become much less common, chronic BOO secondary to BPH may lead to urinary retention, renal insufficiency, recurrent urinary tract infections, gross hematuria, and bladder calculi.

Introduction to Simple Prostatectomy :Simple prostatectomy differs from radical prostatectomy in that the former consists of enucleation of a hyperplastic prostatic adenoma, and the latter involves removal en bloc of the entire prostate, the seminal vesicles, and the vas deferens. Open (simple) prostatectomy has 3 different approaches: (1) retropubic, (2) suprapubic, and perineal. Simple retropubic prostatectomy is the enucleation of a hyperplastic prostatic adenoma through a direct incision of the anterior prostatic capsule. Simple suprapubic prostatectomy is the enucleation of the hyperplastic prostatic adenoma through an extraperitoneal incision of the lower anterior bladder wall.[1] Patients who present for open (simple) prostatectomy are typically age 60 years or older.

Invasive treatment options :In patients in whom medical and minimally invasive options for benign prostatic hyperplasia (BPH) have been unsuccessful, the more invasive treatment options for BPH should be considered, such as the use of transurethral resection of the prostate (TURP) or the employment of open prostatectomy. The advantages of open (simple) prostatectomy over TURP include the complete removal of the prostatic adenoma under direct visualization in the suprapubic and retropubic approaches. However, these procedures do not obviate the need for further prostate cancer surveillance because the posterior zone of the prostate remains as a potential source of carcinoma formation.

Advantages of retropubic prostatectomy :Advantages of the retropubic technique over the suprapubic approach include the following: Superb anatomic prostatic exposure Direct visualization of the adenoma during enucleation to ensure complete removal Precise division of the prostatic urethra, optimizing preservation of urinary continence Direct visualization of the prostatic fossa after enucleation for hemorrhage control Minimal to no surgical trauma to the bladder

Advantages of suprapubic prostatectomy :The major advantage of the suprapubic approach over the retropubic approach is that it permits better visualization of the bladder neck and ureteral orifices and is therefore better suited for patients with the following conditions: Enlarged, protuberant, median prostatic lobe Concomitant symptomatic bladder diverticulum Large bladder calculus Obesity (to a degree that makes access to the retropubic space more difficult)

Advantages of simple perineal prostatectomy :Advantages of perineal prostatectomy include the following: Ability to treat clinically significant prostatic abscess and prostatic cysts Less postoperative pain Ability to avoid the retropubic space

With regard to the last point, above, retropubic or suprapubic surgery is more difficult in patients who have had prior retropubic surgery.

Disadvantages of open (simple) prostatectomy :Open (simple) prostatectomy does have disadvantages when compared with TURP. These include the morbidity and longer hospitalization associated with the open procedure and the potential for greater intraoperative hemorrhage.

A disadvantage to the use of suprapubic approach relates to reduced visualization of the apical prostatic adenoma and the potential complications of postoperative urinary incontinence and intraoperative bleeding. This article reviews the indications for open prostatectomy, discusses the various approaches for this procedure, weighs the advantages and disadvantages of each approach, and provides a brief outline of standard surgical technique.

Indications for Open (Simple) Prostatectomy :The indications for either TURP or open (simple) prostatectomy include the following: Acute urinary retention Persistent or recurrent urinary tract infections Significant hemorrhage or recurrent hematuria Bladder calculi secondary to bladder outlet obstruction Significant symptoms from bladder outlet obstruction that are not responsive to medical or minimally invasive therapy Renal insufficiency secondary to chronic bladder outlet obstruction

Congestive heart failure :The transurethral resection (TUR) syndrome of dilution hyponatremia is unique to TURP and does not occur with open (simple) prostatectomy. The incidence of TUR syndrome during a TURP is roughly 2%. Thus, in patients with a greater risk of congestive heart failure caused by underlying cardiopulmonary disease, open prostatectomy has a much smaller risk of intraoperative fluid challenge.

Prostate size :Consider open (simple) prostatectomy, using either the retropubic or suprapubic approach, when the prostate is larger than 75 g or larger than the surgeon can resect reliably with TURP in 60-90 minutes. Bladder pathology :In patients with concomitant bladder pathology that complicates their outlet obstruction (eg, a large or hard bladder calculus, symptomatic bladder diverticulum), open prostatectomy remains the procedure of choice. Additionally, patients with musculoskeletal disease that precludes proper patient positioning in the dorsal lithotomy position for TURP may benefit from an open prostatectomy. Contraindications to Open (Simple) Prostatectomy Open (simple) prostatectomy is contraindicated in the presence of prostate cancer. If cancer is suspected, a formal prostate biopsy should be performed before surgery is considered. If cystoscopy findings indicate that the obstructing adenoma primarily involves the median lobe, the suprapubic approach may be preferred to the retropubic technique, because the suprapubic procedure optimizes anatomic exposure. In addition, retropubic prostatectomy offers only limited access to the bladder, which is an important consideration if a bladder diverticulum requiring excision coexists or if a large bladder calculus must be directly removed.

The perineal approach can be contraindicated in patients in whom sexual potency remains important. In this procedure, the perineal neurovascular anatomy is invaded more extensively than it is in the other available open techniques.

Preparation:Positioning of Patients :In the retropubic (Millin) prostatectomy, the patient is placed on the operating room table in the supine position in mild Trendelenburg. In the suprapubic approach, place the patient in a supine position on the operative table, with the umbilicus over the break of the table. Next, hyperextend the table slightly, placing the patient in a mild Trendelenburg position.

Complication Prevention :Exclude prostate cancer before performing a prostatectomy in patients with symptomatic bladder outlet obstruction. All men should undergo preoperative prostate-specific antigen (PSA) determination and routine digital rectal examination (DRE). Suspicions evoked by either screening modality should prompt a transrectal, ultrasonographically guided needle biopsy of the prostate to exclude the presence of carcinoma before open (simple) prostatectomy is performed. A urinalysis and urine culture, electrolyte study, complete blood count (CBC), coagulation studies, and, at least, a type and screen should be obtained in all patients prior to proceeding with an open (simple) prostatectomy. Although transrectal ultrasonography may help to document the prostates size, it is not indicated preoperatively and does not assist in the preoperative screening for prostatic malignancy. Imagery of the upper urinary tract is not performed routinely in patients with outlet obstruction unless it is indicated for other reasons (eg, evaluation of hematuria). Chest radiography and electrocardiography are indicated to investigate potential complications from possible preexisting conditions in patients older than age 60 years. Cystoscopy is useful for identifying the presence of urethral stricture disease, bladder calculi, diverticula, and a large median lobe. This information is helpful when the clinician is deciding whether to perform a suprapubic or a retropubic prostatectomy. Preoperative lower urinary tract studies may include a urinary flow rate with documentation of postvoid residual and, possibly, a cystometrogram and pressure or flow evaluation in patients with more complex conditions who may have coexisting bladder instability or detrusor function abnormalities. If anticoagulants (eg, aspirin, other nonsteroidal anti-inflammatory drugs [NSAIDs], warfarin [Coumadin]) are required preoperatively, coordinate their discontinuation with the ordering physician and correct any significant coagulopathy before surgery. Discuss potential risks of open (simple) prostatectomy with the patient preoperatively, including urinary incontinence, erectile dysfunction, retrograde ejaculation, urinary tract infection, and the need for a blood transfusion. Additionally, as with all open pelvic procedures, the risk of deep vein thrombosis and pulmonary embolus always exists.

Technique:Surgical Overview :Open (simple) prostatectomy is an invasive surgical approach for the treatment of medically resistant or advanced lower urinary tract obstruction secondary to BPH. Patients with an exceedingly large prostate or with concomitant bladder calculi or diverticula are ideal candidates for this approach, as these techniques optimize exposure to the entire prostate and to the intravesical bladder.

Retropubic (Millin) Prostatectomy :As previously stated, the patient is placed on the operating room table in the supine position in mild Trendelenburg. A lower midline incision is made and the space of Retzius developed. Initiate the Millin (transverse capsular) prostatectomy by locating the vesicle neck by palpation of the Foley balloon. Place a 1-0 absorbable suture deeply in the capsule of the prostate, just below the vesicle neck. Repeat this technique until a 4-cornered area is created, through which a transverse incision is made into the adenoma across the entire anterior surface while the bladder is retracted cephalad. Place the proximal capsule under tension and achieve hemostasis actively with full suction. Hemostasis can also be achieved by ligating the dorsal venous complex as well as ligating the prostatic arteries as they enter the prostaticovesical junction near the level of the seminal vesicles. Next, identify the plane between the adenoma and the capsule and sharply dissect. Once developed, manually explore this plane while the adenoma is enucleated under direct visualization. Carefully identify the apex of the prostate and sharply divide the urethra under direct visualization. Achieve hemostasis before placement of figure-of-8, 2-0 absorbable sutures at the 5- and 7-o'clock positions through the vesical neck and proximal capsule. Clearly identify the ureteral orifices before resecting a wedge of posterior vesical neck. Using a running 2-0 absorbable suture, evert and approximate the edges. Indigo carmine can be administered to decrease the risk of iatrogenic injury to the ureteral orifices. Introduce a large catheter into the urethra and inflate the balloon. Finally, close the capsule from both ends with 2 continuous 2-0 absorbable sutures. Foley traction may be used as needed for hemostasis. Place an external drain into the space of Retzius to prevent hematoma and urinoma formation. After that, irrigate and close the wound.

Suprapubic Prostatectomy :With the suprapubic approach, place the patient in a supine position on the operative table, with the umbilicus over the break of the table. After that, hyperextend the table slightly, placing the patient in a mild Trendelenburg position. After preparing and draping the patient in the standard fashion, introduce a urethral catheter into the bladder, through which the bladder is filled to approximately 250 mL with sterile water or saline before the catheter is removed. Make a vertical midline incision from below the umbilicus to the pubic symphysis. Alternatively, a low Pfannenstiel incision can be made. Dissect between the laterally retracted rectus abdominus, developing the prevesical space extraperitoneally. Neither the retropubic nor the lateral vesical spaces are necessarily entered. Below the peritoneal dissection, place 2 stay sutures in the anterior bladder wall, make a vertical cystotomy, and carry it within 1 cm of the bladder neck, allowing visualization of the bladder neck and prostate. A transverse stay suture may be placed to prevent caudal extension of the cystotomy. Retract the superior bladder edge cranially and retract the inferior portion distal to the trigone in a caudal direction to display the posterior bladder neck. The urethral orifices are now well visualized and protected as the bladder neck mucosa is incised just distal to the trigone. After circumferentially incising the bladder mucosa over the prostate, using sharp and blunt dissection, develop the plane between the adenoma and the prostatic capsule. Perform a gentle blunt digital dissection, completing the remaining dissection both posteriorly and circumferentially around the prostatic apex and urethra. The prostatic urethra is separated at the apex by carefully pinching 2 fingers together. Make every effort not to tear the prostate or sphincter at this level. Following gross enucleation of the adenoma, manually inspect the prostatic fossa and remove any remaining nodular adenoma. Bleeding within the prostatic fossa can be controlled with electrocautery or suture ligatures. Pass a 22F, 30-mL, 3-way catheter per urethra (and, in select patients, an additional suprapubic tube through a separate anterior cystostomy). Close the bladder in full-thickness through the serosa using a double layer of interrupted 2-0 chromic or Vicryl suture. Inflate the catheter balloon to prevent retraction into the prostatic fossa and drain the space of Retzius.

Laparoscopic and Robotic Simple Prostatectomy :In 2002, Moreno was the first to describe a laparoscopic simple prostatectomy for BPH. Since then, several others have described extraperitoneal laparoscopic prostatectomies for obstructing BPH. The transvesical and transcapsular (Millin) techniques have been performed laparoscopically. Most investigators have found laparoscopic simple prostatectomy to be a feasible alternative to the open (simple) technique. However, this technique has a steep learning curve and requires significant laparoscopic expertise.[2]

In 2008, Sotelo et al published their initial experience with a robotic, suprapubic simple prostatectomy.[3] As with other laparoscopic cases, robotic assistance may prove to be very valuable and may increase the popularity of this minimally invasive approach.

Post-Procedure:Postsurgical Care :Postoperative care of patients who have had an open (simple) prostatectomy parallels care following most major open surgical procedures. Because the need for postoperative blood transfusions is minimized through improvements in understanding of the relevant surgical anatomy and advancements in operative technique, most patients are discharged comfortably on the second day following surgery. For the surgeon, the most significant concern is to observe drain output and fluid status immediately after surgery, as patients generally ambulate and tolerate a regular advancement of their diet by the first day following surgery. Monitor the patient in the clinic after surgery. If the Foley catheter was not removed during the hospitalization, a voiding trial can be performed on an outpatient basis. Review pathology and schedule follow-up examinations for the patient in order to exclude carcinoma. With simple prostatectomy, the risk of prostate cancer development remains and patients must be monitored with DRE and PSA studies.

Complications of Simple (Open) Prostatectomy :Postoperative complications following suprapubic and retropubic prostatectomy include hemorrhage, urinary extravasation, and associated urinoma.[4] Infectious processes, including cystitis and epididymo-orchitis, may also occur, but only rarely when prophylactic antibiotics are administered. Because the risk of injury to the external urinary sphincter is minimal with these procedures, stress urinary incontinence and total urinary incontinence are rare. Coincident erectile dysfunction and bladder neck contracture have been reported postoperatively in approximately 2%-3% of patients following suprapubic prostatectomy. Depending on the degree of preoperative urge incontinence, postoperative urge incontinence may be present for weeks or months. Retrograde ejaculation has been reported in up to 80%-90% of patients after surgery and is a common phenomenon after these procedures. Finally, as with any significant pelvic surgery, the risk of nonurologic complications exists, including deep vein thrombosis, pulmonary embolus, myocardial infarction, and cerebral vascular accident. The incidence of these complications, however, is low and reflects the comorbidities of the patient population being treated.

Introduction to the TUNA Procedure:Transurethral needle ablation (TUNA) of the prostate is a procedure used to treat benign prostatic hyperplasia (BPH). It is performed by placing interstitial radiofrequency (RF) needles through the urethra and into the lateral lobes of the prostate, causing heat-induced coagulation necrosis. The tissue is heated to 110C at an RF power of 456 kHz for approximately 3 minutes per lesion. A coagulation defect is created. Transurethral resection of the prostate (TURP) was originally developed in the United States between 1920 and 1930 and was generally considered the criterion standard for surgical management of BPH. Advances in the surgical treatment of BPH have come via applications of traditional electrosurgical current. TUNA is one of these minimally invasive treatments of prostatism. It began as a treatment in the early 1990s, with the first preliminary trials on humans in 1993. The first studies in the United States began in 1994, and the US Food and Drug Administration approved TUNA of the prostate in 1996. However, a decline in the use of this procedure has occurred as newer techniques to treat BPH (laser ablation/enucleation, thermotherapy) have arisen and become more popular.[1] The TUNA system produces thermal tissue ablation by applying low-level RF energy to prostate tissue. The generated RF is in the form of electrical energy and is delivered by the 2 electrodes, which are in contact with the patient. As the prostate cells resist passage of the current, thermal energy is produced by friction and by the heating of water molecules. This leads to tissue heating and, ultimately, coagulation necrosis. Thermal lesions occur only in a localized area, because the RF signal is transmitted into tissue only by direct contact. Although the ideal use of TUNA has been thought to be in patients with large lateral lobes, Naslund and Stitcher reported that TUNA can be used effectively in patients with large median lobes. The key to this form of treatment is to ensure that the needles are in the median lobe and do not protrude into the bladder. Indications for the Performance of TUNA :Minimally invasive therapy is generally the next step after failed medical management. This therapy is also the primary treatment for patients who are not interested in medical therapy and are unwilling to undergo TURP. Generally, the ideal patient for TUNA is thought to be a man with obstructive symptoms and a prostate of 60 g or less with predominantly lateral lobes. Patients found to have larger glands may be offered different forms of treatment.

Contraindications to the Performance of TUNA :The manufacturer lists the following contraindications to TUNA therapy: Active urinary tract infection Neurogenic, decompensated, or atonic bladder Urethral strictures or muscle spasms that prevent insertion of the cartridge sheath Bleeding disorders or patients taking anticoagulation medication unless antiplatelet medication has been discontinued for at least 10 days ASA class group V patients Clinical or histological evidence of prostatic cancer or bladder cancer Prostate gland that is less than 34 mm or greater than 80 mm in transverse diameter Presence of any prosthetic device in a region that may interfere with the procedure

Patients whose prostate has previously been treated with nonpharmacologic therapies Presence of cardiac pacemaker, implantable defibrillator, or malleable penile implants Patients with any component(s) of an implantable neurostimulation system

Very limited experience has been gained regarding the use of TUNA to treat patients with high bladder necks. At this time, these patients should probably be treated with another form of therapy.

Preparation:Anesthesia Use in TUNA :One advantage of TUNA (in comparison with TURP) is that a general or spinal anesthesia is not required. Most patients are treated with oral sedation (Valium and Demerol) and urethral gel. Local anesthesia is placed with ultrasonographic or digital guidance. TUNA typically is an outpatient procedure.

TUNA Equipment Overview :The needles used in TUNA are covered by insulated sheaths, which allow for control of the length of the exposed needles. Thermosensors on the end of the catheter, in the needle sheaths, and in the rectum measure the temperature in the prostate and periprostatic areas. The shaft of the delivery catheter can be rotated 180.

Preprocedural Considerations :In general, no set workup studies have been determined beyond the standard history and physical examination, which are required before transurethral needle ablation (TUNA) can be performed. The patient needs to have sterile urine prior to undergoing TUNA. If this is not the case, he should be adequately treated with antibiotics. Prior to starting the procedure, transrectal ultrasonography is performed to determine the length and width of the prostate. (The periprostatic block can also be placed at this time under ultrasonographic guidance.) The prostates length helps to determine the number of lesions required to appropriately treat the gland. The width is used to determine the needle length. The number of treatment planes can also be determined using ultrasonography. The fact that the size of the prostate does not correlate with the degree of symptoms is well known. Thus, ultrasonography to evaluate for the size of the prostate would not help in the diagnosis. Also, performing a cystoscopy to evaluate for size would similarly not be helpful in establishing a diagnosis of BPH but would help in determining if a median lobe is present.

Technique:Patient Care Following TUNA :Postoperatively, the patient typically wears a catheter for 1-3 days. The rate of postoperative urinary retention is reportedly between 13% and slightly over 40%. Treatment is typically conservative (ie, catheter drainage), and in most patients, the retention tends to resolve in less than 2 days. Secondary catheterization is reported in 12% of patients, and most patients are able to return to work in 2-3 days.

Postoperative antibiotic coverage is recommended for 3-5 days after TUNA or after the catheter is removed.

Outcome and Prognosis :Numerous clinical trials have been performed worldwide. Various parameters are used to assess the performance of TUNA. Subjective improvement ranges from 56-61% at 6 months, 40-70% at 1 year, and 5773% at 2 years. In a review of more than 10 studies on 546 patients, the overall average improvement was 58% at 1 year, 60% at 2 years, and 66% at 3 years. In a study on the durability of TUNA 5 years after treatment, Hill et al found that patients treated with TUNA had stable responses over 5 years, based on International Prostate Symptom Score (IPSS), quality of life, and peak flow rate (PFR).[3] These were all statistically significant at all yearly intervals when compared to baseline. At 5 years, IPSS scores decreased from 24 to 10.7, quality of life improved from 11.8 to 3.8, and PFR improved from 8.8 mL/s to 11.4 mL/s. This is in contrast to a study by Rosario et al, who demonstrated treatment failure occurring in 83% of men at a median of 20 months. The need for retreatment in this series led the authors to conclude that TUNA is not a cost-effective option for patients in whom medical therapy has failed.[4] The decrease in the postvoid residual urine volume after a TUNA procedure is 13-80%. Acceptable evidence does not exist that demonstrates a significant reduction in prostate size. No long-term data beyond 3 years are available. Few studies exist regarding the efficacy of the TUNA procedure on the treatment of urinary retention secondary to BPH. However, Zlotta et al reported a success rate of 79% (30 of 38) in patients with retention,[5] and Millard et al reported a treatment success rate of 78% (15 of 20) in patients with retention.[6]

TUNA-Associated Complications :The intraoperative and postoperative morbidity and mortality rates associated with TURP are significantly higher than those associated with TUNA. TUNA is associated with fewer sexual side effects and less bleeding. The anesthetic requirement is also lower. As mentioned, reported rates of urinary retention in patients who have undergone TUNA are between 13% and slightly over 40%. Retention appears transient, lasting from 12-48 hours. Postoperative catheter usage alleviates this problem. Urinary incontinence is not reported. Macroscopic hematuria is noted in most patients for up to 24-48 hours. This is usually self-limiting and requires no treatment. Ensure that patients with coagulopathies have them corrected prior to TUNA. Irritative voiding symptoms occur in up to 40% of the patients; however, these are typically self-limiting and resolve within 7 days. These complaints rarely last beyond 4 weeks. Urinary tract infection and epididymitis are essentially nonexistent in the face of sterile urine preoperatively and appropriate antibiotic coverage postoperatively. Coverage is recommended for 3-5 days after TUNA or after the catheter is taken out.

Urethral strictures may occur from instrumentation of the urethra. Reported rates are less than 2%; however, reported rates with standard TURP are as high as 7.3%. Little evidence suggests that retrograde ejaculation occurs. Marginal decreases in ejaculatory fluid are reported. Reported rates after TURP are 50-95%. Impotence is reported in approximately 3% of the patients, and deterioration in function is reported slightly more often. Improvement in erectile function is reported by 14-21% of men. Postoperative hematology and electrolyte changes are not noted in these patients. Some patients fail to resume voiding or do not experience significant improvement in symptoms following TUNA. These patients are typically treated with a formal TURP. Rosario et al reported that 22 out of 71 (31%) men treated with TUNA for symptomatic benign prostatic hyperplasia (BPH) proceeded to a TURP during a 1year follow-up study.[7] Kahn et al, Rodrigo Aliaga et al, Millard et al, and Zlotta et al reported performing a TURP following initial treatment with TUNA in 2 of 45 patients (4%), 7 of 42 patients (14%), 5 of 20 patients (25%), and 8 of 38 patients (21%), respectively.[8, 9, 6, 5] Thus, a total of 44 patients out of 216 (20%) went on to undergo TURP. Long-term follow-up examinations over a period of months to years are needed to reevaluate symptom improvement.

Long-Term Monitoring :Determining the length of time necessary for the coagulation defect to mature is difficult. Pathologic studies performed at 1 month following TUNA continue to show areas of maturing fibrosis and necrosis. Naslund feels that patients may not see improvement in voiding symptoms for 2-6 weeks. Furthermore, the patient may continue to see improvement for up to 2-3 months postoperatively. Therefore, the therapy should not be considered a failure until after 2-3 months.

Urothelial Tumors of the Renal Pelvis and Ureters:-

Urothelial tumors of the renal pelvis and ureters (upper urinary tract) are relatively rare. Tumors of the renal pelvis account for approximately 10% of all renal tumors and approximately 5% of all urothelial tumors. Ureteral tumors are even more uncommon, occurring with one quarter the frequency of renal pelvis tumors. Transitional cell carcinoma (TCC) accounts for more than 90% of urothelial tumors of the upper urinary tract.

Epidemiology :Frequency : The mean age in persons who develop upper urinary tract urothelial tumors is 65 years. The incidence of TCC increases with age. Moreover, TCC tumors are rarely found at autopsy. Upper tract urothelial tumors are more common in men, with a male-to-female ratio of 3:1. Upper tract urothelial tumors are twice as common in white people as in black people. Upper tract TCC is associated with Balkan nephropathy, which is a degenerative interstitial nephritis of unknown etiology that predisposes to upper tract TCC in individuals from rural Balkan areas by a factor of 100-200 greater than that in individuals residing in neighboring communities. Tumors

associated with Balkan nephropathy are generally low-grade, multiple, and bilateral, in contrast to TCC of other etiologies.

Etiology:Tobacco smoking is the factor most strongly associated with upper tract TCC and increases the risk more than 3-fold. Estimates point to smoking as the cause of 70% of upper tract tumors in men and 40% in women. Drinking coffee slightly increases the risk of upper tract TCC; this risk factor is typically observed in people who consume more than 7 cups of coffee per day. Analgesic abuse is also a risk factor for urothelial malignancy. It is independent from and synergistic with renal papillary necrosis. Long-term exposure to analgesics, notably phenacetin, induces a nephropathy that raises the risk of upper tract TCC to as high as 70%. Capillarosclerosis, which is characterized by a thickening of the basement membrane, is the pathognomonic finding of analgesic abuse and is found in 15% of patients with upper urinary tract tumors. Occupational exposure to agents used in the petrochemical, plastic, and tar industries has been linked to an increased risk of TCC. Chronic infections, irritation, and calculi may also predispose to squamous cell carcinoma and, less commonly, adenocarcinoma of the upper urinary tract. Cyclophosphamide has been linked to the development of urothelial tumors. More specifically, a breakdown metabolite called acrolein is thought to be the causative agent. Tumors associated with cyclophosphamide tend to be high-grade. Finally, heredity may play a part in the development of TCC. TCC is associated with Lynch syndrome type II, which is a syndrome that is characterized by early onset of proximal colonic nonpolyposis tumors, numerous synchronous and metachronous colonic tumors, and extracolonic tumors.

Pathophysiology:Types of upper urinary tract tumors :TCC is the most common histology observed, accounting for greater than 90% of upper urinary tract urothelial tumors. TCCs are strongly associated with smoking. Squamous cell carcinoma comprises 1-7% of upper tract urothelial tumors. Squamous cell carcinoma is frequently associated with longstanding infected staghorn calculi. Affected patients frequently present with moderately to poorly differentiated tumors and advanced disease. Adenocarcinoma accounts for less than 1% of upper tract tumors. Patients with adenocarcinoma of the upper urinary tract may also have associated calculi and long-term obstruction, suggesting an etiologic origin for these processes. Inverted papilloma is an unusual lesion that is generally considered a benign histologic lesion; however, it may harbor foci of malignant change.

Molecular mechanisms :Several molecular mechanisms have been associated with the development of upper urinary tract TCC. Tumor suppressor genes p19, p16, RB1, and TP53 have all been associated with upper tract TCC.[1] Losses of TP53, p19, and p16 are associated with low-grade cancers, while a loss of RB1 has been associated with higher-grade, more aggressive tumors.[1] Tumor microsatellite instability (MSI) has been studied as a prognostic indicator for upper tract tumors. In general, high levels of MSI seem to correlate with a more favorable prognosis, particularly in younger patients with T2 or T3/N0 disease (see Staging).[2, 3] In a 2001 study, survivin, a protein apoptosis inhibitor, was measured in the urine of patients with TCC of the bladder and was found to be highly sensitive and specific for this malignancy.[4] The bladder tumor-associated analytes (BTA) test, CYFRA 21-1, and NMP-22 may have a role in patients at risk for recurrent bladder cancer. Fluorescence in situ hybridization (FISH) may be one of the more useful tests for detecting urinary tract cancer, as it yields a greater sensitivity for lower grade tumors than cytology and other tests. Ureteral cancer has been detected with FISH during evaluation for hematuria.[5]

Patterns of spread :Transitional tumors spread conventionally in a cephalad to caudad direction. For instance, studies have shown a high rate of recurrence in the distal ureteral stump in patients treated with nephrectomy and incomplete ureterectomy. Conversely, TCC rarely recurs proximal to the level of resection of a ureteral lesion. Approximately 30%-75% of patients with upper tract urothelial tumors develop bladder tumors at some point during their cancer course. The risk of upper tract TCC in patients with a bladder malignancy is 2-4% but as high as 21-25% in patients with carcinoma in situ. Thus, higher grade increases the risk of upper tract disease. Lymphatic extension is another pattern observed in TCC. The most common locations for spread, depending on the site of the primary tumor, include paraaortic, paracaval, ipsilateral common iliac, and the pelvic lymph nodes. Hematogenous seeding also occurs, with the liver, lung, and bone being common sites for metastases.

Distribution of upper tract transitional cell carcinoma :

Renal pelvis - 58% Ureter - 35% (73% of which are located in the distal ureter) Both renal pelvis and ureter - 7% Bilateral involvement - 2-5%

Presentation: Gross or microscopic hematuria (75%) is the most common clinical presentation of urothelial tumors of the renal pelvis and ureters. Flank pain (18%) results from gradual obstruction/distention of the collecting system or acute colic due to obstruction by a blood clot. Dysuria (6%): Some patients report irritative lower urinary tract symptomatology such as burning upon urination. Weight loss, anorexia, flank mass, or bone pain are symptoms of advanced disease that manifest in a minority of patients.

Indications: Nephroureterectomy with excision of the bladder cuff is indicated in patients with renal pelvis transitional cell carcinoma (TCC), regionally extensive disease, and high-grade or high-stage lesions. Benefits conferred by laparoscopic nephroureterectomy include decreased patient analgesic requirements, shorter hospitalization, and improved cosmetic results. Short-term follow-up has shown that laparoscopic nephroureterectomy appears to yield cancer control equivalent to that of the open procedure. Segmental ureterectomy coupled with ureteral reimplantation can be used for lower-grade superficial urothelial tumors located in the distal ureter. Renal-sparing surgery, including segmental ureterectomy and endoscopic therapy, is typically used in patients with small, lower-grade superficial lesions. Additionally, patients who would be at risk for dialysis after nephroureterectomy and those who are medically unfit for radical surgery are generally treated with minimally invasive and renal-sparing techniques.

Relevant Anatomy:Renal pelvis :The renal pelvis is the portion of the urinary collecting system formed by the confluence of 2 or 3 major calices.

Ureter :The ureter is a 20- to 30-cm tubular structure lying on the psoas muscle. It follows an S-shaped curve, passing medially to the sacroiliac joint and then coursing laterally near the ischial spine before passing medially to penetrate the base of the bladder. It passes through a submucosal tunnel to empty into the bladder.

Bladder cancer:Bladder cancer is a common urologic cancer. Almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder. In North America, South America, Europe, and Asia, the most common type of urothelial tumor diagnosed is transitional cell carcinoma (TCC); TCC constitutes more than 90% of bladder cancers in those regions. TCC can arise anywhere in the urinary tract, including the renal pelvis, ureter, bladder, and urethra, but it is usually found in the urinary bladder. Carcinoma in situ (CIS) is frequently found in association with high-grade or extensive TCC. Squamous cell carcinoma (SCC) is the second most common cell type associated with bladder cancer in developed countries. In the United States, around 5% of bladder cancers are SCCs.[1] Worldwide, however, SCC is the most common form of bladder cancer, accounting for 75% of cases in developing nations (see Epidemiology). In the United States, the development of SCC is associated with persistent inflammation from long-term indwelling Foley catheters and bladder stones, and, possibly, infections. In underdeveloped nations, SCC is often associated with bladder infection by Schistosoma haematobium (see Etiology). Approximately 2% of bladder cancers are adenocarcinomas. Nonurothelial primary bladder tumors are extremely rare and may include small cell carcinoma, carcinosarcoma, primary lymphoma, and sarcoma (see

Pathophysiology). Small cell carcinoma of the urinary bladder accounts for only 0.3-0.7% of all bladder tumors. The clinical course of bladder cancer carries a broad spectrum of aggressiveness and risk. Low-grade, superficial bladder cancers have minimal risk of progression to death; however, high-grade nonmuscleinvasive cancers frequently progress and muscle-invasive cancers are often lethal (see Prognosis). The classic presentation of bladder cancer is painless gross hematuria, which is seen in approximately 8090% of patients. Physical examination results are often unremarkable (see Clinical Presentation). Cystoscopy, cytology, and biopsy when necessary are the principal diagnostic tests (see Workup). Upon presentation, 55-60% of patients have low-grade noninvasive disease, which is usually treated conservatively with transurethral resection and periodic cystoscopy. The remainder have high-grade disease, of which 50% is muscle invasive and is typically treated with radical cystectomy (see Treatment and Management). Carcinoma in situ (CIS) is managed by instilling chemotherapeutic or immunotherapeutic agentsmost commonly bacillus Calmette-Gurin (BCG) vaccineinto the bladder via catheter. These intravesical treatments are not effective in the 20% of patients in whom cancer has invaded the bladder wall; those cases require cystectomy or a combination of radiation therapy and chemotherapy (see Treatment and Management). Bladder cancer has the highest recurrence rate of any malignancy. Although most patients with bladder cancer can be treated with organ-sparing therapy, most experience either recurrence or progression, creating a great need for accurate and diligent surveillance (see Treatment and Management). For more information on bladder cancer, see the following: Urine Tumor Markers in Bladder Cancer Diagnosis Cystoscopy Pathologic Findings in Squamous Cell Bladder Carcinoma Pathologic Findings in Small Cell Bladder Carcinoma Bacillus Calmette-Gurin in the Treatment of Bladder Cancer Treatment of Carcinoma In Situ Transurethral Resection of Bladder Tumors Surveillance for Recurrent Bladder Cancer

Anatomy: The bladder is an extraperitoneal muscular urine reservoir that lies behind the pubis symphysis in the pelvis. At the dome of the bladder lies the median umbilical ligament, a fibrous cord that is anchored to the umbilicus and that represents the obliterated urachus. This ligament contains vessels that must be ligated when divided. The ureters, which transport urine from kidney to bladder, approach the bladder obliquely and posterosuperiorly, entering at the trigone. The intravesical ureteral orifices are roughly 2-3 cm apart and form the superolateral borders of the trigone. The trigone consists of the area between the interureteric ridge and the bladder neck. The bladder neck serves as an internal sphincter, which is sacrificed during a radical cystectomy. In males, the seminal vesicles, vas deferens, ureters, and rectum border the inferoposterior aspect of the bladder. Anterior to the bladder is the space of Retzius, which is composed of fibroadipose tissue and the prevesical fascia. The dome and posterior surface of the bladder are covered by parietal peritoneum, which

reflects superiorly to the seminal vesicles and is continuous with the anterior rectal peritoneum. In females, the posterior peritoneal reflection is continuous with the uterus and vagina. The vascular supply to the bladder arrives primarily via the internal iliac (hypogastric) arteries, branching into the superior, middle, and inferior vesical arteries, which are often recognizable as lateral and posterior pedicles. The arterial supply also arrives via the obturator and inferior gluteal artery and, in females, via the uterine and vaginal arteries. Bladder venous drainage is a rich network that often parallels the named arterial vessels, most of which ultimately drain into the internal iliac vein. Initial lymphatic drainage from the bladder is primarily into the external iliac, obturator, internal iliac (hypogastric), and common iliac nodes. Following the drainage to these sentinel pelvic regions, spread may continue to the presacral, paracaval, interaortocaval, and para-aortic lymph node chains. Almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder. Squamous cell carcinoma of the bladder can involve multiple sites; however, the lateral wall and trigone are more commonly involved by this tumor. All small cell carcinomas of the urinary system identified so far have been located in the urinary bladder, most commonly in the dome and vesical lateral wall.
[2]

Pathophysiology:Bladder cancer is often described as a polyclonal field change defect with frequent recurrences due to a heightened potential for malignant transformation. However, bladder cancer has also been described as resulting from implantation of malignant cells that have migrated from a previously affected site. This occurs less often and may account for only a small percentage of cases. Use of the common term superficial bladder cancer should be discouraged. The term implies a harmless nature, which is misleading in many instances. Because it was used to describe the disparate disorders of low-grade papillary bladder cancer and the markedly more aggressive form, carcinoma in situ (CIS), the World Health Organization has recommended it be abandoned. In its place, the term nonmuscle-invasive bladder cancer should be used and qualified with the appropriate American Joint Committee on Cancer stage (ie, Ta, T1, Tis). Stage T1 cancer invades lamina propria but not the muscle of the bladder. The World Health Organization classifies bladder cancers as low grade (grade 1 and 2) or high grade (grade 3). Tumors are also classified by growth patterns: papillary (70%), sessile or mixed (20%), and nodular (10%).

Transitional cell carcinoma :Transitional cell carcinoma (TCC) arises from stem cells that are adjacent to the basement membrane of the epithelial surface. Depending on the genetic alterations that occur, these cells may follow different pathways in the expression of their phenotype. The most common molecular biologic pathway for TCCs involves the development of a papillary tumor that projects into the bladder lumen and, if untreated, eventually penetrates the basement membrane, invades the lamina propria, and then continues into the bladder muscle, where it can metastasize. Nearly 90% of transitional cell bladder tumors exhibit this type of behavior. This progression only occurs with high-grade cancers. Low-grade cancers rarely, if ever, progress and are thought to have a distinct molecular pathway, different from the high-grade cancers and CIS.

The remaining 10% of TCCs follow a different molecular pathway and are called CIS. This is a flat, noninvasive, high-grade urothelial carcinoma tumor that spreads along the surface of the bladder and, over time, may progress to an invasive form of cancer that behaves the same as invasive TCC. Many urothelial tumors are primarily composed of TCC but contain small areas of squamous differentiation, squamous cell carcinoma (SCC), or adenocarcinoma.

Squamous cell carcinoma :SCC of the urinary bladder is a malignant neoplasm derived from bladder urothelium with pure squamous phenotype.[3, 4, 5] SCC of the bladder is essentially similar to squamous cell tumors arising in other organs. Because many urothelial carcinomas contain a minor squamous cell component, a diagnosis of SCC of the bladder should be rendered only when the tumor is solely composed of squamous cell components, with no conventional urothelial carcinoma component. Reportedly, SCC has less of a tendency for nodal and vascular distant metastases than urothelial carcinoma.
[6, 7]

Rare forms of bladder cancer :Adenocarcinomas account for less than 2% of primary bladder tumors. These tumors are observed most commonly in exstrophic bladders and are often associated with malignant degeneration of a persistent urachal remnant. Other rare forms of bladder cancer include leiomyosarcoma, rhabdosarcoma, carcinosarcoma, lymphoma, and small cell carcinoma. Carcinosarcomas are highly malignant tumors that contain both mesenchymal and epithelial elements. Primary bladder lymphomas arise in the submucosa of the bladder. Leiomyosarcoma is the most common sarcoma of the bladder. Rhabdomyosarcomas most commonly occur in children. Except for lymphomas, all these rare bladder cancers carry a poor prognosis. Small cell carcinoma of the urinary bladder is a poorly differentiated malignant neoplasm that originates from urothelial stem cells and has variable expression of neuroendocrine markers. Morphologically, it shares the same features of small cell carcinoma of other organs, including small cell carcinoma of the lung.

Genetic pathophysiology :As with all cancers, bladder cancer is associated with oxidative DNA genetic changes in the host cells, leading to abnormal and potentially uncontrolled growth. The TP53 tumor suppressor gene and band 9p21, a locus known to be the site of a significant tumor suppressor gene, are two of the most common and significant missing or mutated gene/gene sites in many patients with bladder cancer. In addition, tumor suppressor genes P15 and P16 on chromosome 9, the RB tumor suppressor gene, the erb -b2 oncogene, and the p21-ras, c-myc, and c-jun genes may be mutated. Aneuploidy of chromosomes 3, 7, and 17 is also present in many patients with bladder cancer and may be readily detected using fluorescent in situ hybridization (FISH). See the image of chromosome 3 aneuploidy below.

Photograph in which fluorescence in situ hybridization centromere staining identifies aneuploidy of chromosome 3. Multiple instances of overexpression of the chromosome (note the multiple red dots, which identify centromeres of this chromosome) prove aneuploidy.

Etiology: Up to 80% of bladder cancer cases are associated with environmental exposure. Tobacco use is by far the most common cause of bladder cancer in the United States and is increasing in importance in some developing countries. Smoking duration and intensity are directly related to increased risk.[8, 9, 10] Compared with nonsmokers, smokers have a 2-6 times increased risk of developing bladder carcinoma. The risk appears to be similar between men and women.[11] Nitrosamine, 2-naphthylamine, and 4-aminobiphenyl are possible carcinogenic agents found in cigarette smoke. Occupational exposure to aromatic amines or aniline dyes is presumed to be the cause of bladder cancer in up to 25% of cases. Numerous occupations associated with diesel exhaust, petroleum products, and solvents (eg, auto work, truck driving, plumbing, leather and apparel work, rubber and metal work) have been associated with an increased risk of bladder cancer. Increased risk has also been reported in persons who work with organic chemicals and dyes, such as beauticians, dry cleaners, painters, paper production workers, rope and twine industry workers, dental workers, physicians, and barbers. People living in urban areas are more likely to develop bladder cancer. The etiology is thought to be multifactorial, potentially involving exposure to numerous carcinogens. Several medical risk factors are associated with bladder cancer. Patients who have undergone radiation treatment of the pelvis have an increased risk of bladder cancer. Chemotherapy with cyclophosphamide increases the risk of bladder cancer via exposure to acrolein, a urinary metabolite of cyclophosphamide.[12] Patients with spinal cord injuries who have long-term indwelling catheters have a 16- to 20-fold increased risk of developing SCC of the bladder. In many underdeveloped countries, particularly in the Middle East, Schistosoma haematobium infection causes most cases of squamous cell carcinoma. In one study from Egypt, 82% of patients with bladder carcinoma harbored S haematobium eggs in the bladder wall.[13] In egg-positive cases, the tumor developed in younger age groups, with predominantly squamous cell carcinoma, relative to egg-negative persons. A higher degree of adenocarcinoma has also been reported in schistosomal-associated bladder carcinomas.[13] Three pathogenic species responsible for the disease in humans are S haematobium, S mansoni, and S japonicum. The eggs reside in the pelvic and mesenteric venous plexus. In the bladder, a severe inflammatory response and fibrosis secondary to the deposition of Schistosoma eggs is common. The eggs are found embedded in the lamina propria and muscularis propria of the bladder wall. Many of the eggs are destroyed by host reaction and calcified, resulting in a lesion commonly known as sandy patch, which appears as a granular, yellow-tan surface lesion. It has been reported that S haematobium total antigen induces increased proliferation, migration, and invasion and decreases apoptosis of normal epithelial cells.[14]

Keratinous squamous metaplasia has been associated with the increased risk of developing squamous cell carcinoma, with approximately one half of the cases arising subsequent to the metaplasia.[15, 16] The majority of the cases will arise in the setting of chronic cystitis.[17] Chronic irritation secondary to lithiasis,[3, 4] urinary retention, and indwelling catheters has also been linked to the development of squamous cell carcinoma.[4] Having bladder diverticula may render an increased chance of developing squamous cell carcinoma in individuals.[18] Rarely, bacillus Calmette-Guerin (BCG) treatment for carcinoma in situ has been reported to lead to development of squamous cell carcinoma.[19] Development of bladder cancer at a younger age has been associated with bladder exstrophy.[20, 21, 22, 23] Squamous cell carcinoma has also been described in urachal remnants.[24, 25, 26, 27, 28] Coffee consumption does not increase the risk of developing bladder cancer. Early studies of rodents and a minority of human studies suggested a weak connection between artificial sweeteners (eg, saccharin, cyclamate) and bladder cancer; however, most recent studies show no significant correlation. Although no convincing evidence exists for a hereditary factor in the development of bladder cancer, familial clusters of bladder cancer have been reported. Several genetic mutations have been identified in bladder cancer. Mutations of the tumor suppressor gene p53, found on chromosome 17, are associated with highgrade bladder cancer and CIS. Mutations of the tumor suppressor genes p15 and p16, found on chromosome 9, are associated with low-grade and superficial tumors. Retinoblastoma (Rb) tumor suppressor gene mutations are also noted. Bladder cancer is associated with increased expression of the epidermal growth factor gene and the erb- b2 oncogene and mutations of the oncogenes p21-ras, c-myc, and c-jun.

Epidemiology:United States statistics :The American Cancer Society predicted that 70,530 new cases of bladder cancer would be diagnosed in the United States in 2010 and that 14,680 people would die of the disease.[29] Incidence of bladder cancer increases with age, with the median age at diagnosis being 68 years, and is about 4 times higher in men than in women. Over the past 2 decades, the rate of bladder cancer has been stable in men but has increased in women by 0.2% a year.[30] The male predominance in bladder cancer in the United States reflects the prevalence of transitional cell carcinoma (TCC). With SCCin contrast to TCC the male-to-female incidence ratio is 1:2. Bladder cancer is the fourth most common cancer in men in the United States, after prostate, lung, and colorectal cancer, whereas bladder cancer is not even among the top 10 cancers in women. Accordingly, more males than females are expected to die of bladder cancer in 2010, with 10,410 deaths in males versus 4,270 in females.[29] Nevertheless, women generally have a worse prognosis than men. The incidence of bladder cancer is twice as high in white men as in black men in the United States. However, blacks have a worse prognosis than whites.[30, 31] Limited data indicate that small cell carcinoma of the urinary bladder probably has the same epidemiological characteristics as urothelial carcinoma. Patients are more likely to be male and older than 50 years.[32, 33]

International statistics :Worldwide, bladder cancer is diagnosed in approximately 275,000 people each year, and about 108,000 die of this disease. In developed countries, 90% of bladder cancers are TCC. In developing countries particularly in the Middle East and Africathe majority of bladder cancers are SCCs, and most of these

cancers are secondary to Schistosoma haematobium infection. Recent studies report that urothelial carcinoma is the most common urologic cancer in China. In Africa, the highest incidence of SCC has been seen in schistosomal-endemic areas, notably Sudan and Egypt, where SCC ranges from two thirds to three quarters of all malignant tumors of the bladder. In recent years, a few studies from Egypt have shown a reversal of this trend due to the better control of schistosomiasis in the region, whereas in other parts of Africa the association is unchanged.[7, 34, 35] Increased smoking incidence is believed to have contributed to the shift toward TCC in Egypt, which has a stronger smoking association.

Prognosis:The recurrence rate for superficial transitional cell cancer (TCC) of the bladder is high. As many as 80% of patients have at least one recurrence. The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of CIS. To date, there is no convincing evidence of genetic factors affecting outcome.[36] Nonmuscle invasive bladder cancer has a good prognosis, with 5-year survival rates of 82-100%. The 5-year survival rate decreases with increasing stage, as follows: Ta, T1, CIS 82-100% T2 63-83% T3a 67-71% T3b 17-57% T4 0-22%

Prognosis for patients with metastatic urothelial cancer is poor, with only 5-10% of patients living 2 years after diagnosis. The risk of progression, defined as an increased tumor grade or stage, depends primarily on the tumor grade. The risk of progression increases with tumor grade, as follows: Grade I 2-4% Grade II 5-7% Grade III 33-64%

Prognosis in carcinoma in situ :CIS alone, or in association with Ta or T1 papillary tumor, carries a poorer prognosis and a recurrence rate of 63-92%. Diffuse CIS is an especially ominous finding, with 78% of cases progressing to muscle-invasive disease in one study.

Prognosis in squamous cell carcinoma :Tumor stage, lymph node involvement, and tumor grade have been shown to be of independent prognostic value in SCC.[37, 38] However, pathologic stage is the most important prognostic factor.[36] In one relatively larger series of 154 cases, the overall 5-year survival was 56% for pT1 and 68% for pT2 tumors. However, the 5year survival for pT3 and pT4 tumors was only 19%.

Several studies have demonstrated grading to be a significant morphologic parameter in SCC.[36] In one series, 5-year survival rates for grade 1, 2, and 3 squamous cell carcinoma was 62%, 52%, and 35%, respectively.[36] In the same study of patients undergoing cystectomy, the investigators suggested that a higher number of newly formed blood vessels predicts unfavorable disease outcome.[36] In SCC, the survival rate appears to be better with radical surgery than with radiation therapy and/or chemotherapy. In locally advanced tumors, however, neoadjuvant radiation improves the outcome.[39] Sex and age have not been prognostically significant in SCC.[36]

Prognosis in small cell carcinoma :Patients with small cell carcinoma of the bladder usually have disease in an advanced stage at diagnosis, and they have a poor prognosis.[40, 41, 42] The overall median survival is only 1.7 years. The 5-year survival rates for stage II, III, and IV diseases are 64%, 15%, and 11%, respectively.[43]

Recurrent bladder cancer :Bladder cancer has the highest recurrence rate of any malignancy (ie, 70% within 5 y). Although most patients with bladder cancer can be treated initially with organ-sparing therapy, most experience either recurrence or progression. The underlying genetic changes that result in a bladder tumor occur in the entire urothelium, making the whole lining of the urinary system susceptible to tumor recurrence. Risk factors for recurrence and progression include the following. Female sex Larger tumor size Multifocality Larger number of tumors High tumor grade Advanced stage Presence of CIS

The time interval to recurrence is also significant. Patients with tumor recurrences within 2 years, and especially with recurrences within 3-6 months, have an aggressive tumor and an increased risk of disease progression.

Penile CANCER:Penile tumors can originate anywhere on the penis, but most are found on the glans (48%) and prepuce (21%). The presentation can be a hyperemic area on the glans or near the urethral meatus. The cancers can range from an area of subtle induration to a small excrescence or papule. They can be exophytic or flat, or an ulcerated lesion may be present. A sensation of itching or burning under the foreskin or an ulceration of the glans are the most common presenting symptoms. Pain is rarely present. A circumcised male rarely develops penile cancer; however, men with chronic lymphocytic leukemia are predisposed to the development of squamous cell carcinomas that can occur anywhere on the body, including the penis.

Tumors may initially form on the corona of the glans and spread superficially across the glans and into the prepuce. Phimosis may conceal the cancer, allowing it to progress. Eventually, as the cancer grows, erosion through the prepuce, a foul odor, and a discharge are evident. Buck fascia acts as a natural barrier to the corpora, but over time, the cancer invades the corpora. As these cancers spread over the glans, they may involve the urethral meatus and grow into the urethra. The etiology of these cancers may be related to chronic exposure to carcinogens contained in smegma that collects within the prepuce although no specific carcinogens have been identified. Patients who are diagnosed with penile cancer have various treatment options. If the tumor is smaller than 2 cm (and particularly if it is confined to the prepuce), circumcision may be all that is necessary. Penile cancer tends to remain confined to the skin for long periods, often years, but when it invades the deeper tissues, the cancer has ready access to lymphatics and blood vessels and the growth rate is rapid.

Epidemiology:Frequency :Penile cancer is rare in Western countries. According to the American Cancer Society annual statistics for 2010, 1250 penile cancers were diagnosed in the United States, and 310 deaths were reported (24.8%). This high death rate underscores the seriousness of this cancer. For comparison, only 3% of men with prostate cancer die from this disease. Penile cancer accounts for 0.4-0.6% of all malignancies in the United States and Europe. In the rest of the world, the situation is different and represents an important health problem. Penile carcinoma represents 2030% of all cancers diagnosed in men who live in Asia, Africa, and South America. In urban India, the age-adjusted incidence of penile cancer ranges from 0.7-2.3 cases per 100,000 men. In rural India, the rate of penile cancer is 3 cases per 100,000 men, accounting for more than 6% of all malignancies in this population. In underdeveloped countries such as Uganda, the incidence is 2.8/100,000 and 1% of the men have developed this cancer by age 75. In Brazil, the age-adjusted incidence of penile cancer is 8.3 cases per 100,000 population. Barnholtz-Sloan et al studied the incidence trends of primary penile cancer in the United States using data from The National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) database of 1,817 men. They found that the overall incidence of primary malignant penile cancer has been decreasing over the past 3 decades. The overall incidence was 0.84 per 100,000 from 1973-1982, 0.69 from 1982-1992, and 0.58 from 1993-2002. Most of the cancers were squamous cell and originated on the glans. From 1993-2002, the incidence was highest among Hispanics (1.01 per 100,000), followed by Alaskan Native Americans (0.77 per 100,000) and African Americans (0.62 per 100,000).[1] Penile cancer is rare in circumcised men, particularly if they were circumcised as a neonate. Seyam et al studied penile carcinoma in 22 men who had been circumcised. Eighteen of these patients came from the southwest part of Saudi Arabia and had undergone late ritual circumcision. This practice, known as Tihamah circumcision, involves removing an extensive amount of skin, including some of the pubic skin. This procedure results in extensive cicatrization, which is probably the underlying cause of the resulting squamous cell cancer. Radiation therapy was attempted in a few of the patients, with unsuccessful results, whereas the group treated with surgery had a median survival of 34 months.[2] Penile cancer tends to be a disease of older men. The incidence of penile cancer increases abruptly in men aged 60 years or older and peaks in men aged 80 years. However, the tumor is not unusual in younger men. One study reported that 22% of patients with penile cancer were younger than 40 years, and 7% were younger than 30 years.

Etiology:The frequency of penile carcinoma varies according to hygienic practices and cultural and religious beliefs. Phimosis is present in at least 25-75% of men with this disease. Information on presence of phimosis often goes unrecorded in underdeveloped countries, and epidemiologic data are lacking. Circumcision has been well established as an effective prophylactic measure for penile cancer. Data from most large series have demonstrated that penile cancer is almost never observed in individuals who are circumcised in the neonatal period. The disease is found more frequently when circumcision is delayed until puberty. Adult circumcision offers little or no protection. No firm evidence indicates that smegma acts as a carcinogen, although this belief is widely held. The role of viral infection continues to be studied. Both penile cancer in men and cervical cancer in women have been associated with human papillomavirus (HPV) infection. In women whose sexual partners had penile cancer, the prevalence of cervical cancer is increased 3- to 8-fold. HPV-16 and HPV-18 have been found in one third of men with penile cancer. Whether these viruses are involved with causation of the cancer or are found as saprophytes has not been determined. No data have indicated that herpes viral infections cause penile cancer. Madsen et al studied a population that included 71 patients with invasive or in situ squamous cell carcinoma, 86 prostate cancer controls, and 103 men as population controls. PCR was used to examine for HPV in tissue samples of 37 patients with squamous cell carcinoma. The study found high-risk HPV in 65% of the 37 patients, of whom 22 of 24 (92%) were found to have HPV-16. Risk factors included early and high sexual activity, the lifetime number of sexual partners, the number of sexual partners prior to age 20 years, age at first occurrence of intercourse, penile-oral sex, a history of anogenital warts, and never having used condoms. A history of phimosis and priapism occurring more than 5 years prior to diagnosis were also significant risk factors.[3] Cigarette smoking and chewing tobacco are also considered to be a risk factors. Harish and Ravi reported that the risk for those smoking more than 10 cigarettes a day was 2.14. The combination of chewing tobacco and cigarette smoking raised the risk to 3.39.[4] Maden et al found that the risk of penile cancer in men who were smoking at the time of diagnosis was 2.8 times that of men who never smoked.[5] Penile trauma, usually consisting of small tears or abrasions involving the prepuce, and a history of chronic balanitis that occurred more than 2 years prior to diagnosis had an odds ratio of 23 for carcinoma in situ and 4.6 for invasive cancer. Hellberg et al reported that multiple episodes of balanitis had a relative risk of 9.49.[6] These observations support the theory correlating chronic inflammation to the development of cancer. Abnormalities considered to be nonmalignant include cutaneous horns, pseudoepitheliomatous keratotic and micaceous balanitis, balanitis xerotica obliterans, giant condyloma, and bowenoid papulosis. Penile intraepithelial neoplasia is considered to be premalignant, but only 5-15% of these lesions evolve into invasive squamous cell carcinoma. When carcinoma in situ (CIS) occurs on the glans, it is termed erythroplasia of Queyrat; however, when it occurs on the follicle-bearing skin of the shaft, it is termed Bowen disease. CIS can also develop in the tissue around the urethral meatus and spread down the urethra. These lesions have a red to red-brown appearance and generally have an irregular border. Suspicious lesions should prompt a biopsy to establish a diagnosis. The National Cancer Institutes SEER program was used to gather data on 1605 men diagnosed with squamous cell carcinoma of the penis. CIS was diagnosed in 37% of this population, localized disease was diagnosed in 39%, regional disease was present in 13%, distant disease was present in 2.3%, and unstaged disease remained in 7.9%.

According to SEER data, the proportion of men presenting annually with CIS has tended to increase, although the number of men with localized disease has decreased. Older age at diagnosis was associated with a higher stage of disease. The mean time until death from cancer was 66.6 months in those with CIS, 50.1 months in those with localized disease, 32.4 months in those with regional disease, and 7.4 months in those with distant metastases. Overall, 22.4% of the patients in this database died of this cancer.

Pathophysiology:Penile cancers usually begin as small lesions on the glans or prepuce. They range from white-grey, irregular exophytic to reddish flat and ulcerated endophytic masses. They gradually grow laterally along the surface and can cover the entire glans and prepuce before invading the corpora and shaft of the penis. The more extensive the lesion, the greater the possibility of local invasion and nodal metastasis. Penile cancers may be papillary and exophytic or flat and ulcerative. Untreated, penile autoamputation can occur. The growth rates of the papillary and ulcerative lesions are similar, but the flat ulcerative lesions tend to metastasize to the lymph nodes earlier and are therefore associated with a lower 5-year survival rate. Cancers larger than 5 cm and those involving more than 75% of the shaft are associated with a high prevalence of nodal metastases and a lower survival rate, but a consistent relationship among the size of the cancer, the presence of inguinal node metastases, and survival has not been identified. The Buck fascia, which surrounds the corpora, acts as a temporary barrier. Eventually, the cancer penetrates the Buck fascia and the tunica albuginea, where the cancer has access to the vasculature and from which systemic spread is possible. Metastasis to the femoral and inguinal lymph nodes is the earliest path for tumor dissemination. The lymphatics of the prepuce join with those from the shaft. These drain into the superficial inguinal nodes. Because of lymphatic crossover, cancer cells have access to lymph nodes in both inguinal areas. The lymphatics of the glans follow a different path and join those draining the corpora. A circular band of lymphatics that drains to the superficial nodes is located at the base of the penis and can extend to both the superficial and deep pelvic lymph nodes. The superficial inguinal nodes drain to the deep inguinal nodes, which are beneath the fascia lata. From here, drainage is to the pelvic nodes. Multiple cross connections exist at all levels, permitting bilateral penile lymphatic drainage. Untreated metastatic enlargement of the regional nodes leads to skin necrosis, chronic infection, and, eventually, death from sepsis or hemorrhage secondary to erosion into the femoral vessels. Clinically apparent distant metastases to the lung, liver, bone, or brain are unusual until late in the disease course, often after the primary disease has been treated. Distant metastases are usually associated with regional node involvement. Microscopically, the tumors vary from well-differentiated keratinizing tumors to solid anaplastic carcinomas with scant keratinization. Most tumors are highly keratinized and are of moderate differentiation. Poorly differentiated carcinomas have variable amounts of spindle cell, giant cell, solid, acantholytic, clear cell, small cell, warty, basaloid, or glandular components. Penile carcinoma follows a relentless and progressive course that proves to be fatal in most untreated patients within 2 years. The typical SCC has a recurrence rate of 28% and lymph node metastases are found in 28-39% depending upon the extent and grade of the tumor. The mortality rate is 20-38% with a 10-year survival rate of 78%. Spontaneous remission has not been reported.

Presentation:Typical presentations of penile cancer include a lesion that has failed to heal, a subtle induration in the skin, a small excrescence, a papule, a pustule, a warty growth, a large exophytic growth, or a reddened area on the glans. The malignancy may appear as a shallow erosion or a deep ulceration with rolled edges. Because most of patients with penile cancer are uncircumcised, they may have a phimosis that obscures the tumor and allows it to grow undetected. Many men do not seek medical attention until the cancer has eroded through the prepuce and has become malodorous because of infection and necrosis. In rare cases, an inguinal mass ulcerates, suppurates, or hemorrhages. Few symptoms are associated with the development of penile cancer. Even after significant local tissue destruction, pain is uncommon. Patients with advanced metastatic cancer may report weakness, weight loss, and fatigue; the penile lesion may bleed. The presence of a nonhealing penile lesion usually prompts the patient to visit a physician. While carcinoma may manifest as a hyperemic patch on the glans that is characteristic of erythroplasia of Queyrat or as an ulcerated growth on the inner surface of the prepuce, the differential diagnoses include benign and premalignant lesions. Penile lesions can be categorized as benign, premalignant, or malignant neoplasms. Benign lesions include pearly penile papules, hirsute papillomas, and coronal papillae. These lesions do not require treatment and are usually found on the glans in uncircumcised males. Rashes, ulcerations from irritation, and allergic reactions or infections must be considered. Some histologically benign lesions are potentially malignant (premalignant) or have been associated with the presence of squamous cell carcinoma. The most common is balanitis xerotica obliterans. This is a variation of lichen sclerosus et atrophicus and manifests as a white patch on the prepuce or glans, where it usually involves the urethral meatus. This can produce severe cicatrization, leading to obstruction of the urethra. Leukoplakia manifests as solitary plaque or multiple whitish plaques, which often involve the meatus. Leukoplakia has been associated with squamous cell carcinoma. Viral lesions include condyloma acuminata, which are soft papillomatous growths. They are known as venereal warts and have a predilection for the genital and perineal regions. These lesions are usually sexually transmitted and are caused by HPV. Viral types 6, 11, 42, and 44 are associated with low-grade dysplasia. Types 16, 18, 31, 33, 35, and 39 are associated with neoplastic changes. De Paula et al studied the presence of koilocytosis, which is a feature of productive HPV infection and is characterized by large halos around cell nuclei. Koilocytosis is found in approximately 30%-60% of patients with penile cancer. They found that the presence of koilocytosis correlated with Jackson stage and grade but not with nodal disease or survival.[7] Lichen sclerosis, also known as balanitis xerotica obliterans, is a chronic lymphocyte-mediated skin disease that can develop on any cutaneous surface and has been associated with squamous cell carcinoma of the penis. Biopsy of the lesion should be obtained prior to initiating therapy. A direct causative link between these entities has not been established, but the presence of a chronic inflammatory lesion is thought to promote the development of many types of cancers. A study by Mannweiler et al revealed HPV-negative carcinomas were correlated with advanced lichen sclerosus and lichen planus, differentiated penile intraepithelial neoplasia, and accumulation of T lymphocytes with monoclonal rearrangement of the T-cell receptor locus.{{Ref143} Kaposi sarcoma manifests as a cutaneous neovascular lesion that is raised, usually painful, and often ulcerated with a bluish discoloration. Patients with AIDS are predisposed to develop this condition.

Giant condyloma acuminata or a Buschke-Lwenstein tumor differs from the standard condyloma in that it displaces, invades, and destroys adjacent structures by compression, whereas the standard condyloma remains superficial and never invades. Despite their large size and invasive potential, Buschke-Lwenstein tumors show no signs of malignant change upon histologic examination. Malignant carcinomas include variants of squamous cell carcinoma such as CIS, erythroplasia of Queyrat, or Bowen disease. The diagnosis depends on their appearance and the site of origin. Erythroplasia involves the glans, prepuce, or penile shaft, while similar lesions on the remainder of the genitalia and perineum are termed Bowen disease. Regardless of the terminology and clinical presentation, these are carcinomas with the same malignant potential; biopsies should be performed, and the carcinoma should be staged and treated. Herpes viral infections have not been associated with the development of penile cancers.

Indications:Indications for therapy and therapeutic options depend on the histologic diagnosis of cancer established based on biopsy findings, the location and size of the tumor, and the presence or absence of palpable inguinal lymphadenopathy. All patients with penile cancer require therapy because spontaneous regression does not occur and, untreated, the cancer ultimately causes death. Rippentrop et al studied the surgical therapy status among the 1605 men identified in the SEER database. Surgical therapy was recorded in 1422 patients, of whom 721 (50.7%) underwent some form of surgery. Excisional biopsy was performed in 19.7%, and topical therapy with laser or cryoablation was used in 0.3%. Of those undergoing surgery, 13.1% underwent partial penectomy without lymphadenectomy, 2.1% underwent a combined procedure, and only 0.5% required radical penectomy.[8]

Relevant Anatomy:The anatomy of the penis has important implications for the diagnosis and treatment of penile cancer. Embryologically, the 3 erectile bodies of the penis arise from the paired genital tubercles, which give rise to the corpora cavernosa, the caudal portion of the urogenital sinus that creates the corpora spongiosum, and the paired urethral folds, which join in the midline. For purposes of description, the penis may be divided into the root, which is located within the superficial perineal pouch and is the primary fixation point; the body, which contains the 3 corpora and the overlying tissues; and the glans, which sits as a cap on the corpora cavernosa but is a part of the corpora spongiosa. The superficial fascia is continuous with dartos fascia posteriorly and with the Scarpa and Camper fascia anteriorly. The superficial fascia consists of a single layer with loose connections to the overlying skin. The corpora are covered by a layer of dense fibrous tissue called the tunica albuginea. The corpora cavernosa are incompletely separated by the septum penis, a thin layer of fibrous tissue continuous with the tunica albuginea. The fascia overlying the corpora cavernosa blends with the fascia of the urogenital diaphragm. The erectile tissue within the corpora is composed of a spongelike network of endothelium-lined sinusoidal spaces.

Anatomy:The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. (See the image below.)

Management of localized prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract. The inferior vesical artery, which is derived from the internal iliac artery, supplies blood to the base of the bladder and prostate. The capsular branches of the inferior vesical artery help identify the pelvic plexus arising from the S2-4 and T10-12 nerve roots. The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function.

Pathophysiology:Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most (95%) prostate cancers are adenocarcinomas. Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. Few cases have neuroendocrine morphology. When present, they are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation. Squamous cell carcinomas constitute less than 1% of all prostate carcinomas. In many cases, prostate carcinomas with squamous differentiation arise after radiation or hormonal treatment. Of prostate cancer cases, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Local spread and metastasis :When these cancers are locally invasive, the transitional-zone tumors spread to the bladder neck, while the peripheral-zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces occurs relatively late. The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, occasionally without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread: the mechanical theory and the seed-and-soil theory. The mechanical theory attributes metastasis to direct spread through the lymphatics and venous spaces into the lower lumbar spine. Advocates of the seed-and-soil theory believe that tissue factors that allow for

preferential growth in certain tissues, such as bone, must be present. Lung, liver, and adrenal metastases have also been documented. Specific tissue growth factors and extracellular matrices are possible examples. The doubling time in early-stage disease is as slow as 2-4 years, but this tends to accelerate as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time. Natural history by stage is as follows: T1a - Progression over 10 years (uncommon) T1b - Tumor-related death rate of 10% in 10 years T2 - Ten-year metastasis-free survival rate of 81% with grade 1, 58% with grade 2, and 26% with grade 3 T3 - Lymph node metastasis at presentation in 50% and approximately 25% rate of 10-year diseasefree survival

The natural history of clinically localized disease varies, with lower-grade tumors having a more indolent course, while some high-grade lesions progress to metastatic disease with relative rapidity. Given the typically slow progression of localized disease, several studies have examined the strategy of active surveillance in these cases.

Etiology:Marked variation in rates of prostate cancer among populations in different parts of the world suggests the involvement of genetic factors. For example, the risk of prostate cancer is particularly high in people of subSaharan African ancestry, while the risk tends to be low in many Asian populations. Increased risk in Asians who have migrated to the United States suggest the importance of environmental factors, notably diet.[1] Familial predisposition also occurs.

Genetics :Studies in different populations have identified several variants in the 8q24 region on chromosome 8 that are associated with increased risk of prostate cancer.[2] Gene alterations on chromosome 1, chromosome 17, and the X chromosome have been found in some patients with a family history of prostate cancer. The hereditary prostate cancer 1 (HPC1) gene and the predisposing for cancer of the prostate (PCAP) gene are on chromosome 1, while the human prostate cancer gene is on the X chromosome. Genetic studies suggest that a strong familial predisposition may be responsible for as many as 5-10% of prostate cancer cases. Men with a family history of prostate cancer have a higher risk of developing prostate cancer and are also likely to present 6-7 years earlier. Several reports have suggested a shared familial risk (inherited or environmental) for prostate and breast cancer. BRCA-2 mutations increase the risk for prostate cancer that is more aggressive and develops at a younger age.[1]

Diet :Diet plays a role in the development of prostate cancer. Epidemiological studies have identified a variety of dietary factors, particularly fat intake and obesity. See Prostate Cancer and Nutrition for a complete discussion of this topic.

Hormones :Hormonal causes have also been postulated. Androgen ablation causes a regression of prostate cancer. In addition, as indirect evidence of hormonal causes, eunuchs do not develop adenocarcinoma of the prostate. Hsing and Comstock performed a large study comparing patients with prostate cancer with controls and found no significant difference in levels of testosterone, dihydrotestosterone, prolactin, follicle-stimulating hormone, or estrone. However, elevated levels of luteinizing hormone and of testosterone:dihydrotestosterone ratios were associated with mildly increased risk.[3]

5-Alpha reductase :The Prostate Cancer Prevention Trial studied the prevalence of prostate cancer between a control group and a group given a 5-alpha-reductase inhibitor (finasteride).[4] While the 5-alpha reductase inhibitor appeared to decrease the prevalence of tumors, those that did arise appeared histologically more aggressive. Only longterm follow-up of these patients will determine whether this more aggressive histology accurately reflects the underlying biology of these tumors or whether it is an artifact of the treatment. A similar study was performed with dutasteride, a molecule that blocks not only D1 but also D2 receptors in the prostate. These authors also found a 22.8% relative risk reduction in the development of prostate cancer and did not fully refute the concern about more aggressive cancers. Possibly for this reason, when the concept of 5-alpha reductase for chemoprevention of prostate cancer was brought before the US Food and Drug Administration (FDA) in 2010, they did not approve the drugs for this indication.[5, 6] On June 9, 2011 the US Food and Drug Administration announced revisions to the prescribing information for 5-alpha reductase inhibitors (5-ARIs) to include a warning regarding an increased incidence of high-grade prostate cancer in men taking dutasteride or finasteride compared with placebo.

Epidemiology:Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates in North America, Australia, and northern and central Europe and the lowest rates in southeastern and south central Asia and northern Africa.[1] In the United States, prostate cancer is the most common noncutaneous cancer among males. An estimated 1 in 6 whites and 1 in 5 African Americans will develop prostate cancer in their lifetime, with the likelihood increasing with age. The American Cancer Society estimated that 217,730 new cases of prostate cancer would be diagnosed in 2010.[1] Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years. Between 1989 and 1992, incidence rates of prostate cancer increased dramatically in the US, probably because of earlier diagnoses in asymptomatic men as a result of the increased use of serum PSA testing. In fact, the incidence of organ-confined disease at diagnosis has increased because both PSA testing and standard digital rectal examination are performed. Prostate cancer is also found during autopsies performed in men with other causes of death. The rate of this latent or autopsy cancer is much greater than that of clinical cancer. In fact, it may be as high as 80% by age 80 years. Interestingly, the prevalence of the latent or autopsy form of the disease is similar worldwide. Together with migration studies, this suggests that environmental factors, such as diet, may play a significant promoting role in the development of a clinical cancer secondary to a latent precursor.

In a multivariate analysis, the risks for biochemical recurrence and disease-specific mortality were much higher for men who were smokers at the time of diagnosis versus those who had never smoked. Being exposed to a greater number of pack-years was associated with significantly increased risk for prostate cancer mortality but not for biochemical recurrence. Men who had quit smoking 10 years prior to diagnosis or who had quit more recently but smoked for < 20 pack-yearshad prostate cancermortality risks much like those of men who had never smoked.[7] In a retrospective study at Johns Hopkins Medical Center in Baltimore, a greater connection between cigarette smoking and risk of prostate cancer recurrence was identified in men who had been treated with radical prostatectomy.[8] Because of its genetic linkage, prostate cancer is more common in males with a strong family history of prostate cancer. Likewise, people who smoke, African American males, and patients who consume a diet high in animal fat or high in chromium are at an increased risk.

Prostate cancer mortality :Prostate cancer is the second most common cause of cancer death in males, after lung cancer. The American Cancer Society estimated that 32,050 men would die from the disease in 2010.[1] Death rates from prostate cancer rose steadily from 1975 to 1991, remained level from 1991 to 1994, and has decreased since then. This decrease has been attributed to early diagnosis with routine screening and successful intervention; on the other hand, it has also been dismissed as an artifact of lead-time bias. Continued patient follow-up from completed clinical trials (eg, the Prostate Intervention Versus Observation Trial [PIVOT]) should clarify this point of contention. Regardless, it is important to understand that more men die with prostate cancer than of prostate cancer. Postmortem study findings suggest that up to 80% of men older than 80 years have occult prostate cancer.

Racial demographics :Prevalence rates of prostate cancer remain significantly higher in African-American men than in white men, while the prevalence in Hispanic men is similar to that of white men. The prevalence in men of Asian origin is lower than in whites. Although mortality rates are continuing to decline among white and African-American men, mortality rates in African-American men remain twice as high as in white men, based on 2008 American Cancer Society projections. Hispanic men and African American men present with more advanced disease.[9] Studies have found that young African American men have testosterone levels that are 15% higher than in young white men. Furthermore, evidence indicates that 5-alpha reductase may be more active in African Americans than in whites, implying that hormonal differences may play a role. However, the independent contribution of race is difficult to isolate from effects of health care access, income, education, and insurance status.

Prognosis:The most important and established indicators of prognosis for prostate carcinoma include the Gleason grade, the extent of tumor volume, and the presence of capsular penetration or margin positivity at the time of prostatectomy. High-grade prostate cancer, particularly the percent presence of Gleason grades 4 and 5, is associated with adverse pathologic findings and disease progression. Conversely, low-grade prostate tumors can also be biologically aggressive.

Prognosis by treatment modality :The ranges of the disease-free 10-year survival rates for early localized disease listed below are wide because the outcomes of these treatments vary as a function of tumor aggressiveness (ie, as indicated by Gleason score and PSA level). In addition, series from various institutions show significant differences. Radical prostatectomy (80-95%) Brachytherapy and external radiation (80-95%) Watchful waiting (50-73%)

In a study of men with early prostate cancer (stage T1b, T1c, or T2), Holmberg et al found that over a median of about 6 years followup, death from prostate cancer was lower in patients treated with surgery compared with watchful waiting (4.6% vs 8.9%).[10] In patients with advanced localized disease, the disease-specific 10year survival rate for advanced localized disease in patients treated with brachytherapy and external radiation is 40-62%. Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, from 20% in the 1970s to 3.4% in the 1990s, the risk of extraprostatic disease in patients with clinically localized disease remains high, at 30-60%. Depending on the PSA value, pathologic stage, and histologic grade of the tumor, approximately 30% of patients with clinically localized prostate cancer are estimated to progress despite initial treatment with intent to cure. Cooperberg et al built and validated a model for risk prediction specifically intended for use in patients receiving primary androgen deprivation therapy for prostate cancer, the Japan Cancer of the Prostate Risk Assessment (J-CAPRA). J-CAPRA is scored from 0-12 based on Gleason score, PSA level, and clinical stage. J-CAPRA predicted progression-free survival with a c-index of 0.71 among 13,740 men in a United States registry and predicted cancer-specific survival with a c-index of 0.84 among 19,265 men in a Japanese registry.[11]

Molecular prognostic markers :Several molecular markers have been shown to aid in determining the prognosis of patients undergoing treatment for localized and metastatic prostate cancers. Assessments of the molecular alterations or gene products of TP53, RB, BCL2, cathepsin-D, CDH1, and PTEN, among many others, have been reported. Prospective trials are needed to assess these markers more thoroughly before their implementation in clinical management is recommended. Decreased nuclear expression of the cell cycle inhibitor p27 has been associated with poor outcome in prostate cancer according to previous studies. Ananthanarayanan et al developed and studied an automated method for subcellular scoring of p27 that does not require the segmenting of individual cells. This method of laser-based fluorescence microscopy showed a strong relationship, aside from tumor grade, stage, and prostate-specific antigen, between decreased p27 expression and increased risk of prostate cancer recurrence, regardless of subcellular location. This relationship was not seen via manual scoring.[12]

Prognostic nomograms :The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis. In addition, a series of nomograms has been issued from the Memorial Sloan-Kettering Cancer Center; these nomograms are used to predict disease progression and survival after a variety of treatments.

Patient Education:With the advent of PSA screening, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated. This will allow patients to make informed decisions about screening and, in those diagnosed with prostate cancer, to select the most appropriate treatment.

Cystic Diseases of the Kidney :Cysts develop from renal tubule segments and most detach from the parent tubule after they grow to a few millimeters in size. Cyst development is generally attributed to increased proliferation of tubular epithelium, abnormalities in tubular cilia, and excessive fluid secretion.

Developmental cystic renal disease:MCDK represents abnormal development or formation of the kidney and may involve part, or all of, one or both kidneys. This condition is thought to be secondary to dysfunctional genetics, abnormal differentiation of the metanephros or in utero ureteral obstruction. Patients are observed unless complications arise directly from the kidney or its associated conditions.

Inherited cystic renal disease :ADPKD is due to mutations in the genes PKD1 and PKD2, which encode polycystin proteins. The genetic mechanism of cyst development requires a "second hit," a somatic mutation of the normal PKD allele, which accounts for the onset of ADPKD, usually in those aged 30-50 years. Symptoms primarily include pain, hypertension and renal failure. The goal of treatment is to control blood pressure and to slow the onset of renal failure. ADPKD is associated with involvement of other organs, particularly intracranial aneurysms. ARPKD is due to mutations in PKHD1, a large gene that encodes fibrocystin/polyductin, which plays critical roles in collecting-tubule and biliary development. This disease carries a high neonatal mortality rate, and many individuals who survive eventually require renal transplantation. Symptoms include hypertension and liver disease. Diagnosis is often made in utero. Treatment is supportive in severe cases but otherwise is similar to that for ADPKD. GCKD is often confused with ADPKD, as it is common in individuals with a family history of ADPKD. This disease is distinguished histologically and symptoms and treatment are similar to those in ADPKD. JNPHP and medullary cystic disease are two diseases that some consider a disease complex.[1] They share similar pathologic features but are due to different genetic mutations and have different inheritance patterns. JNPHP is inherited in an autosomal recessive manner and presents in childhood, while MCKD is inherited autosomal dominantly and affects adults. Both diseases present with symptoms of salt wasting and polyuria.

Systemic disease with associated renal cysts :TS is caused by mutations in the suppressor genes TSC1 and TSC2, which encode hamartin and tuberin, respectively. Renal cysts and angiomyolipomas are part of a syndrome that includes seizures and dermatologic findings. VHLS is due to mutations in the VHL gene, which increases the risk for malignancy, including RCC. Affected individuals develop cysts in multiple organs, including the kidney, pancreas, liver, and epididymis.

Acquired cystic renal disease :The exact cause of this disease is not known. It occurs exclusively in patients on dialysis. The severity of disease is directly related to the duration of therapy. Typically, acquired cystic renal disease is asymptomatic but it is known to subsequently increase the risk of RCC.

Epidemiology:Frequency :United States: MCDK has an incidence of 1 per 1000-4000 live births.[2] ADPKD has an incidence of 1 per 400-1000 persons among whites and accounts for 8-10% of all cases of end-stage renal disease (ESRD). ARPKD has an incidence of 1 per 6000-55,000 live births, with a heterozygous carrier frequency of 1 per 70. JNPHP affects 1 per 5000 persons.[3] JNPHP and MCKD account for 10-20% of children with chronic renal failure and for 1-5% of all patients undergoing dialysis or transplantation. TS has an incidence of 1 per 10,000-50,000 persons, and 20-25% of these patients have renal cysts.
[4]

VHLS has an incidence of approximately 1 per 39,000 persons, and two thirds of these individuals develop renal cysts. In acquired cystic renal disease, cysts are present in 8-13% of patients with chronic renal failure prior to dialysis. Following initiation of therapy, 10-20% of patients have acquired cystic renal disease after 3 years of dialysis, 40-60% after 5 years, and more than 90% after 10 years.[5] MSK has an estimated incidence of 1 per 5000 persons and is found in approximately 20% of patients with nephrolithiasis. Simple cysts are the most common cystic renal lesions. They are present in 5% of the general population, increasing in frequency to 25-33% of patients older than 50 years, and account for 6570% of renal masses. Cystic RCC accounts for less than 1% of RCC cases.

Mortality/Morbidity : Cystic renal disease accounts for approximately 10% of all ESRD cases. ADPKD is 1 of the top 4 causes of ESRD and is the etiology of renal failure in 5-10% of patients undergoing dialysis. ARPKD accounts for 5% of ESRD in children. Neonatal mortality secondary to ARPKD approaches 25-35% and is usually related to respiratory compromise.[6] More than 50% of patients with ARPKD require kidney transplant before age 20 years.[7] JNPHP is the most common cause of genetic ESRD in children.[8] TSC is associated with a high frequency of angiomyolipoma. Patients with acquired cystic disease are more likely to develop RCC (5-25%). Additionally, tumors are commonly bilateral, and 15% are metastatic.[5]

Race : ADPKD is found throughout the world in all racial and ethnic groups.

Acquired cystic renal disease is most common in white men and African Americans.

Sex : Multicystic dysplastic kidney is more common in males than in females. Symptomatic progression of ADPKD appears to be more rapid in men. VHLS affects men and women with equal frequency. Acquired cystic renal disease is more common in men. MSK has a male-to-female ratio of 2:1.

Age : ADPKD has a bimodal distribution of onset, with some cases presenting in infancy or childhood.[3] ARPKD presents in infancy, childhood, or adolescence. VHLS typically presents in the third or fourth decade of life with visual or central nervous system symptoms. MSK typically presents between the third and fifth decades of life. Simple cysts are very rare in children but increase in frequency with age.

Prune Belly Syndrome :-

Children with prune belly syndrome can present with myriad renal, ureteral, and urethral abnormalities. Obstruction and/or upper urinary tract dilatation is not unusual in these children. The site of obstruction can vary from as high as the pelviureteral junction to as low as the prostatic membranous urethra. A lack of abdominal muscles leads to a poor cough mechanism, which, in turn, leads to increased pulmonary secretions. Weak abdominal muscles lead to constipation because of an inability to perform the Valsalva maneuver, which helps push the stool out of the rectum during defecation. The mortality rate associated with prune belly syndrome is 20%.

Epidemiology:Frequency :Prune belly syndrome affects 1 per 30,000-40,000 live births. Approximately 3-4% of all prune belly syndrome cases occur in females. Twinning is associated with prune belly syndrome; 4% of all cases are products of twin pregnancies.

Etiology:Prune belly syndrome is associated with trisomy 18 and 21. Patients with prune belly syndrome also have an increased incidence of tetralogy of Fallot (TF) and ventriculoseptal defects.

Pathophysiology:In 1903, Strumme proposed that prune belly syndrome may be caused by in utero bladder obstruction, stating that dilatation of the urinary tract in utero leads to secondary-pressure atrophy of the abdominal wall and the subsequent clinical findings. More recent theories focus on a functional obstruction due to prostatic hypoplasia that leads to a conformational change in the prostatic urethra during voiding, thereby causing obstruction. The most recent theories suggest a transient obstruction at the junction of the glanular and penile urethra. This would explain the high incidence of megalourethra observed in cases of prune belly syndrome. Considering the recent knowledge regarding high-pressure voiding and reflux, the theories involving urethral abnormalities can also explain the upper tract deformities that this syndrome can cause. High-pressure voiding has been discovered to lead to reflux in patients without prune belly syndrome. The obstructive process that occurs may impart a similar effect that mimics the dyssynergic voiding in persons with reflux. This high-pressure voiding thereby leads to changes in the location of the ureter, as well as the deleterious effects of the water-hammer effect on the renal tissue. Therefore, this abnormal high-pressure voiding process could explain reflux that is encountered along with renal dysplasia. The overdistended bladder could result in the abnormal development of the abdominal wall musculature and prevent the descent of the testis. The histopathology of the abdominal wall muscles demonstrates a pattern of developmental arrest rather than one of atrophy. This is also suggested by a lack of any aponeurotic layers. Fetal ascites, which may be transient because the urine is reabsorbed before birth, may explain the abdominal wall defects. The prevailing theory is mesodermal arrest, which would explain the involvement of the genitourinary tract, the testis, and the abdominal wall. A noxious insult would have to occur between the 6th and 10th weeks of gestation. Some place the insult at 3 weeks of embryogenesis, which may explain the prostatic hypoplasia and poor glandular development. The mesodermal arrest theory is supported by the histologic findings in the abdominal wall, the urinary tract, and the male genital system. The abundance of fibrous tissue, collagen, and connective tissue with sparsely placed smooth muscle throughout the urinary tract indicates more of a mesodermal differentiation problem than one of obstruction. The yolk-sac theory is based on the overdevelopment of the allantoic diverticulum that grows out from the yolk sac contiguous with the body stalk. If it becomes enlarged, it is incorporated into the urinary tract as a redundant enlarged urachus, bladder, and prostatic urethra. Unfortunately, this theory does not explain the abnormalities in the development of the upper urinary tract or male genital tract.

Presentation:Pseudoprune belly syndrome :Pseudoprune belly syndrome, which is associated with prune belly syndrome uropathy, is characterized by normal abdominal wall examination findings and incomplete or absent cryptorchidism. In a study of 8 patients with this syndrome, 5 (63%) eventually developed renal failure.[1]

Prune bellylike variant :An abdominal wall defect commonly confused with prune belly syndrome has been termed prune bellylike variant. Some studies have reported abdominal wall defects without urologic anomalies. This defect involves

only the abdominal wall muscles, in particular the internal and external obliques, as well as the transversalis muscles. In contrast with prune belly syndrome, the rectus muscles are not involved. This defect causes weakness laterally, with bulging of the abdominal wall just below the rib cage. In such cases, CT scans of the abdominal wall reveal preservation of the rectus and obliques away from the area. The authors have surgically reconstructed two such defects in young male patients using a laparoscopic modification of the Firlit procedure, with excellent results. This syndrome may be associated with in utero distention of the abdominal cavity. The patient pictured below had evidence of in utero megalocystis that resolved spontaneously.

The lateral subcostal weakness in this patient is due to absence of the internal and

external obliques subcostally.

Bilateral subcostal incisions exposed the

fascial defects.

Note that the previously attenuated fascial defect has been covered

by reapproximated muscle. Laparoscopic view of the fascial defect transilluminated from outside the abdomen. Note that the defect is just a thin layer of attenuated fascia.

Indications:Urethral obstruction should be addressed as soon as it is recognized. Progressive urethral dilation, as described by Passerini-Glazel et al, is the preferred method of treatment. Vesicostomy can also be an effective method of temporary diversion. The literature contains little controversy regarding management of undescended testes in these children. If controversy or confusion arises, it concerns the optimal timing for the orchidopexy and which type of orchidopexy should be performed. The management of the abdominal wall abnormalities is somewhat controversial. Some prefer no surgical reconstruction of the abdominal wall, while others advocate surgical reconstruction. The group that advocates surgical reconstruction is divided into 2 separate factions that support different techniques of abdominal wall reconstruction. The use of a rectus muscle transfer flap to the abdominal wall combined with an abdominal wall plication procedure can help ameliorate some of the back strain in many of these patients. Reconstruction of the urinary tract also is controversial; some advocate prompt reconstruction, while others advocate a more passive approach and operate when necessary. Prune belly syndrome is characterized by elongated, dilated, and tortuous megaureters, which affect 81% of patients. Vesicoureteral reflux is common in these patients. Advocates of conservative treatment argue that, in a nonobstructive system with present suppressive therapy, intervention is not necessary. Those who argue for aggressive therapy in patients with prune belly syndrome point to Waldbaum and Marshall's review of 56 patients, in which 70% died and 16% were gravely ill.[2] Waldbaum and Marshall also argue for aggressive therapy when they point out that, "the purpose of the upper tract is to transport urine, not to store it." Even with aggressive antibiotic therapy, urinary stasis and repeat infections may lead to inevitable loss of renal function. Regardless, ureteral reimplantation in patients with prune belly syndrome can be difficult and is frequently fraught with complications. To attest to this, the author has seen several patients who have previously undergone reimplantation but then developed ureteral strictures of the distal reimplanted ureters and required another reimplantation. Furthermore, reports in the literature have documented ureteral stenosis rates of up to 40% in tapered ureters.

Relevant Anatomy:Infravesical obstruction or obstruction at the prostatic urethra was originally thought to be due to a type I posterior urethral valve. This theory has been replaced by a new notion that the obstruction may be caused by severe angulation at the prostatic and membranous urethral junction. This may be due to a lack of striated

muscle in the membranous urethra or urogenital diaphragm or a ring of obstructive tissue acting as a flap valve due to hypoplasia of the prostate, creating a ballooning of the prostatic urethra. In these patients, studies have also shown that the smooth muscle in the prostate is reduced and the connective tissue content is increased, which may lead to a functional obstruction. This abnormality in the prostatic urethra can be similar to a valve created by anterior urethral diverticulum. Douglas Stephens describes this configuration as a type IV valve in patients with prune belly syndrome, in which the dilated prostatic urethra joins the membranous urethra in various configurations that cause obstruction. However, these theories have not been supported by urodynamic studies, which fail to demonstrate either mechanical or functional outlet obstruction in most cases. Recent studies indicate that the more distal lower ureter is abnormal in several ways, while the more proximal portion of the ureter is more anatomically normal. Histologically, the ureter has a smooth muscle deficiency with fibrous degeneration and a poor blood supply. In addition, a decrease in nerve plexuses is reported, with irregularity in degeneration of nonmyelinated Schwann fibers. Herniation of the bladder is prevalent in patients with prune belly syndrome because the bladder is large and redundant. Patients with urethral obstruction commonly have a patent urachus, which enables the patient to survive; early deaths usually occur in those with urethral obstruction who do not have a patent urachus. Some patients with prune belly syndrome have posterior urethral valves. Prune belly syndrome is characterized by elongated, dilated, and tortuous megaureters, which affect 81% of patients. Typically, patients with prune belly syndrome have megacystis. The bladder is routinely enlarged, although trabeculations are rarely present and muscular hypertrophy is inconsistent. The bladder can be fixed to the umbilicus via urachus, giving it an hourglass configuration radiographically. Bladder-voiding pressures are frequently near-normal, and residual urine volume is insignificant. Snyder et al describe a typical shift to the right, and some patients with prune belly syndrome can void normally.[3] Some authors feel that reduction cystoplasty can improve detrusor force. Some feel that the shape of the bladder in patients with prune belly syndrome can lead to unbalanced voiding and that a decreased bladder capacity would lead to increased detrusor efficiency based on Laplace law. Anterior urethral abnormalities, which range from urethral atresia to megalourethra, are common in patients with prune belly syndrome. Patients who survive urethral atresia or microurethra have a patent urachus. Both scaphoid and fusiform megalourethra are associated with prune belly syndrome. The fusiform type is associated with deficient corpora cavernosa and more severe renal defects. Scaphoid megalourethra is associated with deficiency of the corpus spongiosum with a normal glans and fossa navicularis. The mesenchymal developmental arrest, which accounts for the major features of the syndrome, may also explain the urethral abnormalities. Orthopedic anomalies are common and can affect 50% of patients. Scoliosis and congenital hip dislocations are common. Abnormalities associated with oligohydramnios also are observed.

Cardiac anomalies are reported in 10% of patients :Alhawsawi et al (2009) reported a hepatic arterial aneurysm in a patient with prune belly syndrome. This is a rare defect that may be associated with inflammation or trauma to the arteries of the liver. Atherosclerosis, arthritis, and collagen vascular disease are the most common etiologies of inflammation that result in such aneurysms. The authors postulate that the mesodermal defect may account for the aneurysm.[4]

Gastrointestinal abnormalities, which include malrotation, atresia, stenosis, and volvulus, affect 30% of patients. All may be due to a persistence of the embryonic wide mesentery, with absent fixation to the posterior abdominal wall. The same defect allows the spleen to wander widely and can lead to splenic torsion. Imperforate anus, anorectal agenesis, omphalocele, and gastroschisis are uncommon but have been reported. Chronic constipation has been attributed to a decrease in abdominal wall pressure, which is necessary to aid in evacuation.

Infections and Related Inflammatory Conditions:Urinary Tract Infection in Females: Pathophysiology:The urinary tract is normally sterile. Uncomplicated UTI involves the urinary bladder in a host without underlying renal, metabolic, or neurologic diseases. Cystitis represents bladder mucosal invasion, most often by enteric coliform bacteria (eg, Escherichia coli) that inhabit the periurethral vaginal introitus and ascend into the bladder via the urethra. Because sexual intercourse may promote this migration, cystitis is common in otherwise healthy young women. Generally, urine is a good culture medium. Factors unfavorable to bacterial growth include a low pH (5.5 or less), a high concentration of urea, and the presence of organic acids derived from a diet that includes fruits and protein. Organic acids enhance acidification of the urine. Frequent and complete voiding has been associated with a reduction in the incidence of UTI. Normally, a thin film of urine remains in the bladder after emptying, and any bacteria present are removed by the mucosal cell production of organic acids. If the mechanisms of the lower urinary tract fail, upper tract or kidney involvement occurs and is termed pyelonephritis. Host defenses at this level include local leukocyte phagocytosis and renal production of antibodies that kill bacteria in the presence of complement. In general, there are 3 main mechanisms responsible for UTIs: Colonization with ascending spread Hematogenous spread Periurogenital spread

Complicated pyelonephritis results from structural and functional abnormalities, urologic manipulations, or underlying disease. Complicated pyelonephritis includes pyelonephritis in men and pyelonephritis in the elderly. For more information on this topic, see the Medscape Reference article Pathophysiology of Complicated Urinary Tract Infections.

Bacterial virulence :Uropathogenic bacteria, derived from a subset of fecal flora, have traits that enable adherence, growth, and resistance of host defenses, resulting in colonization and infection of the urinary tract. Adhesins are bacterial surface structures that enable attachment to host membranes. In E coli infection, these include both pili (ie, fimbriae) and outer-membrane proteins (eg, Dr hemagglutinin). P fimbriae , which attach to globoseries-type glycolipids found in the colon and urinary epithelium, are associated with pyelonephritis and cystitis and are found in many E coli strains that cause urosepsis.

Type 1 fimbriae bind to mannose-containing structures found in many different cell types, including TammHorsfall protein (the major protein found in human urine). Whether this facilitates or inhibits uroepithelial colonization is the subject of some debate. Other factors that may be important for E coli virulence in the urinary tract include capsular polysaccharides, hemolysins, cytotoxic necrotizing factor (CNF) protein, and aerobactins. Several Kauffman serogroups of E coli may be more likely to cause UTIs, including O1, O2, O4, O6, O16, and O18. Another example of bacterial virulence is the swarming capability of Proteus mirabilis. Swarming involves the expression of specific genes when these bacteria are exposed to surfaces such as catheters. This results in the coordinated movement of large numbers of bacteria, enabling P mirabilis to move across solid surfaces. This likely explains the association of P mirabilis UTIs with instrumentation of the urinary tract.

Host resistance :Most uropathogens gain access to the urinary tract via an ascending route. The shorter length of the female urethra allows uropathogens easier access to the bladder. The continuous unidirectional flow of urine helps to minimize UTIs, and anything that interferes with this increases the host's susceptibility to UTI. Examples of interference include volume depletion, sexual intercourse, urinary tract obstruction, instrumentation, use of catheters not drained to gravity, and vesicoureteral reflux. Secretory defenses help promote bacterial clearance and prevent adherence. Secretory immunoglobulin A (IgA) reduces attachment and invasion of bacteria in the urinary tract. Women who are nonsecretors of the ABH blood antigens appear to be at higher risk for recurrent UTIs; this may occur because of a lack of specific glycosyltransferases that modify epithelial surface glycolipids, allowing E coli to bind to them better. In premenopausal women, lactobacilli are the predominant vaginal flora and serve to suppress vaginal colonization by the uropathogens. Most antibiotics, except sulfamethoxazole and the quinolones, can eradicate these protective bacteria. Urine itself has several antibacterial features that suppress UTIs. Specifically, the pH, urea concentration, osmolarity, and various organic acids prevent most bacteria from surviving in the urinary tract.

Etiology:E coli causes 70-95% of both upper and lower UTIs. Various organisms are responsible for the remainder of infections, including S saprophyticus, Proteus species, Klebsiella species, Enterococcus faecalis, other Enterobacteriaceae, and yeast. Some species are more common in certain subgroups, such as S saprophyticus in young women. Most complicated UTIs are nosocomial in origin. The most common pathogens include E coli, enterococci, P aeruginosa, Candida species, and K pneumoniae. The most important risk factor for bacteriuria is the presence of a catheter. Eighty percent of nosocomial UTIs are related to urethral catheterization, while 5-10% are related to genitourinary manipulation. Catheters inoculate organisms into the bladder and promote colonization by providing a surface for bacterial adhesion and causing mucosal irritation. For more information on this topic, see the Medscape Reference article Catheter-Related Urinary Tract Infection. Sexual intercourse contributes to increased risk, as does use of a diaphragm and/or spermicide. Women who are elderly, pregnant, or have preexisting urinary tract structural abnormalities or obstruction carry a higher risk of UTI.

UTIs are the most common type of infection following renal transplantation. Susceptibility is especially high in the first 2 months following transplantation. Triggering factors include vesicoureteral reflux and immunosuppression. Corynebacterium urealyticum (ie, CDC group D2) has been reported to cause encrusted pyelitis and cystitis in these patients. Calculi related to UTIs (see the image below) most commonly occur in women who experience recurrent UTIs with Proteus, Pseudomonas, and Providencia species.

Nonobstructing distal left ureteral calculus 2 X 1 X 2 cm. Perinephric abscesses are associated most commonly with E coli, Proteus species, and S aureus but also may be secondary to Enterobacter, Citrobacter, Serratia, Pseudomonas, and Klebsiella species. More unusual causes include enterococci, Candida species, anaerobes, Actinomyces species, and Mycobacterium tuberculosis. Twenty-five percent of infections are polymicrobial. Candiduria is defined as more than 1000 CFU of yeast from 2 cultures. Candida albicans, which is germ tube positive, is the usual culprit. Germ tubenegative Candida species (tropicalis, parapsilosis, glabrata, lusitaniae, krusei) are less common. Risk factors for candiduria include diabetes mellitus, indwelling urinary catheters, and antibiotic use. Candiduria may clear spontaneously or may result in (or from) deep fungal infections.

Epidemiology:United States statistics :UTIs in women are very common; approximately 25-40% of women in the United States aged 20-40 years have had a UTI. UTI accounts for over 6 million patient visits to physicians per year in the United States. Approximately 20% of those visits are to EDs. Cystitis occurs in 0.3-1.3% of pregnancies but does not appear to be related to asymptomatic bacteriuria. Acute pyelonephritis occurs in 1-2% of pregnancies. UTIs occur in 30-50% of renal transplant patients and frequently are silent. In 1998, approximately 3.2% of ED visits were related to symptoms involving the genitourinary tract. Estimates based on office and ED visits suggest per annum about 7 million episodes of acute cystitis and 250,000 episodes of acute pyelonephritis. From 10-15% of nephrolithiasis episodes are secondary to organisms associated with stone production. The incidence of renal and perirenal abscesses is 1-10 cases per 10,000 population. Some studies estimate that UTIs cost at least 1 billion dollars per year.

International statistics :UTIs have been well studied in Sweden and other parts of Europe. As 1 in 5 adult women experience UTI at some point, it is an exceedingly common, clinically apparent, worldwide patient problem. Data from the tropics are less well documented. UTIs appear to be common and associated with structural abnormalities. Chronic infection from Schistosoma haematobium disrupts bladder mucosal integrity and causes urinary tract obstruction and stasis. Salmonella bacteriuria, with or without bacteremia, is very common in patients with schistosomiasis. Treatment requires both antischistosomal and anti-Salmonella agents. Tuberculosis (TB) of the kidney results from hematogenous spread but is relatively rare in developing countries. Unlike most other extrapulmonary manifestations of the disease, TB of the kidney does not become manifest until 5-15 years after the primary infection. Constitutional symptoms are uncommon, and most patients present with symptoms of bladder irritation. Initially, pyuria is observed, and with progression of the disease, proteinuria and blood may be observed as well. Repeated urine samples should be sent for mycobacterial culture. A loss of calyceal architecture and ureteric obstruction may be observed on imaging studies. Concurrent pulmonary disease is present in 5% of patients, and the tuberculin test rarely is helpful. Antituberculous medicines should be administered for 6 months. If the ureter is obstructed, corticosteroids have been advocated; if obstruction persists, surgical intervention is necessary.

Age- and sex-related demographics :Uncomplicated UTIs are much more common in women than men when matched for age. A study of Norwegian men aged 21-50 years showed an approximate incidence of 0.0006-0.0008 infections per personyear, compared with approximately 0.5-0.7 per person-year in similarly aged women in the United States. The largest group of patients with UTI is adult women. The incidence of UTI in women tends to increase with increasing age. Several peaks above baseline correspond with specific events, including an increase in women aged 18-30 years (associated with honeymoon cystitis and pregnancy). Rates of infection are high in postmenopausal women because of bladder or uterine prolapse causing incomplete bladder emptying; loss of estrogen with attendant changes in vaginal flora; loss of lactobacilli, which allows periurethral colonization with gram-negative aerobes, such as E coli; and higher likelihood of concomitant medical illness, such as diabetes. Older adults have a higher incidence of renal corticomedullary abscesses. Renal corticomedullary abscesses affect men and women equally; xanthogranulomatous pyelonephritis affects more women than men. Renal carbuncles are more common in men than women by a ratio of 3:1 and are most common in the second to fourth decades of life. The right kidney is involved most commonly (63%). Of neonates, boys are slightly more likely than girls to present with UTI as part of a gram-negative sepsis syndrome. The incidence in preschool-aged children is approximately 2% and is 10 times more common in girls. UTI occurs in 5% of school-aged girls, but it is rare in school-aged boys.

Prognosis :-

The prognosis for most women with cystitis and pyelonephritis is good; however, about 25% of women with cystitis will experience a recurrence. The prognosis for emphysematous pyelonephritis is not as good. Infected cysts in polycystic kidney disease respond to treatment slowly. Although simple lower UTI (cystitis) may resolve spontaneously, effective treatment lessens the duration of symptoms and reduces the incidence of progression to upper UTI. Younger patients have the lowest rates of morbidity and mortality. Factors associated with an unfavorable prognosis include the following: Old age General debility Renal calculi or obstruction Recent hospitalization Urinary tract instrumentation or antibiotic therapy Diabetes mellitus Chronic nephropathy Sickle cell anemia Underlying cancer Intercurrent chemotherapy

The mortality associated with acute uncomplicated cystitis in women aged 20-60 years appears to be negligible. A longitudinal cohort study of Swedish women showed a higher mortality in women with a history of UTI than in age-matched women without such a history (37% versus 28% in 10 y).[1] These cohorts were not matched for other mortality-related factors, making it difficult to attribute the increased mortality to UTIs. In contrast, the morbidity in terms of quality of life and economic measures is tremendous. Each episode of UTI in a young woman results in an average of 6.1 days of symptoms, 1.2 days of decreased class/work attendance, and 0.4 days in bed. Pyelonephritis is associated with substantial morbidity, including systemic effects such as fever, vomiting, dehydration, and loss of vasomotor tone resulting in hypotension. Complications include acute papillary necrosis with possible development of ureteral obstruction, septic shock, and perinephric abscess. Chronic pyelonephritis may lead to scarring with diminished renal function. Unfortunately, despite appropriate intervention, 1-3% of patients with acute pyelonephritis die. Nosocomial infections develop in about 5% of patients admitted to hospitals, and UTIs account for 40% of these infections. From 2-4% of these patients become bacteremic, with a mortality of 12.5%. In pregnant women, complications of pyelonephritis include pulmonary edema and acute respiratory distress syndrome, transient renal dysfunction, anemia, preterm delivery, and low-birth-weight infants. In renal transplant recipients, UTIs may, but do not always, predispose the patient to graft loss or rejection. Infection of the allograft may lead to life-threatening bacteremia. Complicated UTIs in patients who have diabetes mellitus include renal and perirenal abscess, emphysematous pyelonephritis, emphysematous cystitis, fungal infections, xanthogranulomatous pyelonephritis, and papillary necrosis. In emphysematous pyelonephritis, the mortality rate is 60% in cases in which the gas is localized to the renal parenchyma, regardless of treatment. The mortality is 80% if the gas has spread in the perinephric space and the patient is treated with antibiotics alone. In emphysematous pyelitis, the mortality rate is 20%.

Patient Education:-

Proper adherence to the outpatient medical regimen should be stressed. Behavior modification such as good oral fluid intake to enhance diuresis, frequent voiding (including postintercourse voiding), and drinking fruit juices (eg, cranberry juice) to acidify the urine are helpful in reducing recurrent infection.

Urinary Tract Infection in Males :-

Anatomy:The normal male urinary tract has many natural defenses to infection. Transitional epithelium conducts urine from the kidneys to an elastic bladder, which can store large volumes at low pressures. The male urethra is separated from the rectum by several centimeters of keratinized squamous epithelium; the long urethra provides an additional barrier between the bladder and the perineum. Because of these many defenses, many experts consider UTIs in males, by definition, to be complicated. Complicated infections are those that are more likely to be associated with anatomic abnormalities, requiring surgical intervention to prevent sequelae. The diagnosis and treatment of UTIs in males should proceed with this concept in mind. UTIs can be divided anatomically into upper- and lower-tract infections. In the male, lower-tract disease includes prostatitis, epididymitis, cystitis, and urethritis. Upper-tract disease (pyelonephritis) is similar in males and females. The phrase "significant bacteriuria" is sometimes used to emphasize that the number exceeds that which might be caused by contamination during the collection of the specimen. Bacteriuria can be symptomatic or asymptomatic.

Pathophysiology:As with females, the usual route of inoculation in males is with gram-negative aerobic bacilli from the gut, with Escherichia coli being the most common offending organism. Recent hospitalization, urinary catheter, and fluoroquinolone use in the past 6 months are independent risk factors for fluoroquinolone resistance in community-onset febrile E coli UTI. Fluoroquinolone resistance may be a marker of broader resistance, including extended-spectrum-beta-lactamase (ESBL) positivity.[22] In the normal host, UTI may occur due to infection of other portions of the genitourinary tract, typically the prostate. Older males with prostatic hypertrophy have incomplete bladder emptying, predisposing them to UTI on the basis of urinary stasis. However, in males aged 3 months to 50 years, the incidence of UTI is low; therefore, the possibility of an anatomic abnormality must be entertained in this age group. Entry of microorganisms into the prostate gland almost always occurs via the urethra; with intraprostatic reflux of urine, bacteria migrate from the urethra or bladder through the prostatic ducts. Other possibilities include entry via the hematogenous route, via the lymphatics from the rectum, and during prostatic surgery; many patients have no known precipitating event. Prostatic fluid contains various antibacterial substances, including zinc and antibodies, which are lacking in some patients with chronic bacterial prostatitis. Interestingly, acute prostatitis usually does not result in chronic prostatitis, and chronic bacterial prostatitis is usually not antedated by acute prostatitis. Of men referred for prostatitis, less than 10% have either acute or chronic bacterial prostatitis.

Acute and chronic prostatitis :In the 1800s, prostatitis was thought to be secondary to excessive alcohol consumption or physical or sexual activity. It was often associated with gonorrhea and could be fatal or lead to abscess formation. By the 1920s, most cases were attributed to microorganisms, and antibiotics combined with prostate massage were

standard therapy after World War II. Although the role of bacteria was questioned in the 1950s, it was reemphasized in 1968 when Meares and Stamey described their "4-glass test."[1] (See Prostatitis under Workup.) Acute prostatitis is caused by an acute infection of the entire prostate gland, resulting in fever and localized pain. Microscopically, neutrophilic infiltrates, diffuse edema, and microabscesses may be seen, which may coalesce into larger collections. Chronic prostatitis may be caused by inflammatory or noninflammatory diseases. This condition may arise via dysfunctional voiding, intraprostatic reflux, chronic exposure to microorganisms (see Etiology), autoimmune mechanisms, irritative urinary metabolites, and as a variant of neuropathic pain. Chronic bacterial prostatitis often produces few or no symptoms related to the prostate, but it is probably the most common cause of relapsing UTI in men. Chronic prostatitis has been subdivided by the National Institutes of Health (NIH) into the following categories: Category II: Chronic bacterial prostatitis Category III: Chronic abacterial prostatitis. Category IIIA is chronic inflammatory abacterial prostatitis, and category IIIB is chronic noninflammatory abacterial prostatitis, also known as chronic pelvic pain or prostatodynia. Category IV: Asymptomatic inflammatory prostatitis

Epididymitis :Epididymitis is a clinical syndrome caused by infection or inflammation of the epididymis. This condition is the most common cause of acute scrotum in adult male populations. Long-term complications include abscesses, infarction, recurrence, chronic pain, and infertility The pathophysiology of epididymitis is divided; Chlamydia trachomatis and Neisseria gonorrhoeae are the most common pathogens in patients younger than 35 years, whereas Enterobacteriaceae and gram-positive cocci are frequent pathogens in older patients. In either case, infection results from retrograde ascent of infected urine from the prostatic urethra, into the vas deferens, and, finally, into the epididymis.

Orchitis :Orchitis was first described in approximately 400 BC by Hippocrates. Because of the widespread use of mumps vaccination, it is no longer a common infection in the United States. Orchitis is one of the few genitourinary infections to result from a viral pathogen. Orchitis is one of the few genitourinary infections that results from a viral pathogen. Mumps orchitis occurs in 18% of postpubertal boys infected with the mumps virus. Other viruses that can cause the disease include coxsackie B, mononucleosis, and varicella. Unlike the majority of genitourinary infections, viral particles are spread to the testicle by the hematogenous route. Granulomatous orchitis is rare and results from hematogenous dissemination of tuberculosis, fungi, and actinomycosis.

Pyelonephritis :Pyelonephritis is an infection of the renal parenchyma. Infection usually occurs in a retrograde ascending fashion from the bladder, but it may occur hematogenously. The ureteral orifice becomes edematous and loses its one-way valve function during infection. Retrograde flow of bacteria into the upper urinary tracts and into the renal parenchyma results in clinical symptoms.

Bacteremia, particularly with virulent organisms such as Staphylococcus aureus, can result in pyelonephritis with focal renal abscesses. Bacterial adherence allows for mucosal colonization and subsequent infection by an ascending route. Whereas type 1 pili are produced by most uropathogenic strains of E coli, P-pili, which bind to the uroepithelial glycosaminoglycan layer, are found in most strains of E coli that cause pyelonephritis. Genotypic factors may affect uroepithelial susceptibility to these adherence molecules. Endotoxin from gramnegative organisms can retard ureteral peristalsis. E coli is responsible for approximately 25% of cases in males, with Proteus and Providencia causing many remaining infections; Klebsiella, Pseudomonas, Serratia , and enterococci are less frequent.

Bacterial cystitis :Bacterial cystitis without concomitant infection in other portions of the genitourinary tract is believed to be a rare event in males. The abrupt onset of irritative voiding symptoms (eg, frequency, urgency, nocturia, dysuria) and suprapubic pain are clinically diagnostic. Most cases of bacterial cystitis occur by an ascending mechanism. Bacterial cystitis in the male is uncommon in the absence of anatomic abnormality, defect in bladder emptying mechanism, or urethral catheterization (eg, poor bladder emptying from prostatic obstruction or dysfunctional voiding). Elevated postvoid residuals allow bacteria to multiply to critical levels. High voiding pressures and poor bladder compliance diminish the natural uroepithelial resistance to infection.

Urethritis :Urethritis has been described for thousands of years. The term gonorrhea (gonus meaning seed, rhoia meaning flow) was coined by Galen. The urethral nonsquamous epithelium can be penetrated by N gonorrhoeae, resulting in periurethral microabscesses. Necrotic debris is sloughed into the urethra lumen, producing a milky penile discharge. Gonococcal urethritis remains the most commonly reported communicable bacterial disease in the United States.

Urinary catheterassociated UTIs :Up to 25% of hospitalized patients have urinary catheters inserted; of these individuals, 10-27% develop UTIs. In fact, UTI accounts for approximately 40% of all nosocomial infections; 15% of these infections occur in clusters and often involve highly resistant organisms. The single most important risk factor for nosocomial bacteriuria and UTI is the presence of an indwelling urethral catheter; 80% of nosocomial UTIs are associated with the use of urethral catheters. Once the urethral catheter is in place, the daily incidence of bacteriuria is 310%. Because most become bacteriuric by 30 days, that is a convenient dividing line between short- and long-term catheterization. According to the Infectious Diseases Society of America (IDSA) 2009 guideline for diagnosis, prevention, and treatment of catheter-associated urinary tract infection (CAUTI) in adults, if an indwelling catheter has been in place for more than 2 weeks at the onset of CAUTI and remains indicated, the catheter should be replaced to promote continued resolution of symptoms and to reduce the risk of subsequent catheter-associated infection.
[2]

The Centers for Disease Control and Prevention (CDC) 2009 guideline for prevention of CAUTI recommends catheter use only for appropriate indications. Catheters should be kept in place only for as long as needed. Indwelling catheters in operative patients should be removed as soon as possible postoperatively. Use of urinary catheters for treatment of incontinence should be avoided in patients and nursing home residents.[3]

The ISDA 2009 guideline for CAUTIs states that indwelling catheter may be considered at the patients request in exceptional cases and when other approaches to management of incontinence have proven ineffective.[2]

Etiology:Risk factors for UTI and bacterial causes of prostatitis, epididymitis, orchitis, pyelonephritis, cystitis, and urethritis are discussed in this section.

Risk factors :Obstruction from any cause is a major risk factor for the development of UTI, as are instrumentation of the urinary tract, catheterization, and urologic surgery. In males older than 50 years, prostatic hypertrophy with partial obstruction is the main contributor to the increase in UTI. Risk factors observed more commonly in elderly or institutionalized males include cognitive impairment, fecal or urinary incontinence, and the use of catheters. Catheter-associated bacteriuria risk factors include female sex, significant comorbid conditions (especially diabetes mellitus), age older than 50 years, lack of systemic antibiotic(s), and a serum creatinine level greater than 2 mg/dL. Risk factors for bacteremia secondary to catheter-associated UTI (CAUTI) are male sex, UTI caused by Serratia marcescens, older age, underlying urologic disease, and an indwelling catheter. In young men, risk factors for acute cystitis include homosexual behavior with anal intercourse, intercourse with a female infected or colonized with a uropathogen, lack of circumcision, and human immunodeficiency virus (HIV) infection with CD4 counts of 200/L or less.

Prostatitis :Acknowledged pathogens of the prostate are gram-negative uropathogens (eg, Enterobacteriaceae, such as E coli, Klebsiella, and Pseudomonas). Probable pathogens include Enterococcus and S aureus, and possible pathogens include coagulase-negative Staphylococcus, Chlamydia, Ureaplasma, anaerobes, Candida, and Trichomonas. Acknowledged nonpathogens of the prostate include diphtheroids, lactobacilli, and Corynebacterium. Viruses and cell walldeficient bacteria have a controversial association with prostatitis. Rare cases have been reported from Clostridia and Burkholderia (formerly Pseudomonas) pseudomallei (the causative agent of melioidosis). Unusual pathogens reported in patients with acquired immunodeficiency syndrome (AIDS) include cytomegalovirus (CMV) and some fungi (Aspergillus, Histoplasma, and Cryptococcus). The prostate is a known reservoir for Cryptococcus neoformans. Chronic bacterial prostatitis is the most common cause of relapsing UTI in men, with E coli as the main causative organism (80%), but other gram-negative bacteria and enterococci may also be observed. Rare cases may be caused by yeasts (eg, Candida, Blastomyces, Histoplasma, Cryptococcus) and mycobacteria. Whether Staphylococcus epidermidis, S aureus, and diphtheroids are pathogenically significant is doubtful, and the evidence supporting a causative role for Chlamydia and Ureaplasma is not convincing. Bacterial pathogens cannot be demonstrated in cases of nonbacterial prostatitis.

Epididymitis :Chlamydia trachomatis and Neisseria gonorrhoeae are the most common pathogens in patients younger than 35 years with UTI, whereas Enterobacteriaceae and gram-positive cocci are frequent pathogens in older patients.

Orchitis :Orchitis is one of the few genitourinary infections resulting from viral pathogens, such as the mumps, coxsackie B, Epstein-Barr (EBV), and varicella (VZV) viruses. Granulomatous orchitis is rare and results from hematogenous dissemination of tuberculosis, fungi, and actinomycosis. Brucella also been associated with orchitis; clinically, these patients resemble patients with tuberculosis. Colorado tick fever has also been associated with epididymoorchitis. Secondary orchitis is a more common condition; it is a late complication of untreated epididymitis.

Pyelonephritis and cystitis :Bacteria responsible for pyelonephritis and cystitis in males include E coli, Klebsiella, Enterobacter, Proteus, Pseudomonas, Serratia, Enterococcus, and Staphylococcus species.

Urethritis :N gonorrhoeae is the most common cause of urethritis in males; nongonococcal causes of urethritis (NGU) include C trachomatis (in up to 50% of cases), Ureaplasma urealyticum, Trichomonas vaginalis, and herpes simplex virus (HSV). The role of Mycoplasma in urethritis is controversial.

Catheter-associated bacteriuria :Short-term catheters are placed for a mean duration of 2-4 days. The usual indications are for acute illnesses, output measurement, perioperative routine, and acute retention. Approximately 15% of patients develop bacteriuria, usually with a single organism (E coli). Catheter-associated bacteriuria usually resolves after the catheter is removed; however, one third may have symptoms, and bacteremia is the most serious complication. Approximately 10-30% develop a fever, and the risk of postoperative wound infection associated with bacteriuria is increased. Long-term catheters are placed for chronic medical or neurologic problems, including chronic urinary retention and incontinence. Essentially, all patients develop bacteriuria, which is polymicrobial in up to 95% of cases. New pathogens often emerge, whereas many persist because of adherence properties (fimbrial adhesion in Providencia and E coli) or their effect on the local environment (Proteus and Morganella). Catheter obstruction may occur via an interaction between bacteria, the glycocalyx, protein, and crystals; Proteus mirabilis is a potent producer of urease, which alkalinizes the urine, precipitating struvite and apatite.

Epidemiology :Although this article exclusively addresses urinary tract infection (UTI) in males, the clinician should appreciate that the incidence of UTI is much higher in females during adolescence and childbearing years (adult women are 30 times more likely than men to develop a UTI). The incidence of UTI in men approaches that of women only in men older than 60 years; in men aged 65 years or older, 10% have been found to have bacteriuria, as compared with 20% of women in this age group. Internationally, there is a similar incidence in

developed countries; however, in developing countries where men have shorter life spans, the incidence of UTI due to prostatic hypertrophy is lower. The incidence of male urinary tract infection (UTI) is related to age; young men rarely develop a UTI, and the prevalence of bacteruria is 0.1% or less. There is an early peak incidence during the first 3 months of life; in neonates, a UTI occurs more frequently in boys than in girls (with a male-to-female ratio of 1.5:1), and it is often part of the syndrome of gram-negative sepsis. The cumulative incidence of symptomatic UTI (including pyelonephritis) in boys during the first 10 years of life has been reported at 1.1-1.6%. The incidence of true UTI in adult males younger than age 50 years is low (approximately 5-8 per year per 10,000). In this population, the symptoms of dysuria or urinary frequency are usually due to sexually transmitted disease (STD)related infections of the urethra (eg, gonococcal and nongonococcal urethritis) and prostate.[4] In men older than 50 years, the incidence of UTI rises dramatically (range, 20-50% prevalence) because of enlargement of the prostate, prostatism, debilitation, and subsequent instrumentation of the urinary tract. The spectrum of causative agents is also somewhat broader in these older men.

Prostatitis, epididymitis, orchitis, and urethritis :In contrast to UTI, prostatitis affects men of all ages and, from 1990-1994, accounted for almost 2 million office visits per year in the United States. Prostatitis syndromes account for 25% of male office visits for genitourinary complaints, 8% of visits to urologists, and 1% of visits to primary care physicians. Of these men, 5% have bacterial prostatitis, 64% have nonbacterial prostatitis, and 31% have prostatodynia. Epididymitis has a bimodal distribution, corresponding to different age groups and pathogens. Most cases in men younger than 35 years are due to sexually transmitted pathogens. Older patients are more likely to have obstructive prostatism or a history of instrumentation or catheterization. Gonococcal urethritis is more common in ethnic minorities, lower socioeconomic groups, and those living in urban centers. The risk to a male having intercourse with an infected female is 17%. Some of these associations may be limited by confounding. The peak age for urethritis is 20-24 years. Mumps orchitis occurs in 18% of postpubertal boys infected with the mumps virus.

Prognosis:The natural history of UTIs varies based on the site of the infection, the host, and the pathogen. Asymptomatic bacteruria appears to be a benign finding in men; it does not contribute to mortality in elderly patients, it does not impair renal function, and it does not cause hypertension. Otherwise healthy males without anatomic abnormality who promptly seek treatment experience little morbidity besides the discomfort of an infection. In more complicated cases (eg, prolonged infection, anatomic variations), the sequelae of infection can be more significant. Risk factors for serious morbidity, renal impairment, or mortality from UTIs have been well characterized and include the following: Urinary obstruction (eg, calculi) Infection with urea-splitting bacteria Congenital urinary tract anomalies Renal papillary necrosis Recent urinary tract instrumentation, hospitalization, or broad-spectrum antibiotic therapy

Catheter drainage Diabetes or compromised immune system Spinal cord injury with high-pressure bladders Acute bacterial prostatitis Development of emphysematous pyelonephritis Older patients who present with signs of dehydration, hypoperfusion, or overt shock

Patients with nosocomial UTIs have their hospital stay extended by an average of 3 days, and these patients are 3 times more likely to die during hospitalization. Approximately 2-4% of patients with nosocomial UTIs develop bacteremia, which is associated with a 13% mortality rate. The urinary tract is the second most common source of nosocomial bacteremia (17%). Bacteremia also occurs in approximately 20% of men with acute pyelonephritis or acute bacterial prostatitis. The current literature does not mention any patients dying from prostatitis or after a vigorous prostatic massage, but this was often reported in the preantibiotic era. In elderly patients, UTI is a significant cause of morbidity and death, with the expected death rate as high as 3% in those who develop pyelonephritis. The high mortality rate is largely due to delayed presentation and the development of bacteremia/sepsis. Emphysematous pyelonephritis is an acute necrotizing parenchymal and perirenal infection caused by gasforming bacteria. Women are affected more often than men, and nearly all cases occur in patients with diabetes. The overall mortality rate is 43%.

Bladder Stones :Bladder calculi are an uncommon cause of illness in most Western countries, but they result in specific symptoms and are a significant source of discomfort. This article discusses the diagnosis and current management techniques for vesical calculus disease.

Problem :Vesical calculi refer to the presence of stones or calcified materials in the bladder (or bladder substitute that functions as a urinary reservoir). These stones are usually associated with urinary stasis, but they can form in healthy individuals without evidence of anatomic defects, strictures, infections, or foreign bodies. The presence of upper urinary tract calculi is not necessarily a predisposition to the formation of bladder stones.

Frequency :The incidence of primary bladder calculi in the United States and Western Europe has been steadily and significantly declining since the 19th century because of improved diet, nutrition, and infection control. In these countries, vesical calculi affect adults, with a steadily declining frequency in children. In the Western hemisphere, vesical calculi primarily affect men who are usually older than 50 years and have associated bladder outlet obstruction. However, bladder calculi remain common in less-developed countries and areas such as Thailand, Burma, Indonesia, the Middle East, and North Africa. Although the prevalence of bladder calculi is declining in these populations, it remains a disease that affects children, among whom the disease is far more common in boys than in girls.[6] In 1977, Van Reen published a symposium on idiopathic urinary bladder stone disease.[7] Unfortunately, no definitive worldwide data accurately reflect the frequency of bladder calculi. This is mostly because of poor hospital records in developing regions of the world. Despite several studies in countries with a high incidence of the disease, the reporting is not uniform.

Etiology:Bladder outlet obstruction remains the most common cause of bladder calculi in adults. Prostatic enlargement, elevation of the bladder neck, and high postvoid residual urine volume cause stasis, which leads to crystal nucleation and accretion. This ultimately results in overt calculi. In addition, patients who have static urine and develop urinary tract infections are more likely to form bladder calculi. In a study of patients with spinal cord injuries (newly acquired neurogenic bladders) who were monitored for more than 8 years, 36% developed bladder calculi. More recent reports indicate that, because of better care of patients with injured spinal cords, this rate has dropped to less than 10%. Bladder inflammation secondary to external beam radiation or schistosomiasis can also predispose to vesical calculi.[8] The dystrophic calcifications that develop radiotherapy-related bladder and prostate damage might serve as a nidus for stone formation. Congenital or acquired vesical diverticula may serve a reservoir of urinary stasis, leading to stone formation. Other rare anatomic abnormalities that have been implicated as contributors to stasis and stone formation include sliding inguinal hernias containing the urinary bladder.[9] Multiple underlying risk factors predispose to bladder stones in pediatric patients who undergo bladder augmentation. Mathoera et al (2000) described risk factors for stone formation in 89 pediatric patients who had undergone bladder augmentation and presented with bladder calculi. Cloacal malformations, vaginal reconstructions, ureteral reimplantations, and bladder neck surgery were all associated with higher risk for stone formation. Preventive antibiotic therapy for recurrent infections decreased the amount of struvite stone formation but yielded no statistically significant reduction in overall stone formation.[10] Other etiologic factors for bladder stone formation include foreign bodies in the bladder that act as a nidus for stone formation. These are subclassified into iatrogenic and noniatrogenic bodies. The first group includes suture material, shattered Foley catheter balloons, eggshell calcifications that form on a catheter balloon, staples, ureteral stents, migrating contraceptive devices, erosions of surgical implants, and prostatic urethral stents.[11, 12, 13, 14, 15] Stones on suture material may have an early presentation if sutures were originally placed within the bladder lumen or may have a delayed presentation if they are caused by erosion through the bladder wall.[16] Noniatrogenic causes include objects placed into the bladder by the patients for recreational and various other reasons.[17] Metabolic abnormalities are not a significant cause of stone formation in patients with urinary diversions. In this group of patients, the stones are primarily composed of calcium and struvite. In rare cases, medications (eg, viral protease inhibitors) may be the source for bladder calculus formation.[18] In general, if an otherwise healthy person in the United States or Europe is found to have a bladder stone, a complete urological evaluation must be undertaken to find a cause for urinary stasis. Examples include benign prostatic hyperplasia, urethral stricture, neurogenic bladder, diverticula, and congenital anomalies such as ureterocele and bladder neck contracture. In females, examples include an incontinence repair that is too tight, cystoceles, and bladder diverticula.[19]

Pathophysiology:Most vesical calculi are formed de novo within the bladder, but some may initially have formed within the kidneys as a dissociated Randall plaque or on a sloughed papilla and subsequently passed into the bladder, where additional deposition of crystals cause the stone to grow. However, most renal stones that are small enough to pass through the ureters are also small enough to pass through a normally functioning bladder and unobstructed urethra. In older men with bladder stones composed of uric acid, the stone most likely formed in the bladder. Stones composed of calcium oxalate are usually initially formed in the kidney. The most common type of vesical stone in adults is composed of uric acid (>50%). Less frequently, bladder calculi are composed of calcium oxalate, calcium phosphate, ammonium urate, cysteine, or magnesium

ammonium phosphate (when associated with infection).[20, 21] Interestingly, patients with uric acid bladder calculi rarely ever have a documented history of gout or hyperuricemia. In many cases, the core is composed of one chemical, while layers of different chemicals form around it. Pediatric stones are composed mainly of ammonium acid urate, calcium oxalate, or an impure mixture of ammonium acid urate and calcium oxalate with calcium phosphate.[22] The common link among endemic areas relates to feeding infants human breast milk and polished rice. These foods are low in phosphorus, ultimately leading to high ammonia excretion. These children also usually have a high intake of oxalate-rich vegetables (increased oxalate crystalluria) and animal protein (low dietary citrate).[23, 7, 22] Bladder stones in patients with spinal cord injuries are often composed of struvite or calcium phosphate. Vesical calculi may be single or multiple, especially in the presence of bladder diverticula. Vesical calculi can be small or large enough to occupy the entire bladder. Their physical features range from soft to extremely hard and from having smooth-faceted surfaces to jagged spiculated surfaces, the latter termed "jack" stones based on their resemblance to the metal objects in the children's game Jacks (see image below). In general, most vesical calculi are mobile within the bladder, although some stones are fixed when they form on a suture, on the intravesical portion of a papillary tumor, or on retained stents.

Two delicate jack stones removed prior to open prostatectomy. In regions where vesical lithiasis is endemic among children, stone formation is more common among boys younger than 11 years, more common among people from low socioeconomic backgrounds, not usually associated with renal calculi, and relatively less likely to reoccur after treatment (when compared with upper tract calculi).[24]

Clinical :The presentation of vesical calculi varies from completely asymptomatic to symptoms of suprapubic pain, dysuria, intermittency, frequency, hesitancy, nocturia, and urinary retention.[21] Parents of children with vesical calculi may notice priapism and occasional enuresis.[8] Other common signs include terminal gross hematuria and sudden termination of voiding with some degree of associated pain referred to the tip of the penis, scrotum, perineum, back, or hip. The discomfort may be dull or sharp and is often aggravated by sudden movements and exercise. Assuming a supine, prone, or lateral head-down position may alleviate the pain initiated by the stone impacting the bladder neck by causing it to roll back into the bladder. Less specific signs of vesical calculi include microscopic or gross hematuria, pyuria, bacteriuria, crystalluria, and urine cultures that demonstrate urea-splitting organisms. A history of prior pelvic surgery should be sought in all patients, especially when synthetic materials were implanted.[25]

Common physical examination findings include suprapubic tenderness, fullness, and, occasionally, a palpable distended bladder if the patient is in acute urinary retention. Associated findings include cystoceles in women, stomal stenosis (if the patient had undergone prior urinary diversion), and neurological deficits in patients with neurogenic bladder. Historically, bladder calculi were diagnosed based on transurethral passage of van Buren sounds. The contact of the van Buren sounds with the stones causes transmission of a clicking noise or vibration, which confirms the presence of the stone. Because of advancements in cystoscopy, this maneuver is rarely used today. Currently, abdominopelvic planar radiography is used to easily identify radio-opaque stones. However, adult calculi, which are composed predominantly of uric acid, are radiolucent and, unless coated with calcium, are more difficult to visualize on radiographs. Cystoscopy, noncontrast CT scanning, and ultrasonography are common diagnostic methods used to confirm the presence of bladder calculi.[8]

Indications :Because a bladder stone is in itself a sign of an underlying problem, removal of the stone and treatment of the underlying abnormality are nearly always indicated. Management of the underlying cause of stone formation (eg, bladder outlet obstruction, infections, foreign body, diet) has been integral to preventing recurrence. Recent literature describes treatment of bladder calculi without relieving outlet obstruction, but the follow-up period was not long enough to warrant this as general practice.[26] In men, the main anatomical problem that leads to vesical obstruction is prostatic enlargement. The prostate forms a ringlike growth around the vesical neck and, when hypertrophic, can significantly impede the flow of urine. Stasis due to this blockage is responsible for the deposition of layer upon layer of new stone material. In women, voiding dysfunction and urinary stasis can occur but are less commonly associated with calculi. Typical anatomic findings include cystoceles, enteroceles, or findings of prior urethral surgery, all of which contribute to elevated residuals. With rare exceptions, any foreign body that cannot escape the bladder is calcified and eventually forms a stone.

Contraindications:The only contraindication to bladder stone removal would be existence of the stone in a medically unstable or near-terminal asymptomatic patient. In general, most vesical calculi procedures are performed via endoscopy. However, when the stone is too large or too hard or if the patient's urethra is too small (eg, in children) or surgically altered, complicating access to the bladder, the open or percutaneous suprapubic surgical approach is preferable. Relative contraindications exist to certain types of bladder stone ablative techniques. Electrohydraulic lithotripsy (EHL) should be used with great caution in patients with small-capacity bladders and those with cardiac-pacing or defibrillation devices. Percutaneous lithotripsy may be more hazardous in patients who have undergone prior lower abdominal surgery or prior pelvic surgery or who have small-capacity noncompliant bladders. Pregnancy is a relative contraindication to some forms of lithotripsy (eg, extracorporeal shock-wave lithotripsy [ESWL], EHL, mechanical lithotrity), but the benefits of eliminating a source of infection, retention, or pain with other modalities (eg, holmium laser, lithoclast), as well as a potential complicator of vaginal delivery if stones are large, may outweigh the risk of intervention.[27] Otherwise, the usual contraindications to any type of surgery also apply here.

Workup:Lab Studies Urinalysis: Urinalysis is usually inexpensive, rapid and provides useful information in this setting. On the dipstick, bladder calculi can be associated with test results that are positive for nitrite, leukocyte esterase, and blood. Since bladder calculi usually cause dysuria and pain, most patients reduce their daily fluid intake and raise their urine specific gravity. Adults with uric acid bladder calculi are expected to have an acidic pH. Microscopy usually demonstrates red blood cells (RBCs) and pyuria (WBCs). Microscopic crystals are usually consistent with the composition of the stone. Urine culture and sensitivity: A culture of the urine is integral to help document and direct treatment of associated infections. CBC count: In patients with outlet obstruction and infection, the white blood cell (WBC) count may be elevated, with a left shift. Comprehensive metabolic panel: The creatinine level may be elevated in outlet obstruction. Other findings may give a clue to an underlying abnormality.

Imaging Studies Urography of the kidneys, ureters, and bladder The initial imaging study of choice is plain radiography of the kidneys, ureters, and bladder (KUB) because it is the least expensive and easiest radiologic test to obtain. Alone or as the first film of an intravenous pyelogram (IVP), KUB demonstrates the presence of radio-opaque stones. Pure uric acid and ammonium urate stones are radiolucent but are occasionally coated with a layer of opaque calcium sediment. Laminations are common, with the layers stratified according to metabolic and infectious status and the degree of periodic hematuria (see image below).[8]

Multiple laminated bladder calculi in a patient with a neurogenic bladder. Cystography and intravenous pyelography If the clinical suspicion remains high and the initial KUB reveals no stones, the next step is cystography or IVP. These tests demonstrate the stone as a filling defect in the bladder. If the filling defect moves when the patient is repositioned, the presence of a stone is highly likely (differential diagnoses include clot, fungal ball, and papillary urothelial carcinoma on a stalk). Nonmobile filling defects could be calculi attached to the bladder wall via a stitch or in a diverticulum (differential diagnoses include urothelial carcinoma, clot, and calculus). IVP may also be used to identify associated abnormalities such as upper-tract calculi, ureterocele, cystocele, enlarged prostate, and bladder diverticula.[8]

Ultrasonography:With the recent widespread availability of ultrasonography, this relatively inexpensive and rapid modality can be more widely used to diagnose bladder calculi. The sonogram, showing a classic hyperechoic object with posterior shadowing, is effective in identifying both radiolucent and radio-opaque stones.[28]

Computed tomography scan : CT scan is usually obtained for other reasons (eg, abdominal pain, pelvic mass, suspected abscess) but may demonstrate bladder calculi when performed without intravenous contrast. Unenhanced spiral CT scan is highly sensitive and specific in diagnosing calculi along the urinary tract. Even pure urate calculi can be detected with this method. The stone may be obscured if contrast has been administered.[8]

Pelvic magnetic resonance imaging :MRI is an expensive imaging modality that yields poor resolution of calculi. It is not recommended in the evaluation of bladder calculi. If performed, MRI may show an incidental black hole of low water content corresponding to a calculus in an otherwise full bladder.

Tc-99m MAG-3 renal scanning :As with MRI, Tc-99m MAG-3 renal scanning is a poor imaging modality in this condition. It may demonstrate the incidental finding of focal photopenia within the bladder resulting from calculus formation.[29]

Other Tests Diagnostic Procedures :Cystoscopy remains the most commonly used test to confirm the presence of bladder stones and plan treatment. This procedure allows for the visualization of stones and assessment of their number, size, and position. Additionally, examination of the urethra, prostate, bladder wall, and ureteral orifices allows identification of strictures, prostatic obstruction, bladder diverticula, and bladder tumors.[8] See an endoscopic view in the image below.

Endoscopic view of a spiculated jack stone with erythematous bladder mucosa in the background.

Histologic Findings :The presence of long-standing untreated bladder calculi is associated with dysplasia and squamous cell carcinoma of the bladder. Occasionally, a calculus is found adherent to a transitional cell carcinoma. If a suspicious area does not clear after successful removal of the calculus and treatment of any associated infection, biopsy is performed to rule out malignant degeneration.

Treatment & Management :Medical therapy :The only potentially effective medical treatment for bladder calculi is urinary alkalinization for the dissolution of uric acid stones. Stone dissolution may be possible if the urinary pH can be made greater than or equal to 6.5. Potassium citrate (Polycitra K, Urocit K) at 60 mEq/d is the treatment of choice. However, overly aggressive alkalization may lead to calcium phosphate deposits on the stone surface, making further medical therapy ineffective.[8] Other agents for stone dissolution, such as Suby G or M solution, are rarely used. Renacidin can be used to dissolve phosphate or struvite calculi, but treatment is slow and invasive because it must be used in conjunction with indwelling irrigating catheters. Patients must also be monitored closely for signs of sepsis or hypermagnesemia. Further measures include irrigations of the bladder or continent diversions with saline for a mechanical flushing of debris or with one of the above solutions for preventing stone formation.[6] When underlying errors of metabolism are discovered during 24-hour urine evaluation of stone disease, various treatments are available to prevent further calculus development. However, the discussion of these treatments is beyond the scope of this article.

Surgical therapy :"Cutting for the stone" is a phrase that has been used since the time of Hippocrates. Historically, stones were removed via the high operation, using a suprapubic incision, or the low operation, using a perineal incision. In the absence of antibiotic therapy and adequate hemostatic techniques, both operations were associated with a high morbidity and mortality rate. Civiale performed the first documented blind transurethral lithotripsy in 1822. Even with the introduction of the cystoscope in 1877, bladder injury was always a risk. The predominant technique in the 1800s and early 1900s was to fill the bladder with 150 mL of fluid, grasp the stone with the lithotrite, rotate it to free the engaged stone from the mucosa, and crush the stone manually. This was repeated until the fragments were small enough to suction out of the bladder with an Ellik evacuator. Common complications included mucosal injury, bladder wall perforation, sepsis, and hemorrhage.[1] Currently, 3 different surgical approaches to this problem are used. Unlike in renal and most ureteral calculi, ESWL has shown little efficacy for bladder calculi in most centers,[30] but some studies suggest that ESWL performed with the patient in the prone position can be considered for treatment.[5] The first approach in adults is transurethral cystolitholapaxy. After cystoscopy is performed to visualize the stone, an energy source is used to fragment it, and the fragments are removed through the cystoscope. The energy sources are mechanical (ie, lithoclast [pneumatic jack hammer]), ultrasonic, electrohydraulic (ie, EHL [spark-induced pressure wave]), manual lithotrite, and laser. The pulsed-dye or other wavelength-specific light sources (eg, holmium) fracture the stone by direct absorption, vaporization, water absorption, and pressure wave generation.[31] Because of recent advancements in instrumentation, the smaller caliber of the pediatric urethra can be accommodated, allowing these approaches to be applicable in selected children.[32] The second approach in adults (and often primary approach in the pediatric population) is percutaneous suprapubic cystolitholapaxy. The percutaneous route allows the use of shorter- and larger-diameter endoscopic equipment (usually with an ultrasonic lithotripter), which allows rapid fragmentation and evacuation of the calculi.[33] Often, a combined transurethral and percutaneous approach can be used to aid in stone stabilization and to facilitate irrigation of the stone debris. The authors favor the combined approach with the use of the ultrasonic lithotripter or the pneumatic lithoclast. The holmium laser is also effective but is generally slower, even with the 1000-micron fiber.[34]

The EHL unit has been associated with a higher incidence of bladder mucosal injury. Options for accessing the bladder may be challenging in certain circumstances, such as in patients who have undergone prior bladder reconstruction or after prior bladder neck procedures for improved continence. Paez et al (2007) described percutaneous removal of bladder stones via ultrasound-assisted access of the bladder through prior suprapubic tube tracts. In one case, they used a Mitrofanoff catheterization channel with a 30F Amplatz sheath. They reported no complications, and percutaneous treatment was judged a safe alternative in this population subset. This same procedure has also been described in continent diversions with urethral closure. First described in 1963 by Barnes et al and supported by numerous subsequent articles, transurethral lithotripsy combined with transurethral resection of the prostate (TURP) or transurethral incision of the prostate (TUIP) can be accomplished easily and safely.[37, 38] Completing the stone ablation prior to these prostatic interventions is advisable, as hemorrhage and excess fluid absorption are potential complications when performed in the reverse order. In a 2009 study by Tugcu et al, 64 patients underwent TURP in addition to concomitant bladder calculi surgery. The participants were divided and treated with either (1) a percutaneous suprapubic approach with a 30F access sheath or (2) transurethral cystolitholapaxy with a 23F sheath and pneumatic lithotripter. The patients who underwent percutaneous stone removal had a statistically significantly larger stone burden, and the mean operative time of the percutaneous approach was nearly half that of the transurethral removal.[39] The third approach, open suprapubic cystotomy, is used to remove the stone or stones intact and can be used with larger and harder stones and when open prostatectomy and/or bladder diverticulectomy are indicated. Open prostatectomy is generally indicated when the prostate volume exceeds 80-100 g. The advantages of suprapubic cystolithotomy include rapidity, easy removal of several calculi at one time, removal of calculi that are adherent to bladder mucosa, and the ability to remove large stones that are too hard or dense to fragment expeditiously via transurethral or percutaneous techniques. The major disadvantages include postoperative pain, longer hospital stay, and longer bladder catheterization times.

Preoperative details :After diagnosis and treatment planning have been completed, the usual preoperative evaluation, including urine culture and sensitivity, CBC count, comprehensive metabolic panel (ie, serum chemistries), coagulation studies, chest radiography, and ECG, is completed. When a sterile urine culture is not attainable preoperatively, appropriate antibiotic therapy should be started a minimum of 24 hours in advance of the anticipated procedure. Anesthesia: Regional or general anesthesia can be used depending on the patient's comorbidities and the anesthesiologist's preference. Performance under local anesthesia (eg, urethral and intravesical lidocaine, tetracaine, dicyclomine) can be accomplished in certain patients harboring a low stone burden. The procedure requires pain tolerance similar to that for rigid cystoscopy with a 17F sheath.[40] Positioning: The preferred position is the dorsal lithotomy, although supine positioning also can work well if flexible cystoscopes and/or percutaneous access are used. Antibiotics: Appropriate oral or intravenous antibiotics are administered prior to the start of the operation based on the findings of the preoperative urine culture and sensitivity. When the urine culture is sterile, an oral fluoroquinolone generally provides adequate prophylaxis. Preparation: The lower abdomen and perineum are shaved, prepared using Betadine or another antiseptic solution, and draped in the usual sterile fashion. The irrigant of choice is isotonic sodium chloride solution, although sterile water or sorbitol can be substituted for short procedures. Significant absorption of a hypotonic solution may be a problem if bleeding is encountered.

Intraoperative details :The most commonly used contemporary treatment for bladder calculi is transurethral cystolitholapaxy. This can be performed using rigid or flexible cystoscopes; larger-caliber, rigid, continuous-flow scopes provide better visualization.

Procedural details :A cystoscope with a camera to provide video imaging is used to identify the stone under direct vision. If previous gross hematuria was noted, careful removal of all clots is necessary to ensure identification of all stone material. The bladder mucosa and bladder neck must also be fully assessed. Lithotripsy is performed, and the small remnant fragments are removed with one of several commercially available evacuators. Once inspection reveals no residual fragments in the bladder or any diverticula, attention can be paid to the bladder outlet or diverticula for further management of obstruction. For TUIP and TURP, the irrigant is changed to 3% sorbitol, and the operation is completed in the usual fashion. If percutaneous access to the bladder has been established, the access sheath or a large-bore catheter can be left in place to assist with continuous irrigation during TURP. If the bladder is not obstructed but a diverticulum needs to be addressed, sterile water or sorbitol can be used for diverticular fulguration and incision of the diverticular neck. While generally safe if performed expeditiously, reports have indicated that combined operations are associated with significantly increased complication rates (ie, 20%-30%). A catheter is generally left in place overnight if TURP or TUIP has been performed. Incision of a diverticular neck may require that a catheter be left for a few days to protect against urinary extravasation.

Lithotripsy instrumentation :Energy sources used to fragment the stone vary. A commonly used type of energy source is EHL. Other sources include the pulse-dye laser, the holmium laser, ultrasound, and the lithoclast (pneumatic jackhammer).[41] The EHL probe was first introduced in 1959; since then, it has been widely used with excellent results. The EHL probe (5F-9F) can be inserted through the working port of the cystoscope and advanced 1 cm beyond the lens. The probe must remain at least 1 cm away from the bladder mucosa to prevent injury and perforation of the bladder. The probe is then positioned 1-2 mm away from the stone, and fragmentation is initiated under direct vision to avoid bladder injury. Pinning the stone against the bladder wall may reduce the duration of the procedure, but take care not to involve the ureteral orifices. Fragmentation of the stone is initiated by cracking the outer layers until the stone is reduced to a size suitable for evacuation. A manual suction evacuator (eg, Microvasive, Ellik) is commonly used to remove the fragments, although grasping forceps can also be used. Frequent drainage of the bladder or low-pressure continuous irrigation during the procedure is important to prevent bladder rupture. The success rate of EHL is 92%-100% for stone sizes of 3-6 cm. Relative contraindications to EHL include smallcapacity bladder, possibly pregnancy, and the presence of a cardiac-pacing or defibrillation devices. The lithoclast and laser (holmium) lithotripters are used for calculi in all locations throughout the urinary tract, and they have largely supplanted the EHL unit when available. Ultrasonic lithotripsy is also commonly used for renal and bladder calculi.[8]

Special situations :Percutaneous lithotripsy has become the treatment of choice in the pediatric population because it prevents potential injury to the small-caliber urethra while providing an approach that is less invasive than open surgery, thus reducing pain and hospital stay. Access is obtained in a fashion similar to renal access. A rigid nephroscope, graspers, the ultrasonic lithotripter, and suction are used for rapid stone fragmentation and

evacuation. Contraindications include prior lower abdominal surgery, prior pelvic surgery, and small-capacity noncompliant bladders.[42, 43, 44] A report by Isen et al (2008) studied the use of a semirigid ureteroscope with holmium laser lithotripsy for bladder stones in 27 boys aged 3-14 years. At 2 weeks postsurgery, all patients were stone-free, and only two had required repeat intervention owing to obstruction by stone fragments. This treatment was recommended as an alternative approach to bladder stones in children with stones smaller than 2 cm.[45]

Postoperative details:The usual postoperative course includes a short duration of catheterization, until the effects of anesthesia abate. The antibiotic coverage is continued according to preoperative findings and discontinued after the appropriate length of treatment, usually 5-7 days for an active preoperative infection or until the drains and catheters are removed. Hospitalization is unnecessary unless secondary procedures have been performed or the open surgical approach was used. Anticoagulants should be avoided until any hematuria has resolved.

Follow-up :Typical follow-up is 3-4 weeks postoperatively with KUB or bladder ultrasonography to document clearing of all the fragments. Thereafter, metabolic evaluation may be pursued as indicated and periodic KUB at approximately 6- to 12-month intervals is warranted. A metabolic stone profile analysis is indicated in patients with uric acid stones, concurrent upper tract calculi, a strong family history of stone disease, calculi without obstruction, and recurrent calculi. Complications :Transurethral litholapaxy is, by far, the most common general modality used to treat bladder calculi and has been associated with relatively few minor complications. Common complications include urinary infection (11%), fever (9%), bladder perforation (2%), hyponatremia (2%), and hemorrhage (1%). Fever and urinary tract infection are clinical diagnoses marked by fever, dysuria, elevated WBC count, and positive findings on urinalysis and cultures. Treatment involves intravenous antibiotics and good bladder drainage. Gross hematuria is not uncommon and, when present, usually self-limiting. In severe cases, 3-way catheter irrigation and blood transfusions may be necessary. Bladder perforation is usually diagnosed intraoperatively when irrigating solution suddenly does not return during the procedure. Intraoperative cystography is used to confirm the diagnosis. Extraperitoneal perforation is managed with a Foley catheter, while intraperitoneal perforation usually requires retrieval of extravasated stone debris, open surgical repair of the bladder wall, and placement of a Foley catheter. The catheter is left for 5-7 days, and, prior to removal of the catheter, cystography may be performed to rule out leakage. Hyponatremia can be a consequence of cystolitholapaxy in combination with TURP. Low serum sodium levels with mental status changes and lethargy confirm the diagnosis. The treatment involves termination of the procedure and administration of intravenous furosemide, isotonic sodium chloride solution or other isoosmotic intravenous fluids postoperatively, and, occasionally, short-term use of 3% hypertonic sodium chloride solution if the patient is acutely symptomatic and not otherwise responding. Symptoms generally develop as the serum sodium level falls below 125 mg/dL.[46]

Future and Controversies:The incidence of bladder stones in children is slowly declining, even in endemic areas. This is mostly due to improved nutrition, better prenatal and postnatal care, and improved awareness of the problem in the

endemic areas. In the 21st century, the incidence of this disease in children will probably continue to decline and the disease will largely become a disease of adults. The aggressive treatment of lower urinary tract symptoms with alpha-blockers and 5-alpha-reductase inhibitors should further decrease the overall incidence of bladder stones because of improved bladder emptying. The removal of bladder stones will continue to progress toward minimally invasive techniques, thus decreasing hospital stay and recovery times. Continued advancement of surgical equipment and the ability to downsize, without the sacrifice of effectiveness, could eventually make open surgery for stones obsolete. Additionally, continued aggressive management of neurogenic bladder, specifically in the pediatric neurogenic bladder population, may lead to a rise in both the incidence of struvite stones as well as the development of creative and minimally invasive surgical techniques in augmented bladders.

Urolithiasis is the most common cause of nonobstetrical abdominal pain that requires hospitalization among pregnant patients.[1, 2] The relative incidence and rate of recurrent calculi in pregnant patients (1 per 1500 pregnant patients) is similar to that in nonpregnant patients.[3] Symptomatic stones are found in the ureter twice as often as in the renal pelvis and affect both ureters in equal frequency. Eighty to ninety percent are diagnosed after the first trimester.

Pregnancy and Urolithiasis:Urolithiasis in pregnancy is often a diagnostic and therapeutic challenge for multiple reasons. First, potential adverse effects of anesthesia, radiation, and surgery often complicate traditional diagnostic and treatment modalities. Second, many signs and symptoms of urolithiasis can be found in a normal pregnancy or may be associated with broad differential diagnoses of other sources of abdominal pathology. Appendicitis, diverticulitis, or placental abruption was mistakenly diagnosed in 28% of patients in a 1992 study by Stothers and Lee. Finally, most stones (64-84%) pass spontaneously with conservative treatment.[6, 7] However, if the calculus does not pass, it may initiate premature labor, produce intractable pain, cause urosepsis in the setting of urinary tract infection, or interfere with the progression of normal labor. Of the various imaging modalities currently available, renal ultrasonography has become the first-line screening test for urolithiasis in pregnant patients, while limited intravenous pyelography (IVP) or CT scanning is reserved for more complex cases. Ideally, no ionizing radiation should be used in the first or second trimesters, if at all possible. MRI has limited utility in urinary stone disease, and nuclear renography is reserved for functional studies to direct treatment. These are of limited value during pregnancy. Treatment of stones in pregnancy ranges from conservative management (eg, bed rest, hydration, analgesia) to more invasive measures (eg, stent placement, ureteroscopy with stone manipulation, percutaneous nephrostomy). With appropriate diagnosis and management, the outcome for both the mother and baby is excellent.

Prophylaxis:Prevention is the best cure for urolithiasis, and multiple investigators have suggested prophylactic measures to prevent the difficult course of treating urolithiasis in pregnancy. Denstedt and Razvi (1992) suggested prophylactic treatment of asymptomatic caliceal stones in women of childbearing age who are planning pregnancies.[8] Biyani and Joyce (2002) recommended metabolic evaluation in known stone formers, as well as prophylactic treatment of asymptomatic stones prior to pregnancy.[4] In support of their recommendation,

they sited Glowacki et al (1992), whose study monitored 107 asymptomatic patients with renal calculi over 31.6 months. They found that 31.8% became symptomatic over that period.[9] Women with cystinuria who desire pregnancy should seek genetic counseling, and management of their disease should begin prior to pregnancy.[10]

Pathophysiology:Although pregnancy-induced urinary stasis and hypercalcemia of pregnancy have been proposed as likely etiologic factors in urolithiasis, this has been disputed. Pregnancy-related events that tend to enhance stone formation include decreased ureteral peristalsis, physiological hydronephrosis, infection, and increased urinary calcium excretion. Augmented excretion of urolithiasis inhibitors, such as citrate, magnesium, and glycosaminoglycans, neutralize these phenomena in pregnant patients, who are no more likely to form urinary calculi than nonpregnant patients.[8] Coincident to the increased hypercalciuria in pregnancy is an increase in total circulating blood volume, making the relative supersaturation of calcium insignificant.

Anatomic and physiologic changes during pregnancy :Hydroureteronephrosis is the most significant renal alteration during pregnancy. Physiologic dilatation of the collecting system begins in the first trimester at 6-10 weeks' gestation and persists until 4-6 weeks following delivery.[5] Early theories suggest that hydronephrosis of pregnancy may be a hormonally induced phenomenon whereby ureteral smooth muscles relax in response to high levels of circulating progesterone. In early pregnancy, increased progesterone secretion dilates the ureters and reduces ureteral peristalsis, causing hydronephrosis. Alternatively, the predominant theory ascribes ureteric dilatation to compression of the ureter by the enlarging gravid uterus at the level of the pelvic brim, where the ureter crosses the iliac vessels. Dilatation is greater on the right side than on the left because of pressure due to physiologic engorgement of the right ovarian vein and dextrorotation of the uterus.[4] Swanson and associates (1995) observed that hydroureteronephrosis was not routinely found below the pelvic brim and was altogether absent in patients who had undergone urinary diversion.[5]

Volume changes during pregnancy :Glomerular filtration rate (GFR) and renal plasma flow (RPF) increase by as much as 25-50% during pregnancy. Both of these changes are attributable to increases in cardiac output, decreases in renal vascular resistance, and increases in serum levels of progesterone, aldosterone, deoxycorticosterone, placental lactogen, and chorionic gonadotropin. GFR and RPF enhancements also contribute to the increase in glucose, amino acid, protein, and vitamin secretion. As a result of the GFR and RPF modulations, which peak at 9-11 weeks' gestation, renal volume increases during pregnancy by as much as 30% above the reference range. The sustained elevation of prolactin levels in the pregnant patient has a growth hormonetype effect by increasing the glomerular surface area, which also contributes to an increase in renal volume. Along with increases in GFR and RPF, the filtered load of sodium, calcium, and urate increases. Although calcium and urate excretion increases, sodium excretion remains unchanged. The urinary excretion rate of calcium stone inhibitors, such as citrate and magnesium, also increases in the pregnant patient; likewise, increased glycosaminoglycans and acidic glycoproteins inhibit oxalate stone formation (eg, nephrocalcin). This explains why pregnancy is not associated with a net increase in the rate of stone formation relative to nonpregnant patients. The net effect of these physiologic changes is a stable relative supersaturation of important ions such as calcium oxalate, urate, and phosphate.

Uric acid stone formation :The formation of uric acid stones requires continued and excessive oversaturation of urine with uric acid or extreme aciduria. Dehydration, hyperuricosuria, and significantly acidic urine contribute to uric acid supersaturation and stone formation. However, during gestation, urine tends to be more alkaline, probably because of greater intrinsic purine use and increased urinary citrate excretion. Thus, renal units are generally protected against uric acid stone formation during pregnancy.

Calcium oxalate and calcium phosphate stone formation :Although pathologic calcium oxalate supersaturation has been identified in the urine of pregnant women, the incidence of crystalluria is no higher than in women who are not pregnant. In the pregnant patient, physiologic absorptive hypercalciuria is due to elevated levels of serum 1,25 dihydroxycholecalciferol (1,25 vitamin D). This hormone, which is secreted by the placenta, augments calcium absorption in the GI tract and suppresses parathormone production, increasing renal excretion of calcium. Additionally, dietary supplementation of calcium during gestation further augments calcium excretion. Some reports suggest that calcium excretion increases 200-300% compared with that in healthy patients who are not pregnant. However, increased concentration of the aforementioned urolithiasis inhibitors present in urine during gestation and increased urine fluid output counters the increased risk imposed by any hypercalciuria.

Struvite stones :Struvite stones form only when the urinary tract is infected with urea-splitting organisms (eg, Proteus species). These infected stones are usually composed of pure magnesium ammonium phosphate but may be formed around a coexisting calcium, uric acid, or cystine stone. Struvite stones appear to develop more commonly in the presence of a congenital abnormality of the collecting system.

Epidemiology:Frequency :United States :The reported incidence of urinary calculi in pregnant women is around 1 per 1500 pregnant women, which is similar to that in nonpregnant patients.[3] Approximately 80-90% of pregnant patients with urinary calculi present with symptoms during the second or third trimester because spontaneous stone passage is more difficult at this stage of pregnancy. Ureteral stones occur twice as often as kidney stones in pregnant patients. Approximately 64-84% of renal calculi pass spontaneously with conservative management,[6, 7] especially if they 4 mm or smaller. Stones that are 7 mm or larger are much less likely to pass without intervention and often require some type of treatment.

Mortality/Morbidity :Urolithiasis associated with ureteral obstruction and upper urinary tract infection mandates immediate treatment; this is a true urologic emergency that can potentially lead to urosepsis, perinephric abscess

formation, or even death in pregnant women. Urolithiasis in a pregnant patient may initiate premature labor or interfere with the progression of normal labor, which poses a significant health risk to the fetus.

Race :Hispanic people and white people are most commonly predisposed to urinary calculi. Black people are less predisposed to kidney stone formation. The exact cause of this discrepancy is not known, but dietary influences may play a role. Calculi in black individuals are more likely to become infected than those in white individuals.

Sex :The reported incidence of urolithiasis is higher in men, with a male-to-female ratio of 3:1, although this ratio is decreasing, possibly because of dietary or obesity trends in the United States.

Age :Urinary stones in women usually manifest during the third to fifth decades of life, with an average age of 24.6 years. Urolithiasis occurs in pregnant women at rates similar to age-matched nonpregnant women.[5]

Urethral Strictures in Males :Urethral strictures arise from various causes and can result in a range of manifestations, from an asymptomatic presentation to severe discomfort secondary to urinary retention. Establishing effective drainage of the urinary bladder can be challenging, and a thorough understanding of urethral anatomy and urologic technology is essential. Consultation with a urologist should be obtained for any patient presenting to the emergency department with urinary retention secondary to urethral stricture disease.

Urethral strictures. Cross-sectional diagram of the penis.

Urethral strictures. Schematic of penile anatomy.

History of the Procedure:Urethral stricture disease has been cited as long ago as ancient Greek writings that reported establishing bladder drainage with the passage of various catheters. Historically, the treatment consisted of urethral dilation with sounds. Hamilton Russell described the first surgical procedure for repair of a urethral stricture in 1914. In contemporary times, several surgical options are available.

Problem:Urethral strictures can result from inflammatory, ischemic, or traumatic processes. These processes lead to scar tissue formation; scar tissue contracts and reduces the caliber of the urethral lumen, causing resistance to the antegrade flow of urine. The term urethral stricture generally refers to the anterior urethra and is secondary to scarring in the spongy erectile tissue of the corpus spongiosum. A posterior urethral stricture is due to a fibrotic process that narrows the bladder neck and usually results from a distraction injury secondary to trauma or surgery, such as radical prostatectomy. The focus of this article is anterior urethral stricture disease.

Etiology:The most common causes of urethral stricture today are traumatic or iatrogenic. Less-common causes include inflammatory or infectious, malignant, and congenital. Infectious urethral strictures are secondary typically to gonococcal urethritis, which remains common in certain high-risk populations.

Pathophysiology:Urethral strictures occur after an injury to the urothelium or corpus spongiosum causes scar tissue to form. A congenital stricture results from inadequate fusion of the anterior and posterior urethra, is short in length, and is not associated with an inflammatory process. This is an extremely rare cause.

Presentation:The most common presentation includes obstructive voiding symptoms, urinary retention, or urinary tract infections. Obstructive voiding symptoms are characterized by a decreased force of stream, incomplete

emptying of the bladder, urinary terminal dribbling, and urinary intermittency. These symptoms are progressive in many patients.

Indications:Surgical treatment of urethral stricture disease is indicated when the patient has severe voiding symptoms, bladder calculi, increased postvoid residual, or urinary tract infection or when conservative management fails.

Relevant Anatomy:The urethra is divided into anterior and posterior segments. The anterior urethra (from distal to proximal) includes the meatus, fossa navicularis, penile or pendulous urethra, and bulbar urethra. The posterior urethra (from distal to proximal) includes the membranous urethra and the prostatic urethra. The urethra lies within the corpus spongiosum, beginning at the level of the bulbous urethra and extending distally through the length of the penile urethra. The bulbar urethra begins at the root of the penis and ends at the urogenital diaphragm. The penile urethra has a more central position within the corpus spongiosum in contrast to the bulbous urethra, which is more dorsally positioned. The membranous urethra involves the segment extending from the urogenital diaphragm to the verumontanum. The prostatic urethra extends proximally from the verumontanum to the bladder neck. The soft-tissue layers of the penis, from external to internal, include the skin, superficial (dartos) fascia, deep (Buck) fascia, and the tunica albuginea surrounding the corpora cavernosa and corpus spongiosum. The superficial vascular supply to the penis comes from the external pudendal vessels, which arise from the femoral vessels. The external pudendal vessels give rise to the superficial dorsal penile vessels that run dorsolaterally and ventrolaterally along the penile shaft, providing a rich vascular supply to the dartos fascia and skin. The deep penile structures receive their arterial supply from the common penile artery, which arises from the internal pudendal artery. The common penile artery gives off several branches, including the bulbourethral, cavernosal, and deep dorsal penile arteries. The corpus spongiosum receives a dual blood supply via anastomoses between dorsal and urethral artery branches in the glans. The scrotum receives its vascular supply via branches from both the external and internal pudendal arteries.

Urethral strictures. Cross-sectional diagram of the penis.

Urethral strictures. Schematic of penile anatomy.

Contraindications:Urinary tract infections should be adequately treated prior to treatment. Malignancy should be ruled out with an endoscopic biopsy.

Treatment of CIS Versus TCC:Treatment of carcinoma in situ (CIS) differs from that of papillary transitional cell carcinoma (TCC). Endoscopic surgery, which is the initial treatment of papillary cancers, is not effective for CIS because the disease is often so diffuse and difficult to visualize that surgical removal is not feasible. When a combination of papillary tumor and CIS is present, the papillary tumor is removed before treatment of the CIS is initiated.

Bacillus Calmette-Gurin:Bacillus Calmette-Gurin (BCG) is the most common intravesical agent used to treat carcinoma in situ (CIS). Approximately 70% of patients have an initial response to BCG vaccine. Rates of tumor progression vary according to the particular study, but more than 75% of patients who initially have a complete response remain disease free for more than 5 years. This is equivalent to 45-50% of those who initially respond. At 10 years, approximately 30% of patients with CIS who are treated with BCG are disease free. A failure to respond to BCG vaccine may be defined as persistent or recurrent tumor when a BCG vaccine reaction is evident. If this occurs within the course of a year, an alternative strategy is to combine BCG with interferon-alfa (IFN-alfa). In this situation, 50 million units of IFN-alfa can be instilled into the bladder, with the BCG vaccine administered 1 hour later. The IFN-alfa up-regulates the major histocompatibility complex/BCG vaccine antigen complex, which enhances the immunologic response. With this combination, doses of BCG vaccine as small as one tenth of a vial have been shown to be effective. IFN-alfa is well tolerated, and the lower doses of BCG vaccine are usually associated with decreased adverse effects.

Chemotherapeutic Agents:Chemotherapeutic agents that can be administered intravesically to treat carcinoma in situ (CIS) include the following:

Mitomycin-C Gemcitabine Doxorubicin Valrubicin Thiotepa Cisplatin

No evidence suggests that these adjuvant therapies are as effective as bacillus Calmette-Gurin (BCG). These agents may increase the time to disease recurrence, but no evidence indicates that they prevent disease progression.

Mitomycin-C:Mitomycin-C is the most commonly used chemotherapeutic agent. It is used in both the perioperative and the treatment periods. Immediately following a transurethral resection of a papillary tumor, mitomycin-C, 40 mg in 20 mL of saline, is instilled into the bladder and held there for an hour. In the treatment phase, the same dosing is used, but the patient's urine should be alkalinized for maximum effect. The treatments are administered weekly for at least 6 weeks before a maintenance program is started, consisting of monthly instillations for one year. Mitomycin-C is usually well tolerated, but excess use can cause symptoms of cystitis; if this occurs, the instillation frequency should be reduced. A bladder retention time of 2 hours is usually advised, although this practice has never been thoroughly studied. With the use of this protocol, a recurrence-free incidence rate of 41% has been reported. These data demonstrate that although intravesical chemotherapy does not match the results obtained with BCG vaccine, this is an effective agent, and its benefits can be maximized by following these recommendations.

Gemcitabine :Gemcitabine is the most recent addition to the list of effective intravesical agents. This chemotherapy drug is administered according to the same protocol as BCG (ie, 6 weekly treatments followed by maintenance for 1 y). This agent has caused very few side effects. Gemcitabine is a prodrug that requires activation by intracellular phosphorylation. It has shown selective killing in human transitional cell carcinoma (TCC) cell lines and does not affect normal fibroblast cell lines. Serial administration of weekly doses of 1500-2000 mg in 50 mL of saline has shown complete responses in 50% of patients with CIS.

Doxorubicin :Doxorubicin (Adriamycin) is a chemotherapy agent that can be effective, although comparison studies indicate that it is not as effective as mitomycin-C or BCG. It is administered in a dose of 50 mg in 50 mL of saline.

Valrubicin :Valrubicin has been approved as intravesical chemotherapy for CIS that is refractory to BCG. In patients whose conditions do not respond to BCG, the overall response rate to valrubicin is approximately 20%. In some patients, valrubicin chemotherapy can delay time to cystectomy. Valrubicin is currently not commercially available.

Thiotepa and cisplatin :Thiotepa was the original chemotherapeutic agent used for bladder cancer. It is now rarely used because of its limited efficacy. Cisplatin also provides limited benefit and is rarely used to treat CIS.

Mycobacterial Cell Wall-DNA Complex:Morales et al treated 55 patients with 6 weekly instillations of either 4 mg or 8 mg of mycobacterial cell wallDNA complex following endoscopic tumor resection, and the complete response rate for the 4-mg group at 12 and 18 months was 38%, while the 8-mg group had response rates of 38% and 62% at 12 and 18 months, respectively. Morales et al have been studying the effects of intravesical mycobacterial cell wallDNA complex as an alternative to standard BCG and as therapy following failure of BCG instillations. The 25 patients in the 4-mg group had received prior therapy and had tumor recurrence.[1]

Additional Therapies:Photodynamic therapy has been shown to be effective, but it has limited usefulness because of adverse effects. This treatment involves the intravenous injection of a porphyrin derivative followed 24 hours later with exposure of the bladder surface to laser light. The laser is introduced through a cystoscope; its light activates the cytotoxic agent, which has preferentially concentrated within the cancer cells. The major adverse effect is severe photosensitivity, which can last for several months. Colombo et al have reported beneficial results using a combination of intravesical mitomycin-C and local microwave-induced hyperthermia. They compared a group of these patients with patients receiving only mitomycin-C and found a significant improvement in survival in the patients receiving combined therapy.[2] Consider patients with recurrent carcinoma in situ (CIS) for an early cystectomy. Recurrent CIS, despite intravesical bacillus Calmette-Gurin (BCG), is associated with a 63% risk of progression to muscle-invasive bladder cancer. Recurrence after BCG treatment may also occur in the upper urinary tract or prostatic urethra. Excellent long-term survival outcomes have been reported in patients with CIS who receive radical cystectomy

Emergency Medicine Treatment & Management :-

Emergency Department Care: Patients presenting with balanitis but without phimosis should receive the following recommendations and treatment: o Gentle retraction of the foreskin daily and soak in warm water to clean penis and foreskin. o In pediatric patients and patients with mild balanitis xerotica, a 2-month trial of antifungals may be attempted; the patient or mother should retract the foreskin gently and apply 0.05% betamethasone twice a day. This applies to children older than 3 years. Success is seen particularly in male children older than 10 years compared with those aged 3-10 years. Success ranges from 65-95%. o Topical steroids have had only limited success in patients with moderate-to-severe balanitis xerotica obliterans. These patients are more likely to have distal scarring of the foreskin. o In recurrent cases, 1% pimecrolimus cream was used instead of steroids, with a 64% success rate.

Apply bacitracin (not Neosporin) for pediatric patients if bacterial infection is suspected. Apply topical clotrimazole for adult men with probable candidal balanitis. Obtain a culture of discharge in complicated cases such as those with associated cellulitis, then treat empirically with appropriate antibiotics (typically first-generation cephalosporin). o A study of 1185 boys concluded that fluticasone proprionate 0.05% was effective and safe in treating associated phimosis, with successful results in 91.1% of patients.[3] Patients presenting to the ED with phimosis and severe urinary obstruction as a complication of balanitis should receive the following care (recommended that surgical intervention be performed by a urologist, if available): o Steroid cream and gentle retraction of the foreskin, if the phimosis is not too tight, may be used before surgery is contemplated.[4, 5] o Without damaging the glans penis, dilate the foreskin using a clamp. If the glans penis is adherent to the foreskin, the procedure may be contraindicated. Local anesthesia, analgesia, and/or sedation may be required. o Perform a dorsal slit incision by cutting the foreskin over the dorsal shaft of the penis to enlarge the foreskin opening. This procedure requires local anesthesia and, possibly, sedation. o Perform a formal circumcision (preferably in the operating room).[6, 7] o Circumcision is not a preventative treatment of balanitis in those younger than 3 years old. o o o

Consultations: Consult a urologist if a dorsal slit incision or circumcision is contemplated.

Medication Summary The goal of balanitis therapy is to eradicate infection and prevent complications.

Antimicrobial agents (topical):Class Summary :Therapy must cover all likely pathogens in the context of the clinical setting.

Clotrimazole topical (Mycelex, Lotrimin) : Adult Dosing & Uses:Dosing Forms & Strengths :cream/topical solution/lotion/powder 1%

Other Indications & Uses :Apply to affected area BID

OTC products indicated for treatment of tinea pedis, tinea cruris, tinea corporus Prescription products indicated for Candida albicans, tinea versicolor, in addition to over-the-counter product indications See also combo with betamethasone (Lotriderm/Lotrisone)

Pediatric Dosing & Uses:Dosing Forms & Strengths :cream/topical solution/lotion/powder 1%

Other Indications & Uses :Apply to affected area BID

Adverse Effects:Frequency Not Defined :Blistering Erythema Edema Pruritus Burning Stinging Peeling Urticaria Skin fissures General irritation of the skin Elevated serum AST (SGOT) concentrations (15%)

Contraindications & Cautions:-

Contraindications :Hypersensitivity to clotrimazole

Cautions :Pregnancy category B during 2nd & 3rd trimester; safety in 1st trimester not established

Pregnancy & Lactation:Pregnancy Category:Lactation: excretion in milk unknown; use with caution A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA:Information not available.

Pharmacology:Absorption: minimal

Mechanism of Action :Antifungal activity

Alters cell membrane permeability, apparently by binding with phospholipids in the fungal cell membrane

Pricing & Images:BRAND FORM. UNIT PRICE PILL IMAGE

clotrimazole - TARGET CORP

1 % Cream

No Pricing Available

clotrimazole - PERRIGO CO.

1% Cream

clotrimazole - CVS

1 % Cream

$0.40

clotrimazole - TARO PHARM USA

1 % Cream

$1.66

BRAND

FORM.

UNIT PRICE

PILL IMAGE

clotrimazole - GLENMARK PHARMA

1 % Cream

$1.66

clotrimazole - TARO PHARM USA

1 % Cream

$0.22

Lotrimin AF - S-P HEALTHCARE

1 % Cream

No Pricing Available

BRAND

FORM.

UNIT PRICE

PILL IMAGE

Gyne-Lotrimin - SOUTHWOOD PHARM

1 % Cream

$0.66

Cruex Prescription Strength - NOVARTIS CONSUM

1 % Cream

$0.43

Clotrimazole Foot - MAJOR PHARMACEU

1 % Cream

$0.37

BRAND

FORM.

UNIT PRICE

PILL IMAGE

Jock Itch - WALGREEN CO.

1 % Cream

$0.75

clotrimazole - TEVA USA

1 % Solution

$0.93

Fungi Cure - ALVA-AMCO PHARM

1 % Spray, NonAerosol

No Pricing Available

BRAND

FORM.

UNIT PRICE

PILL IMAGE

clotrimazole - ROXANE LABS.

10 mg Troche

$2.01

clotrimazole - PADDOCK LABS.

10 mg Troche

$2.01

clotrimazole - PHYSICIANS TC.

10 mg Troche

$4.91

BRAND

FORM.

UNIT PRICE

PILL IMAGE

3-Day Vaginal - CVS

2 % Cream

$0.53

Clotrimazole-3 - WALGREEN CO.

2 % Cream

$0.59

Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability. For adult use, especially those with a positive history of candidiasis in a sexual partner. Bacitracin (AK-Tracin) :-

Adult Dosing & Uses :Dosing Forms & Strengths :ointment 500unit/g

Topical Infection :Apply ointment qDay-TID with polymyxin B

with polymyxin B/neomycin

Other Indications & Uses :Prevention or treatment of superficial skin infections caused by susceptible organisms Spectrum: Gram-positive organisms

Pharmacology:Mechanism of Action :Inhib bacterial cell wall synthesis, by preventing the incorporation of amino acids and nucleotides into the cell wall Absorption :Not substantially absorbed from intact or denuded skin, wounds, or mucous membranes

bacitracin - PHARMACIA/UPJHN

50,000 unit Recon Soln No Pricing Available - PFIZER US PHARM

bacitracin

50,000 unit Recon Soln No Pricing Available

bacitracin - SAGENT PHARMACE

50,000 unit Recon Soln No Pricing Available - APP PHARMACEUTI

bacitracin

50,000 unit Recon Soln No Pricing Available - FERA PHARMACEUT

bacitracin

500 unit/g Ointment No Pricing Available

Prevents transfer of mucopeptides into growing cell wall, which inhibits cell wall synthesis and bacterial growth. More commonly used in pediatric patients or patients who are not sexually active.

Corticosteroids, topical:Class Summary :These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. Betamethasone 0.05% (Alphatrex, Diprolene, Maxivate)

Adult Dosing & Uses:Dosing Forms & Strengths :ointment 500unit/g

Topical Infection :Apply ointment qDay-TID Other Indications & Uses :Prevention or treatment of superficial skin infections caused by susceptible organisms Spectrum: Gram-positive organisms

Pharmacology:Mechanism of Action :Inhib bacterial cell wall synthesis, by preventing the incorporation of amino acids and nucleotides into the cell wall Absorption :Not substantially absorbed from intact or denuded skin, wounds, or mucous membranes bacitracin - CVS

500 unit/g Ointment $0.18

bacitracin - WALGREEN CO.

500 unit/g Ointment $0.24

bacitracin - QUALITEST

500 unit/g Ointment $0.26

For treatment of inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.

Immunosuppressant agents:Class Summary :Regulates key factors responsible for the immune response. Pimecrolimus (Elidel cream)

Dosing Forms & Strengths :cream 1%

Atopic Dermatitis : Apply thin layer to affected area BID

Pediatric Dosing & Uses:-

Dosing Forms & Strengths :cream 1%

Atopic Dermatitis :<2 years old: Safety & efficacy not established >2 years old: Apply thin layer to affected area BID

Adverse Effects:>10% : Burning Headache Irritation Pruritus Erythema Frequency Not Defined : Skin infections Rash Application site pain Paraesthesia Desquamation Dryness Fever <1% : Basal cell carcinoma of skin Malignant melanoma Squamous cell carcinoma

Malignant lymphoma Septic arthritis

Pharmacology:Absorption: minimal systemic; no accumulation w/ prolonged use Mechanism of Action : Calcineurin inhibitor; inhibits T-cell activation; also shown to inhibit release of inflammatory mediators from mast cells

Pricing & Images:BRAND FORM. UNIT PRICE PILL IMAGE

Elidel - VALEANT

1 % CreamNo Pricing Available

Elidel 1 % Cream$3.80 - DISPENSEXPRESS,

BRAND

FORM.

UNIT PRICE

PILL IMAGE

Elidel - PHYSICIANS TC.

1 % Cream$7.70

First nonsteroid cream approved in the US for mild-to-moderate atopic dermatitis. Derived from azcomycin, a natural substance produced by fungus Streptomyces hygroscopics var. ascomycetous. Selectively inhibits production and release of inflammatory cytokines from activated T-cells by binding to cytosolic immunophilin receptor macrophilin-12. The resulting complex inhibits phosphatase calcineurin, thus blocking T-cell activation and cytokine release. Cutaneous atrophy was not observed in clinical trials, a potential advantage over topical corticosteroids. Indicated only after other treatment options have failed.

References:1. Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A. Renal cystic diseases: a review. Adv Anat
Pathol. Jan 2006;13(1):26-56. [Medline].

2. Kalyoussef E, Hwang J, Prasad V, Barone J. Segmental multicystic dysplastic kidney in children.

Urology. Nov 2006;68(5):1121.e9-11. [Medline].

3. Guay-Woodford LM. Renal cystic diseases: diverse phenotypes converge on the cilium/centrosome 4. 5. 6. 7.
complex. Pediatr Nephrol. Oct 2006;21(10):1369-76. [Medline]. Thomsen HS, Levine E, Meilstrup JW, Van Slyke MA, Edgar KA, Barth JC, et al. Renal cystic diseases. Eur Radiol. 1997;7(8):1267-75. [Medline]. Choyke PL. Acquired cystic kidney disease. Eur Radiol. 2000;10(11):1716-21. [Medline]. Avner ED, Sweeney WE. Renal cystic disease: new insights for the clinician. Pediatr Clin North Am. Oct 2006;53(5):889-909, ix. [Medline]. Gunay-Aygun M, Avner ED, Bacallao RL, Choyke PL, Flynn JT, Germino GG, et al. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a first National Institutes of Health/Office of Rare Diseases conference. J Pediatr. Aug 2006;149(2):159-64. [Medline]. Saunier S, Salomon R, Antignac C. Nephronophthisis. Curr Opin Genet Dev. Jun 2005;15(3):324-31. [Medline]. Siqueira Rabelo EA, Oliveira EA, Silva JM, Oliveira DS, Colosimo EA. Ultrasound progression of prenatally detected multicystic dysplastic kidney. Urology. Nov 2006;68(5):1098-102. [Medline]. Welch TR, Wacksman J. The changing approach to multicystic dysplastic kidney in children. J Pediatr. Jun 2005;146(6):723-5. [Medline]. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF, et al. Volume progression in polycystic kidney disease. N Engl J Med. May 18 2006;354(20):2122-30. [Medline]. Wilson PD. Polycystic kidney disease. N Engl J Med. Jan 8 2004;350(2):151-64. [Medline]. Gusmano R, Caridi G, Marini M, Perfumo F, Ghiggeri GM, Piaggio G, et al. Glomerulocystic kidney disease in a family. Nephrol Dial Transplant. May 2002;17(5):813-8. [Medline].

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14. Onal B, Kogan BA. Natural history of patients with multicystic dysplastic kidney-what followup is 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.
needed?. J Urol. Oct 2006;176(4 Pt 1):1607-11. [Medline]. Mostov KE. mTOR is out of control in polycystic kidney disease. Proc Natl Acad Sci U S A. Apr 4 2006;103(14):5247-8. [Medline]. Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. PNAS. Apr 4 2006;103:5466-5471. [Medline]. Torres, Vicente, Harris, Peter, Yves, Pirson. Autosomal dominant polycystic kidney disease. The Lancet. April 14, 2007;369:1287-1301. Mercado-Deane MG, Beeson JE, John SD. US of renal insufficiency in neonates. Radiographics. Nov-Dec 2002;22(6):1429-38. [Medline]. Borges Oliva MR, Hsing J, Rybicki FJ, Fennessy F, Mortele KJ, Ros PR. Glomerulocystic kidney disease: MRI findings. Abdominal Imaging. Nov 2003;28:889-892. [Medline]. Bosniak MA. The use of the Bosniak classification system for renal cysts and cystic tumors. J Urol. May 1997;157(5):1852-3. [Medline]. Song C., et al. Differential Diagnosis of Complex Cystic Renal Mass Using Multiphase Computerized Tomography. Journal of Urology. 2009/06;181:2446-2450. Garcia-Rojo, D. Comparison of Contrast-Enhanced Ultrasound (CE-US) and Computed Tomography (CT) in the Evaluation of Complex Cystic Renal Masses. Journal of Urology. May 31, 2010;183:e243. Li, G.,, et al. CA9 molecular marker for differential diagnosis of cystic renal tumors. Urologic Oncology. Sept. 3, 2010. Torres VE, Harris PC. Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol. Jan 2006;2(1):40-55; quiz 55. [Medline]. Zerem, E. Simple renal cysts and arterial hypertension: does their evacuation decrease the blood pressure?. Journal of Hypertension. Oct. 27, 2009;10:2074-2078. Sweeney WE, Chen Y, Nakanishi K, Frost P, Avner ED. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int. Jan 2000;57(1):33-40. [Medline]. Aperis G. Tolvaptan: A new therapeutic agent. Review Recent Clinical Trials. Sept. 22, 2010. Serra A., et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. New England Journal of Medicine. Aug. 26, 2010;9:820-829. Rane, A. Laparoscopic management of symptomatic simple renal cysts. International Urology Nephrology. 2004;36:5-9. Emre, H. "Stepped procedure" in laparoscopic cyst decortications during the learning period of laparoscopic surgery: Detailed evaluation of initial experiences. Journal of Minimal Access Surgery. Apr 6, 2010;2:37-41. Kilciler, M. Finger assisted laparoscopic renal cyst excision: a simple technique. Urology Journal. Jun 10, 2010;7:90-94. Busato, W. Percutaneous endocystolysis, a safe and minimally invasive treatment for renal cysts: a 13-year experience. Journal of Endourology. Sept. 2010;24:1405-1410. Lucas, S. Staged Nephrectomy Versus Bilateral Laparoscopic Nephrectomy in Patients with Autosomal Dominant Polycycstic Kidney Disease. Journal of Urology. Nov. 2010;184:2054-2059. Webster, W. Surgical Resection Provides Excellent Outcomes for Patients with Cystic Clear Cell Renal Cell Carcinoma. Urology. May 2007;900-904. Bloom DA, Brosman S. The multicystic kidney. J Urol. Aug 1978;120(2):211-5. [Medline]. Bonsib SM. Non-neoplastic diseases of the kidney. In: Bostwick DG. Urologic Surgical Pathology. St Louis, Mo: Mosby-Year Book; 1997. Bosniak MA. How does one deal with a renal cyst that appears to be Bosniak class II on a CT scan but that has sonographic features suggestive of malignancy (e.g., nodularity of wall or a nodular, irregular septum)?. AJR Am J Roentgenol. Jul 1994;163(1):216. [Medline]. Bosniak MA. The current radiological approach to renal cysts. Radiology. Jan 1986;158(1):1-10. [Medline].

39. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, et al. Deletion of the 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.
TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. Nat Genet. Dec 1994;8(4):328-32. [Medline]. Chauveau D, Duvic C, Chretien Y, Paraf F, Droz D, Melki P, et al. Renal involvement in von HippelLindau disease. Kidney Int. Sep 1996;50(3):944-51. [Medline]. Clarke A, Hancock E, Kingswood C, Osborne JP. End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant. Apr 1999;14(4):988-91. [Medline]. Davidson AJ, Hartman DS, Choyke PL, Wagner BJ. Radiologic assessment of renal masses: implications for patient care. Radiology. Feb 1997;202(2):297-305. [Medline]. Fick GM, Johnson AM, Hammond WS, Gabow PA. Causes of death in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. Jun 1995;5(12):2048-56. [Medline]. Freire M, Remer EM. Clinical and radiologic features of cystic renal masses. AJR Am J Roentgenol. May 2009;192(5):1367-72. [Medline]. Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med. Oct 2 2008;359(14):1477-85. [Medline]. Grantham JJ, Nair V, Winklhofer F. Cystic disease of the kidney. In: Brenner BM, ed. Brenner and Rector's the Kidney. 6th ed. Philadelphia, Pa: WB Saunders Co; 2000:1171-1200. Israel GM, Bosniak MA. Follow-up CT of moderately complex cystic lesions of the kidney (Bosniak category IIF). AJR Am J Roentgenol. Sep 2003;181(3):627-33. [Medline]. Israel GM, Hindman N, Bosniak MA. Evaluation of cystic renal masses: comparison of CT and MR imaging by using the Bosniak classification system. Radiology. May 2004;231(2):365-71. [Medline]. Lang EK, Macchia RJ, Gayle B, Richter F, Watson RA, Thomas R. CT-guided biopsy of indeterminate renal cystic masses (Bosniak 3 and 2F): accuracy and impact on clinical management. Eur Radiol. Oct 2002;12(10):2518-24. [Medline]. Laube M, Hess B, Terrier F, Vock P, Jaeger P. [Prevalence of medullary sponge kidney in patients with and without nephrolithiasis]. Schweiz Rundsch Med Prax. Oct 24 1995;84(43):1224-30. [Medline]. Levine E, Slusher SL, Grantham JJ, Wetzel LH. Natural history of acquired renal cystic disease in dialysis patients: a prospective longitudinal CT study. AJR Am J Roentgenol. Mar 1991;156(3):501-6. [Medline]. Lonergan GJ, Rice RR, Suarez ES. Autosomal recessive polycystic kidney disease: radiologicpathologic correlation. Radiographics. May-Jun 2000;20(3):837-55. [Medline]. Matson MA, Cohen EP. Acquired cystic kidney disease: occurrence, prevalence, and renal cancers. Medicine (Baltimore). Jul 1990;69(4):217-26. [Medline]. Miller MA, Brown JJ. Renal cysts and cystic neoplasms. Magn Reson Imaging Clin N Am. Feb 1997;5(1):49-66. [Medline]. Ohlson L. Normal collecting ducts: visualization at urography. Radiology. Jan 1989;170(1 Pt 1):33-7. [Medline]. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. Apr 2 1994;343(8901):824-7. [Medline]. Siegel CL, McFarland EG, Brink JA, Fisher AJ, Humphrey P, Heiken JP. CT of cystic renal masses: analysis of diagnostic performance and interobserver variation. AJR Am J Roentgenol. Sep 1997;169(3):813-8. [Medline]. Silverman SG, Israel GM, Herts BR, Richie JP. Management of the incidental renal mass. Radiology. Oct 2008;249(1):16-31. [Medline]. Wolf JS Jr. Evaluation and management of solid and cystic renal masses. J Urol. Apr 1998;159(4):1120-33. [Medline]. Yent ER. Medullary sponge kidney. In: Schrier RE, Gottschalk CW. Disease of the Kidney. 5th ed. Little Brown: Boston, Mass; 1993:525-32.