Urinary System: Cytology, Histology, Cystoscopy, and Radiology

Preface

Cells from the urinary tract have been evaluated using light microscopy for well over 100 years. Currently, the diagnosis of urinary tract lesions is made using cystoscopy and cytology/histology. In spite of extensive use in clinical practice, cytology and biopsy of the urinary tract continue to have limitations with intraobserver/interobserver reproducibility, as does cystoscopy. All three methods—cytology, histology, and cystoscopy—are important in making a timely and accurate diagnosis. For pathologists, this difficulty is compounded by a myriad of diagnostic entities and the ever-changing field of molecular diagnostics and terminology. Rather than attempting to be encyclopedic, we decided to focus this book, Urinary Systems: Cytology, Histology, Cystoscopy, and Radiology, on urinary cytology, bladder biopsy interpretation, and biopsy diagnosis of renal mass lesions. In addition, a major feature of this atlas-style book, differentiating it from other genitourinary pathology resources, is the incorporation of cystourethroscopic/ureterorendoscopic features of urologic lesions contributed by urologists along with radiologic features of renal mass lesions and ancillary tests for the detection of urothelial carcinoma. These are all critical pieces in solving the puzzle of managing patients with genitourinary disease.

Urinary Systems is presented to the reader in a practical, focused, and easily accessible format. The majority of the text is set out in bullet-point items and is focused on the diagnostic hallmarks of each disease entity and its differential diagnosis. Numerous practical pearls are offered throughout the text that we hope will help practicing surgical pathologists and cytopathologists with common diagnostic conundrums. If a picture is worth a thousand words, then this relatively compact book certainly has the substantial content that one would expect from a major genitourinary pathology textbook. More than 400 high-quality, color illustrations and a comprehensive list of references are provided to enhance and complement the text.

Finally, because of the complexity of genitourinary pathology, the literature is somewhat controversial. We have attempted to provide the readers a balanced view of the existing controversial areas.

We are very fortunate to have as the contributors to this book great colleagues and peers in the fields of pathology, radiology, and urology. Without their unwavering support and their generosity in sharing their knowledge, this book would not have been possible. We are immensely grateful to all of them.

—Xiaoqi Lin, MD, PhD

—Longwen Chen, MD, PhD

—Ritu Nayar, MD

The urinary system is composed of the kidneys, ureters, bladder, and urethra. The primary function of the urinary system is to eliminate metabolic waste products. To achieve this, paired renal arteries carry blood to the kidneys, ramify, and terminate into approximately one million glomeruli per kidney. Each glomerulus (Figure 1-1) includes a complex tangle of selectively permeable capillaries. Portions of the blood that are not filtered return to the circulation via the renal veins. Filtered substances may exit the body via Bowman's space, the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule, the collecting ducts, the pelvicalyceal system, the ureters, the bladder, and finally the urethra. Alternately, filtered substances may be resorbed by the nephron, which is lined by cuboidal epithelium. Urothelium (Figure 1-2) forbids further resorption after the urine reaches the pelvicalyceal system.¹ The kidneys perform multiple additional functions including maintenance of body salt/water balance, acid/base balance, and endocrine secretion (erythropoietin, renin, and prostaglandins).

The kidneys account for approximately 4% of all noncutaneous malignancies diagnosed in the United States.² The classic clinical presentation of renal cell carcinoma (RCC) is hematuria, abdominal mass, and pain. This triad is now uncommon as a result of advances in abdominal imaging that provide earlier detection and improved survival.³ The histologic subtypes of RCC exhibit great diversity in clinical behavior. For example, mucinous tubular and spindle cell carcinoma is indolent and rarely metastasizes.⁴ Conversely, only about half of patients with collecting duct carcinoma survive three years after diagnosis.⁵ Renal sarcomas and lymphomas occur far less frequently than RCC. Benign renal neoplasms include angiomyolipoma, oncocytoma, and metanephric adenoma.

Figure 1-1 Normal renal cortex. Glomeruli, renal tubules, and stroma (H&E stain, 400×).

Figure 1-2 Normal bladder wall. Urothelium, submucosa, and muscularis propria (H&E stain, 200×).

Malignancies of ureters, bladder, and urethra account for approximately 6% and 2% of cancer incidence in men and women, respectively.² These patients often present with painless hematuria.⁶ Fortunately, many patients with urothelial carcinoma will not die of the disease; however, tumor invasion through the muscularis propria (detrusor muscle) reduces five-year survival to approximately 6% and 20% for patients with and without visceral metastasis, respectively. Urothelial papilloma and inverted papilloma are the most common benign neoplasms of the urinary tract.

Neoplasia of the urinary tract must be excluded in patients older than 40 years complaining of hematuria. The evaluation often begins with cystourethroscopy (Figure 1-3), urinary cytology (Figure 1-4), and computed tomography (CT) of the abdomen and pelvis with and without contrast. Cystourethroscopy with biopsy (Figure 1-5) is a safe procedure with few complications and contraindications.⁷ The sensitivity of cystourethroscopy and biopsy is excellent for papillary and invasive lesions of the bladder and ureters, but it is only 40% for flat urothelial carcinoma in situ.⁸ Urinary cytology is insensitive for low-grade lesions.⁹ Fluorescence in situ hybridization testing for common genetic alterations in urothelial carcinoma is ordered in some laboratories to increase sensitivity of urine cytology.¹⁰

Investigation of renal neoplasia usually begins with CT and ultrasound imaging. CT detects lesions with greater sensitivity, whereas ultrasound is superior in categorizing lesions as cystic or solid. Traditionally, tissue diagnosis of renal lesions was established after total or partial nephrectomy. Currently, a greater proportion are diagnosed with CT or ultrasound-guided biopsy (fine-needle aspiration and/or needle core; Figure 1-6) prior to definitive surgery. Magnetic resonance imaging (MRI) of the inferior vena cava and right atrium is useful for investigating direct vascular invasion by RCC.¹¹ Positron emission tomography (PET) with CT, which is employed in staging many carcinomas, has not been proven to be of value in RCC staging.¹²

Figure 1-3 An example of flexible cystoureteroscope and biopsy needle.

Figure 1-4 Hologic® ThinPrep processor, one method of processing urine cytology slides.

Figure 1-5 An example of cystoscopic biopsy forceps.

Figure 1-6 TEMNO Evolution™ needle core biopsy gun, an example of needle core biopsy devices.

MRI of the urinary tract is roughly equivalent to CT in the detection of urothelial neoplasms¹³ and obviates risks of contrast nephropathy and radiation. Contraindications of MRI include patient claustrophobia and corporeal ferromagnetic objects. Intravenous pyelography is useful to identify small lesions of the ureter and renal pelvis, but the injected contrast material is nephrotoxic and poses particular risk to patients with pre-existing renal insufficiency. PET is a helpful adjunct to CT in staging patients with suspected metastatic urothelial carcinoma.

Urothelial carcinoma of the bladder that does not penetrate the muscularis propria is usually treated with transurethral resection of the bladder tumor, intravesicular Bacillus Calmette-Guerin therapy, and meticulous follow-up, including urine cytology. Muscle invasive disease is treated with radical cystectomy, urinary diversion, and cisplatin-based systemic chemotherapy.

Localized RCC can be cured with radical or partial nephrectomy. Tumors that metastasize, invade the adrenal gland, or extend to Gerota's fascia are often treated with nephrectomy and systemic chemotherapy. Interleukin-2, interferon-α, and vascular endothelial growth factor inhibitors are recommended chemotherapeutic agents.¹⁴

REFERENCES

1. Staack A, Hayward SW, Baskin LS, Cunha GR. Molecular, cellular and developmental biology of urothelium as a basis of bladder regeneration. Differentiation. 2005;73(4):121–133.

2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.

3. Gudbjartsson T, Thoroddsen A, Petursdottir V, et al. Effect of incidental detection for survival of patients with renal cell carcinoma: results of population-based study of 701 patients. Urology. 2005;66(6):1186–1191.

4. Pillay N, Ramdial PK, Cooper K, Batuule D. Mucinous tubular and spindle cell carcinoma with aggressive histomorphology—a sarcomatoid variant. Human Pathol. 2008;39(6):966–969.

5. Wright JL, Risk MC, Hotaling J, Lin DW. Effect of collecting duct histology on renal cell cancer outcome. J Urol. 2009;182(6):2595–2599.

6. Wallace DM, Raghavan D, Kelly KA, et al. Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol. 1991;67(6):608–615.

7. Kadi N, Menezes P. ABC of flexible cystoscopy for junior trainee and general practitioner. Int J Gen Med. 2011;4:593–596.

8. Jocham D, Witjes F, Wagner S, et al. Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol. 2005;174(3):862–866; discussion 866.

9. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology. 2003;61(1):109–118; discussion 118.

10. Dimashkieh H, Wolff DJ, Smith TM, et al. Evaluation of urovysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer Cytopathol. 2013;121:591–597.

11. Semelka RC, Shoenut JP, Magro CM, et al. Renal cancer staging: comparison of contrast-enhanced CT and gadolinium-enhanced fat-suppressed spin-echo and gradient-echo MR imaging. J Magn Reson Imaging. 1993;3(4):597–602.

12. Ramdave S, Thomas GW, Berlangieri SU, et al. Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol. 2001;166(3):825–830.

13. Tekes A, Kamel I, Imam K, et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J Roentgenol. 2005;184(1):121–127.

14. Motzer RJ, Agarwal N, Beard C, et al. Kidney Cancer: NCCN Clinical Practice Guidelines in Oncology. 2012; http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf.

Endoscopic intervention for urologic disease is useful both for diagnostic and potentially for therapeutic purposes.¹ Cystoscopy (cystourethroscopy) can be used to evaluate and treat pathology in the urethra and bladder including urethral strictures, prostatic enlargement, bladder tumors, and so forth. Ureteroscopy (ureterorenoscopy) is used to evaluate and treat pathologic conditions of the ureter, renal pelvis, and renal calyx.

Cystoscopes and ureteroscopes may be rigid or flexible depending on the diagnostic or therapeutic function desired and whether the patient is meant to be sedated instead of fully anesthetized, as flexible endoscopes are usually more comfortable. Sizes of these endoscopes may vary, but adult cystoscopes average 17–21 Fr, whereas adult ureteroscopes average 7–11 Fr.

Endoscopy is contraindicated in the setting of infection, and complications include urethral, bladder, or ureteral perforation; urinary tract infection; or generalized sepsis.

2.1 NORMAL MUCOSA OF THE URINARY TRACT

Cystoscopic examination of the normal bladder and ureteral orifice:

• The normal vascularity and mounding of the trigone at the ureteral orifice as seen in Figure 2-1.

Urethroscopic examination of the lateral lobes of the prostatic urethra and the verumontanum at the base of the urethra:

• The prostatic urethra runs through the prostate gland just distal to the bladder neck. The ejaculatory ducts are located within the verumontanum near the prostatic apex. The external urethral sphincter surrounds the urethra just distal to the verumontanum (Figure 2-2).

2.2 DEBRIS

Debris can be the result of urinary infection or medications.

Cystoscopic examination of the bladder:

• Irregular in shape, rough surface material on the urothelial surface as seen in Figure 2-3.

Differential diagnoses:

• Possibly mistaken for an urothelial lesion. Debris can be easily irrigated clearly to differentiate it from potential neoplasm.

Clinical management:

• No further clinical management is necessary for urinary debris.

2.3 STONES

Urinary stones are most commonly associated with metabolic abnormalities and may cause symptoms if they migrate from the kidney and obstruct the ureter. The most common composition of stones is calcium oxalate, but they may also consist of calcium phosphate, uric acid, or struvite (infection stones associated with urease-producing bacteria). Stones may also be associated with foreign bodies such as surgical clips and retained stents or with poor bladder emptying and infection in the setting of neurogenic bladder or bladder outlet obstruction such as benign prostatic hyperplasia (BPH).

Cystoscopic examination of the bladder:

• Cystoscopic image: Surveillance cystoscopy following right nephroureterectomy demonstrates a bladder calculus at the site of the resected bladder cuff. The foreign body (partially eroded plastic clip) in the foreground acts as the nidus of the stone (Figure 2-4).

• Ureteroscopic image: Ureteral calculus—the red beam of the holmium laser aimed at the lower portion of the stone (Figure 2-5).²

Figure 2-1 Cystoscopic image of the normal bladder and ureteral orifice.

Figure 2-2 Urethroscopic image of the lateral lobes of the prostatic urethra and the verumontanum at the base of the urethra.

Figure 2-3 Cystoscopic image of debris in the bladder.

Figure 2-4 Cystoscopic image of stone in the bladder.

Clinical management:

• Stone treatment is most commonly performed using endoscopic techniques (ureteroscopy, percutaneous nephrolithotomy) with holmium laser lithotripsy or with extracorporeal shock wave lithotripsy. When necessary, patients are also encouraged to improve bladder emptying with medication or transurethral resection of prostate for BPH, or intermittent catheterization for neurogenic bladder.

Figure 2-5 Ureteroscopic image of stone in the ureter.

2.4 TREATMENT EFFECTS

Patients with bladder cancer are treated with surgical excision followed by intravesical bacillus calmette-guerin (BCG) or intravesical administration of chemotherapy. These patients are always surveilled with urine cytology, cystoscopy, and biopsy. Following primary treatment of bladder tumors, lesions are often noted on surveillance cystoscopy. Many of these lesions are benign, which can only be differentiated from neoplasm on pathologic analysis.³

Cystoscopic examination of the bladder:

• Postsurgical excision site: Abnormal lesion in the area of previous resection area with possible necrosis (Figures 2-6A and B). Histology of biopsies shows fibromuscular tissue with chronic inflammation, dystrophic calcifications, and focal giant cell reaction.

• Necrotic exudate with focal neutrophilic infiltrate, polarizable amorphous material, and retained sutures.

• BCG treatment effect seen in patients with a history of carcinoma in situ treated with BCG with injected mucosa. Biopsy of the area was consistent with acute and chronic inflammation with reactive urothelial atypia (Figure 2-7).

Differential diagnosis:

• Urothelial carcinoma versus nonneoplastic etiology (inflammation/scarring).

Clinical management:

• Follow up biopsy and urine cytology.

2.5 NEO-URETERAL ORIFICE WITH URETERAL STENT

Patients with urothelial carcinoma of the distal ureter can be treated with distal ureterectomy with ureteroneocystostomy.

Cystoscopic examination of the bladder:

• Cystoscopic appearance of neo-ureteral orifice (Figure 2-8) with ureteral stent in place (Figures 2-9A and B) seen in patients with a history of distal ureteral urothelial carcinoma status post right robotic distal ureterectomy with ureteroneocystostomy.

Clinical management:

• Follow-up with interval urine cytology, surveillance cystoscopy, and ureteroscopy.

2.6 STUDER ILEAL ORTHOTOPIC NEOBLADDER

Following cystoprostatectomy, urinary diversion is accomplished using bowel with orthotopic neobladder, Indiana pouch, or ileal conduit. The choice of diversion is based on patients’ factors and choice. Orthotopic neobladder provides the benefit of preserved native urinary tract anatomy but is marked by a high incidence of nighttime urinary incontinence.

Cystoscopic examination of the bladder:

• Typical appearance of a Studer ileal orthotopic neobladder with mucosal folds noted (Figure 2-10).

2.7 COLOVESICAL FISTULA

Patients may have a history of diverticulitis or colon cancer and present with pneumaturia, fecaluria, and urinary tract infection with multiple organisms.

Cystoscopic examination of the bladder:

• Significant debris and midline posterior area with mucosal erythema and central defect (Figure 2-11).⁴

Differential diagnosis:

• Possible diagnoses include diverticulitis, inflammatory bowel disease, or enteric neoplasm.

Clinical management:

• Cystoscopic biopsy can rule out neoplasm and define the area of involvement of the bladder. Definitive treatment involves en bloc partial colectomy with partial cystectomy.

Figure 2-6A Cystoscopic image of postsurgical excision site in the bladder.

Figure 2-6B Cystoscopic image of postsurgical excision site in the bladder.

Figure 2-7 Cystoscopic image of BCG treatment effect in the bladder.

Figure 2-8 Cystoscopic image of neo-ureteral orifice.

2.8 ENDOMETRIOSIS

Patients often present with a history of endometriosis, monthly pelvic pain, and development of dysuria and hematuria.⁵

Cystoscopic examination of the bladder:

• An extrinsic prominence at the posterior wall near the trigone (consistent with the uterus) and bluish nodules (Figures 2-12A and B).

Figure 2-9A Cystoscopic images of neo-ureteral orifice with ureteral stent.

Figure 2-9B Cystoscopic images of neo-ureteral orifice with ureteral stent.

Figure 2-10 Cystoscopic image of Studer ileal orthotopic neobladder.

Figure 2-11 Cystoscopic image of colovesical fistula in the bladder.

Differential diagnoses:

• Differential diagnosis includes urothelial neoplasm or other benign mucosal lesions.

Clinical management:

• Cystoscopic biopsy can confirm the diagnosis. Definitive management involves partial cystectomy. Ureteral involvement may require ureterolysis or ureteral resection with ureteroneocystostomy. Combined partial cystectomy with ureteroneocystostomy may be necessary in extreme cases.

2.9 AMYLOIDOSIS

Amyloidosis is uncommonly seen in the urinary tract. Urethral amyloidosis is a rare diagnosis marked by obstructive or irritative symptoms. Recurrence is common as systemic amyloid deposits are common.⁶

Figure 2-12 A and B Cystoscopic images of endometriosis in the bladder.

Urethroscopic examination of the urethra:

• Dense urethral stricture due to amyloidosis (Figure 2-13).

Differential diagnoses:

• Urethral stricture due to fibrosis or neoplasm.

Clinical management:

• Biopsy should be taken to confirm the diagnosis. A high level of clinical suspicion is needed to alert pathologist to the possible diagnosis. Definitive treatment with