Renal Pelvis and Ureter

3

Renal Pelvis and Ureter E V A C O M P E R A T, ST E P H E N M . B O N S I B A N D L I A N G C H E N G

C HA P T E R OU T LI N E Development 164 Anatomy 164 Congenital Malformations 165 Abnormalities in Number or Location of Ureters 165 Refluxing Megaureter 166 Ureteropelvic Junction Obstruction 166 Primary Megaureter 167 Ureterocele 168 Paraureteral Diverticulum 168 Ureteral Dysplasia 169 Nonneoplastic Proliferative, Metaplastic, and Inflammatory Lesions 169 Hyperplasia, von Brunn Nests, and Ureteropyelitis Cystica and Glandularis 169 Squamous and Glandular Metaplasia 169 Nephrogenic Adenoma 170 Reactive Changes (Reactive Atypia) 170 Malakoplakia 170 Endometriosis 170 Retroperitoneal Fibrosis 170 Neoplasms 172 Benign Epithelial Neoplasms 172 Malignant Epithelial Neoplasms 172 Mesenchymal Neoplasms 177

T

he renal pelvis and ureter are muscular conduits lined by urothelium that function to propel urine from the renal calyceal system to the urinary bladder.1 The ureter and renal pelvis are affected by developmental, reactive, and neoplastic disorders. The developmental disorders are a group of closely related entities that include abnormalities in ureteral number, ureteral location, and structure and function of pelvic and ureteral muscularis propria. The mucosa is the site of major reactive and neoplastic disorders.1

Development The ureter and renal pelvis develop from the ampullary bud, which arises from the distal mesonephric duct during the fourth week of development.2 Contact of the ampullary bud with metanephric

164

blastema induces nephrogenesis. During the months that follow, the ampullary bud elongates and branches dichotomously in parallel with development of the nephrons to create the adult metanephric kidney with its renal pelvis and ureter.3 As the ureter elongates, there is a period of luminal obliteration followed by recanalization in the fifth week. Recanalization begins in the middle of the ureter and extends proximally and distally with the ureteropelvic and ureterovesical junctions, which are the last segments to recanalize.4 The mesonephric duct distal to the ampullary bud (the common nephric duct) is incorporated into the developing urogenital sinus, whereas the ureteral orifice migrates to the trigone of the urinary bladder.2 The common nephric duct forms the trigone and contributes to the prostatic urethra in the male. Concomitant development of the male and female reproductive tracts from the mesonephric (wolffian) and M€ ullerian ducts, respectively, and division of the cloaca into bladder and hindgut occur nearby as the ureter and kidney develop. Thus multiple malformations in these areas often occur together.3

Anatomy The lumen of the renal pelvis and ureter is lined by the urothelium, which rests on a basement membrane over a lamina propria composed of highly vascular loose connective tissue (Fig. 3.1A). The urothelium is composed of three to five layers of cells in the pelvis and four to seven layers of cells in the ureter (Fig. 3.1B).1,4 The pelvis and ureter have a continuous muscular wall that originates in the fornices of the minor calyces as small interlacing fascicles of smooth muscle cells.5 These take on a spiral architecture in the pelvis and ureter that is necessary for effective peristalsis.5 The muscularis propria is not divided into distinct layers. Near the bladder, the ureter acquires an external sheath from the detrusor muscle, and the muscle fascicles become oriented longitudinally.5 The longitudinal fibers continue through the wall of the bladder and into the submucosa, where they spread about the ureteral orifice to contribute to the trigone muscle. Ultimately they terminate near the bladder neck in the female and at the verumontanum in the male. Peristalsis is initiated by “pacemaker” cells in the renal pelvic muscle near the calyces. These generate electrical impulses that propagate from cell to cell through gap junctions. Effective peristalsis requires both continuity of gap junctions and appropriate quantity and organization of muscle fascicles.6 As discussed later, disruption of this pattern, even focally, may cause ureteral incompetence or functional obstruction.3,5

CHAPTER 3 Renal Pelvis and Ureter

165

Fig. 3.1 Adult ureter. (A) Cross section showing adventitia, muscularis propria, and irregular contour of relaxed mucosa. (B) The mucosa consists of a few layers of urothelial cells overlying loose connective tissue. No muscularis mucosa is visible.

Congenital Malformations Genitourinary tract malformations occur in 10% of the population and are the most common group of congenital anomalies (Fig. 3.2).7 Some, such as bifid ureters, are clinically insignificant.8 Others are associated with ureteral incompetence or obstruction, with increased risk for renal damage or renal dysplasia.4 Some are components of multiple malformation syndromes (e.g., VATER [vertebrae, anus, trachea, esophagus, renal] association or prune belly syndrome), are associated with chromosomal abnormalities (e.g., trisomy syndromes), or have a familial predisposition.9,10 Congenital malformations of the ureters frequently occur together (Table 3.1). Patients with ureteropelvic anomalies usually present with symptoms of ureteral or pelvic distention, such as flank pain or mass, or with complications such as infection, calculi, or renal insufficiency. Magnetic resonance imaging is the examination of reference.11 Most such lesions encountered in surgical pathology consist of intrinsic structural defects of the muscularis, usually involving the ends of the ureters, the last segments to recanalize during embryogenesis. These malformations are congenital and

Fig. 3.2 Bifid ureter joining to form a single ureter above the bladder.

of developmental origin, but patients may present at any age from newborn to adulthood. Surgical therapy usually consists of excision of the abnormal segment to preserve renal function. The pathologist should define the anatomic basis of the functional deficit, which usually consists of a distinct but localized defect in smooth muscle quantity or organization (Table 3.2).12 Recognition of these lesions requires an appreciation of the normal muscle pattern, and their histologic demonstration requires well-oriented sections in which the pattern of the muscle fascicles is highlighted by a trichrome stain. For most lesions, longitudinal orientation of the specimen best shows the deviation from the normal muscle pattern. Primary megaureter (discussed later) is an exception in which cross sections optimally display the predominance of circular fibers and thickening of the periureteral sheath.13

Abnormalities in Number or Location of Ureters Ureteral agenesis, ureteral duplication, and ureteral ectopia are a group of related malformations resulting from defective formation of the ampullary bud.2 Isolated failure of bud formation causes ureteral agenesis with absence of the ipsilateral hemitrigone and kidney.2 Another cause of agenesis of the ureter and kidney is wolffian duct failure, which is often associated with genital tract malformations (e.g., absent testis or unicornuate uterus).2,7 Unilateral agenesis of the kidney and ureter is associated with additional urologic malformations in 20% to 40% of patients.14,15 Bilateral renal agenesis (Potter syndrome) is lethal because of associated pulmonary hypoplasia; treatment possibilities exist but introduce ethical problems.16 Bifid ureter and duplex ureter, the most common (0.8% of all autopsies) ureteral anomalies, result from premature branching of the ampullary bud or development of two separate ampullary buds.17 Premature branching results in two separate renal pelves and proximal ureters that join to form a single ureter at some point above the bladder (Fig. 3.3). Duplex ureters (Fig. 3.3) have two separate ureteral orifices in the bladder.18 The ureter from the lower pole usually has its orifice normally situated on the trigone or displaced laterally. The orifice of the ureter from the upper pole can be normally placed, but displacement toward the bladder neck or to an extravesical location is more common.19 Ureteral ectopia

166

CHAPTER 3

TABLE 3.1

Renal Pelvis and Ureter

Common Associations Among Ureteral Anomalies

Ureteral Anomaly

Bifid/Duplex

Bifid/duplex Ectopia Reflux Obstruction of ureteropelvic junction Ureterocele Diverticulum Primary megaureter

TABLE 3.2

+ + + + -

Ectopia

Reflux

+

+ +

+ + + + -

Obstruction of Ureteropelvic Junction + + +

+ + + -

Ureterocele

Dysplasia

+ + + +

+ + + + + + +

+ -

-

Ureteral Muscle Findings in Ureteral Anomalies

Ureteral Anomalies Refluxing megaureter Obstruction of ureteropelvic junction Primary megaureter Ureterocele Paraureteral diverticulum

Muscle Normal

Muscle Deficient

Muscle Dysplastic

Longitudinal Fiber Predominance

Circular Fiber Predominance

Sheath Thick

+ +

+ +

+ +

+

-

-

+ +

+ +

+ + +

-

+ -

+ -

pyelonephritis, or a distal ureter excised for reflux, obstruction, or ureterocele.7,8

Refluxing Megaureter

Fig. 3.3 Duplex ureter near point of confluence.

results from abnormally high or low origin of the ampullary bud from the mesonephric duct. Eighty percent of ureteral orifice ectopia is associated with the ureter from the upper pole of a duplicated system.3,4 The ectopic ureteral orifice may be intravesical (lateral or caudal to the normal site) or extravesical in the urethra, vestibule, or genitalia. Symptoms are influenced by gender and the site of the ureteral orifice, and may consist of urethral dribbling, vaginal “discharge,” epididymoorchitis, or pyelonephritis if reflux or obstruction are present.20 The greater the degree of ectopia in a lateral or extravesical location, the more likely it is that the corresponding renal unit will be dysplastic. The resected specimen thus may include a segmental or complete nephrectomy for dysplasia or

Reflux from the bladder is the most common ureteral problem requiring surgical intervention. Patients usually present in early childhood with urinary tract infections and often already have renal scars (reflux nephropathy).21 Reflux may be unilateral or bilateral, and in about one-third of cases, the patients’ siblings have similar urologic abnormalities.22 Vesicoureteral reflux is caused by incompetence of the ureterovesical junction. There is a 2:1 predominance of females over males, possibly resulting from the additional mechanical support provided to the bladder by the prostate and seminal vesicles.23 The affected ureters have abnormally short submucosal segments or deficiency of longitudinal fibers in the intramural segment, or both. Short submucosal segments are apparent to the urologist but difficult to demonstrate histologically. Deficiency of longitudinal fibers can be identified in longitudinal sections of the intramural segment and may appear to the urologist as an abnormally thin and translucent segment of distal ureter (Fig. 3.4). Excision of the defective distal ureteral segment and reimplantation of the ureter is usually curative.21

Ureteropelvic Junction Obstruction Ureteropelvic junction obstruction is the most common cause of ureteral obstruction and may present at any age. When occurring in childhood, it is frequently bilateral (16%), associated with other urologic malformations (15% to 20%), predominantly on the left side, and predominantly in boys; urinary tract infections are frequent. In contrast, cases presenting in adulthood are most often

CHAPTER 3 Renal Pelvis and Ureter

167

Fig. 3.5 Funnel-shaped zone of ureteropelvic junction obstruction.

Fig. 3.4 Longitudinal section showing mucosal aspect of distal ureter in reflux. Note the thin wall.

unilateral and occur in women. Treatment usually includes laparoscopic or robotic surgery.24 The two most common causes are defects in the muscularis (75%) and renal nonrotation associated with polar vessels (6% to 24%).25 The obstructed ureteropelvic junction is characteristically funnel shaped (Fig. 3.5). It may have a grossly visible area of thin muscle, a valvelike intraluminal protrusion of edematous mucosa or muscularis, or may be stenotic. The histologic appearance is varied. There may be segmental smooth muscle attenuation, often with a predominance of longitudinal fibers, diffuse lack of fascicular organization of pelvic muscles (i.e., dysplastic; see Ureteral Dysplasia section later in this chapter), segmental absence of smooth muscle, or stenotic lumen with normal muscle (Fig. 3.6). “Valves” or “pleats” have also been described that probably result from herniation at the site of muscle abnormality.26 Renal polar blood vessels are common anatomic variants of the renal vasculature that usually do not obstruct the ureter because of the medial origin at the renal hilum. In congenitally nonrotated kidneys the pelvis is anterior, and polar vessels may cause significant ureteral obstruction.

Primary Megaureter Primary megaureter is a nonrefluxing form of ureteral dilation. The gross appearance is distinctive (Fig. 3.7), consisting of narrow and straight ureters immediately above the bladder that merge with segments that are fusiform and markedly dilated. This fusiform

Fig. 3.6 Ureteropelvic junction obstruction.

dilation differs from the tortuous appearance of ureteral dilation secondary to reflux or obstruction. In 80% of cases, there is functional obstruction at the level of the narrow segment that must be excised.27 In cross section the narrow segment shows predominance of circular fibers, hypoplasia, and fibrosis of the smooth muscle, or thickening of the periureteral sheath (Fig. 3.8). The only abnormality of the dilated segment is smooth muscle hypertrophy. In the other 20% of cases the narrow segment of ureter has normal muscle, and the dilated segment above it has an almost complete absence of muscle.28 This has been referred to as dysplastic ureters (see Ureteral Dysplasia section later in this chapter) and is commonly associated with dysplastic kidney.7,29 However, this terminology may be misleading because there is no relationship with dysplastic (preneoplastic) urothelium.

168

CHAPTER 3

Renal Pelvis and Ureter

portion may undermine and distort the trigone, often resulting in obstruction or reflux of the normally situated lower pole ureter or, if the ureterocele is large, the contralateral ureter as well. Ureterocele rarely affects a single ureter.31 Microscopically, the muscle of the wall of ureterocele varies from hypertrophic to atrophic or absent (Fig. 3.10).5 Consistent with the usual ectopic location of the ureteral orifice associated with duplex kidneys, 70% of cases have segmental dysplasia of the upper pole of the kidney.28

Paraureteral Diverticulum

Fig. 3.7 Primary megaureter with abrupt dilation at the superior end.

Herniation of the urinary bladder involving the distal ureter is called paraureteral diverticulum. It is usually congenital and detected in childhood, but may result from urethral or bladder neck obstruction at any age.32 Vesicoureteral reflux is commonly associated with paraureteral diverticulum. The location of the ureteral orifice within the diverticulum correlates with the risk for renal dysplasia (Fig. 3.11). When the ureter opens into the dome

Fig. 3.8 Primary megaureter segment showing smooth muscle hyperplasia. Fig. 3.10 Ureterocele showing thinning or lacking muscle in its wall.

Fig. 3.9 Ureterocele of upper pole ureter. Orifice is near bladder neck.

Ureterocele Ureterocele consists of congenital dilation of the distal ureter within the bladder (Fig. 3.9). It may balloon into the bladder and occasionally protrudes into the urethra.30 Most ureteroceles occur in the upper pole ureter of a duplicated system in which the ureter usually passes dorsal to the lower pole ureter. Its dilated

Fig. 3.11 Bilateral paraureteral diverticula. Probes indicate ureteral orifices at the mouth of each diverticulum.

CHAPTER 3 Renal Pelvis and Ureter

of the diverticulum (a form of lateral ectopia) rather than near its orifice, the likelihood of renal dysplasia is great. There are few histologic studies of diverticula, but deficient ureteral muscle and sheath development have been reported.33

Ureteral Dysplasia Ureteral dysplasia refers to ureters composed of infrequent smooth muscle cells lacking organization and failing to form fascicles. It is unrelated to urothelial dysplasia. Tokunaka et al. showed that involved muscle cells possess thin actin filaments but lack thick myosin filaments essential for normal contractility.28 Recognition of ureteral dysplasia is important because of the strong association with ipsilateral renal dysplasia (56% to 70% of cases). Dysplastic ureters vary in appearance from atresia to dilation (Fig. 3.12), and may have an anomalous location. Recognition of the dysplastic nature is not possible on gross examination, because ureters with normal muscle fascicle formation may have a similar appearance.34

Nonneoplastic Proliferative, Metaplastic, and Inflammatory Lesions

and glandularis.6,7 Simple hyperplasia consists of an increase in the number of layers of urothelial cells without cytologic atypia that commonly accompanies inflammation and neoplasia. von Brunn nests are small, cohesive aggregates of normal urothelial cells within the lamina propria (Fig. 3.13). They are most common in the trigone of the bladder but are also found in 10% of normal ureters at autopsy.7 When von Brunn nests have central lumens lined by urothelium or columnar cells, they are referred to as ureteritis or pyelitis cystica and ureteritis or pyelitis glandularis (Fig. 3.14), respectively. These changes are common in patients with stone disease.1 Although usually microscopic, ureteritis and pyelitis cystica may rarely produce grossly visible fluid-filled cysts that elevate the urothelium (Fig. 3.15).1

Squamous and Glandular Metaplasia Squamous metaplasia is the most common form of urothelial metaplasia.1,36,37 It may be nonkeratinizing or keratinizing (Fig. 3.16), with or without atypia. When squamous metaplasia is encountered in the renal pelvis and ureter, it is often keratinizing. The keratin may be so copious that squames are seen in the urine or collect in the pelvis, forming a mass.38,39 Keratinizing squamous metaplasia

Nonneoplastic lesions of the ureter share similarities with those in the bladder, although inverted lesions may be more common in the ureter.35

Hyperplasia, von Brunn Nests, and Ureteropyelitis Cystica and Glandularis The most common nonneoplastic urothelial proliferative lesions are simple hyperplasia, von Brunn nests, and ureteropyelitis cystica

Fig. 3.13 von Brunn nests of the ureter.

Fig. 3.12 Dysplastic megaureter associated with bilateral renal dysplasia.

169

Fig. 3.14 Ureteritis glandularis.

170

CHAPTER 3

Renal Pelvis and Ureter

whereas it is less common in the upper urinary tract. Its etiology may be inflammatory or idiopathic, and similar alterations may be produced by irradiation and catheterization.46,47 The resultant striking cytologic atypia characteristically affects superficial cells, which can be enlarged. The cells have low nuclear/cytoplasmic ratios, nuclear or cytoplasmic vacuoles, and smudged chromatin; intraepithelial abscess formation has been described.37,48 The mixture of normal urothelial cells with occasional large atypical cells is distinctive. Reactive atypia may be encountered in the urothelium of patients who have vesicoureteral reflux.49 Contrary to the bladder, instillations normally do not interfere with the urothelium, so changes may not be seen. These aspects can be very difficult to analyze in urinary cytology.48,50

Malakoplakia Fig. 3.15 Ureteritis cystica with cobblestone appearance of vesicles protruding into the ureteral lumen.

Malakoplakia is an uncommon chronic granulomatous disease that occurs most frequently in the urinary tract of middle-aged women as a complication of recurrent infection.51,52 Bladder involvement is 4 to 10 times more common than that of the renal pelvis and ureter.1,37 Nevertheless, malakoplakia has become a rare finding with improved treatment of urinary tract infections.53 The typical lesion is a yellow-brown soft (“malakos”) plaque (“plakos”) (Fig. 3.17) that often has central umbilication. Microscopically, masses of large eosinophilic histiocytes (von Hansemann histiocytes) are present, many of which contain basophilic inclusions (Michaelis–Gutmann bodies; Fig. 3.17). Periodic acid–Schiff stain and special stains for calcium and iron enhance the targetoid appearance of these cytoplasmic inclusions and indicate their mineralized nature.1,37 Malakoplakia is discussed in detail in Chapter 5.

Endometriosis

Fig. 3.16 Keratinizing squamous metaplasia of the ureter.

is usually the result of chronic irritation. Conditions such as chronic infection, indwelling catheters, and calculi are present in 60% to 70% of patients. Keratinizing squamous metaplasia may coexist with squamous cell carcinoma and urothelial carcinoma.40 Mucinous (glandular, enteric, intestinal, colonic) metaplasia indicates the presence of colonic-type mucinous epithelium, often containing enterochromaffin cells.41 Intestinal metaplasia of the renal pelvis and ureter is rare, and most cases coexist with adenocarcinoma.42,43

Nephrogenic Adenoma Nephrogenic adenoma is rare in the upper urinary tract, often appearing as an exophytic lesion that may cystoscopically mimic urothelial carcinoma.44 Microscopically, it consists of a benign papillary and tubular proliferation lined by cuboidal or hobnail epithelium.45 Nephrogenic adenoma is discussed in detail in Chapter 5.

Reactive Changes (Reactive Atypia) Reactive changes may affect the urothelium and mimic urothelial carcinoma in situ. In the bladder this is a well-known phenomenon,

Endometriosis is defined by the presence of endometrial tissue beyond the confines of the uterine cavity. It affects approximately 10% to 20% of premenopausal women.54 However, only 1% to 2% of all cases involve the urinary tract. Ureteral endometriosis is especially rare.54 Antonelli et al. reported the largest series of ureteral endometriosis (19 cases), of which 4 cases (21%) had coexisting bladder endometriosis.55 Presenting symptoms include flank pain, gross hematuria, dysuria, uremia, and pelvic mass. Approximately 50% of cases are asymptomatic. The lesion is similar in appearance to those in other organ sites, consisting of benign endometrial glands and stroma (Fig. 3.18). It may also present as a polypoid lesion. Malignant transformation of ureteral endometriosis is exceptional.56

Retroperitoneal Fibrosis Retroperitoneal fibrosis is a proliferative process of inflammation and fibrosis occurring in elderly men that may encase affected structures, with the ureters frequently exhibiting medial deviation on intravenous pyelography.57 It may be primary and idiopathic, although a variety of secondary causes have been identified, including iatrogenic (drugs, surgery, irradiation), inflammatory (vasculitis, aneurysms, diverticulitis, inflammatory bowel disease), and neoplastic (sclerosing lymphoma, urothelial carcinoma) disorders. Regardless of etiology, the typical histology is a prominent mixed inflammatory cell infiltrate with fibroplasia and edema (Fig. 3.19).57 The major challenge is to identify those secondary causes that merit different therapy. Idiopathic retroperitoneal

CHAPTER 3 Renal Pelvis and Ureter

171

Fig. 3.17 Malakoplakia (A) Malakoplakia involving both kidney and ureter. (B) Malakoplakia involving the ureter. Malakoplakia has a yellowish appearance. (C) Malakoplakia of the ureter. Whole-mount view. (D) Malakoplakia is characterized by granulomatous inflammation, composed of numerous macrophages with target or “owl-eye”-shaped intracytoplasmic basophilic inclusions (Michaelis-Gutmann bodies).

Fig. 3.18 Endometriosis of the ureter.

Fig. 3.19 Retroperitoneal fibrosis.

172

CHAPTER 3

Renal Pelvis and Ureter

fibrosis has been linked to the immunoglobulin G4 (IgG4)-driven autoimmune process.58 IgG4-related sclerosing disease is a recently recognized entity and encompasses many organ systems with multiple organ involvement. Recent data indicate that a significant proportion of idiopathic retroperitoneal fibrosis cases in females are associated with clonal expansion of fibroblasts.59

Neoplasms Neoplasms of the ureter and pelvis represent less than 10% of upper tract tumors in adults; renal cell carcinoma comprises most of the remaining cases.35,60-62 Pyelocaliceal tumors are approximately twice as common as ureteral tumors.61 Ninety-five percent are epithelial, and 80% are malignant. Of the malignant neoplasms, urothelial carcinoma and primary nonurothelial carcinoma account for 90% and 1.9%, respectively.61,63

Benign Epithelial Neoplasms Inverted Papilloma Inverted papilloma is a benign urothelial tumor that occurs less commonly in the renal pelvis and ureter than in the urinary bladder.64 It is almost twice as common in the ureter as in the renal pelvis.65 Men predominate (male/female ratio ¼ 9:1), with a mean age at presentation of about 65 years.65 In the upper tract, it may be symptomatic, presenting with hematuria, or it may be found incidentally on radiologic examinations performed for reasons unassociated with inverted papilloma. Inverted papilloma may be multiple and associated with urothelial carcinoma at other sites. Grossly, it may form a mass mimicking carcinoma (Fig. 3.20). The tumor consists of trabeculae of histologically typical urothelium (see Chapter 6).1,37 Rarely, urothelial carcinoma may arise within inverted papilloma of the ureter, which is the major differential diagnosis.66

Malignant Epithelial Neoplasms Urothelial Dysplasia and Carcinoma In Situ In keeping with the concept of the urothelium of the renal pelvis, ureter, and bladder as a single anatomic unit affected by similar neoplastic influences, the same relationships between dysplasia and cancer shown for bladder cancer apply in the upper tract. The mucosa adjacent to invasive pelvic and ureteral tumors is abnormal (dysplasia or carcinoma in situ) in 95% of specimens. Patients presenting with concomitant carcinoma in situ have a worse outcome than those who present with pure/primary carcinoma in situ, suggesting a need to differentiate these two entities in the treatment decision process.62,67 Grossly, the mucosa appears normal or erythematous (Fig. 3.21). The histologic criteria are identical to those described in Chapter 6 (Fig. 3.22). There is an excellent prognosis for upper tract carcinoma in situ treated with radical nephroureterectomy or bacillus Calmette–Guerin.68-71 Urothelial Carcinoma Urothelial carcinoma of the upper tract is epidemiologically similar to that of the bladder. The incidence and prevalence of upper urinary tract urothelial carcinoma is not well defined, because they are usually combined with other forms of neoplams.72,73 Pyelocaliceal tumors are approximately twice as common as ureteral tumors. There is a male predominance (male/female ratio ¼ 3:1), and it is most common in older individuals aged 70 to 90 years.74 Hematuria is the principal symptom, but flank pain also is frequent.61 Upper tract involvement likely represents 5% to 10% of cases of urothelial carcinoma, with an estimated annual incidence in Western countries of almost 2 cases per 100,000 inhabitants.61,72,73,75 Cigarette smoking, industrial carcinogens, and chronic irritation (stones and infection) are risk factors.61,69,76 Phenacetin abuse

Urothelial Papilloma Urothelial papilloma consists of a small (several millimeters or less), delicate papillary structure most often found incidentally. Biopsies of this structure are only rarely performed because of a tendency for urologists to fulgurate this small, clinically innocent-appearing lesion. Microscopically, it consists of thin, delicate fibrovascular fronds invested by epithelium of normal thickness that lacks atypia. By definition, there is no extension into the lamina propria.1 No recent literature is available for the upper urinary tract.

Fig. 3.20 Inverted papilloma of the ureter.

Fig. 3.21 Red patches of urothelial carcinoma in situ of the ureter.

CHAPTER 3 Renal Pelvis and Ureter

Fig. 3.22 Urothelial carcinoma in situ of the ureter.

is the most important causative factor in some populations, accounting for nearly 25% of renal pelvic tumors and more than 10% of ureteral tumors. Balkan nephropathy and exposure to thorium-containing radiologic contrast material are risk factors for upper tract carcinoma, but not for bladder involvement.61,7779 Advanced age, race (black non-Hispanic patients), obesity (body mass index 30), Eastern Cooperative Oncology Performance Status (1), smoking history, the presence of hydronephrosis, and systemic symptoms are associated with worse prognosis.74,78,80 The right and left sides are equally affected, and approximately 2% to 8% of cases are bilateral. Multifocality is a significant problem for patients with upper tract tumors.61,72,81 There is no survival difference between patients with unilateral or synchronous bilateral upper urinary tract cancers in some studies.82 However, patients with bilateral subsequent (metachronous) upper tract tumors have a shorter survival.82-84 More recent studies indicate tumor multifocality is a poor prognostic factor.83,85 Ureteral carcinoma seems to have a worse prognosis than renal pelvic involvement, perhaps because the former is usually more invasive. In a report limited to upper urinary tract cancer, muscular invasion was found in the ureter and renal pelvis in 78% and 38%, respectively. Ureteral carcinoma tends to have higher grade and stage than in the bladder.61,68,80 In the ureter the most common location of tumor is the distal segment.86,87 Due to the high rate of recurrence (more than 15%) in the ureter distal to the resected tumor, nephroureterectomy with resection of a cuff of urinary bladder is the operation of choice.88 Recurrence in the bladder occurs in 22% to 47% of cases of upper tract urothelial carcinoma. Patients may also have urothelial carcinoma in the contralateral upper tract (2% to 6%).89,90 In 9% to 17% of cases, concurrent bladder carcinoma is present, and nearly 50% of patients with upper tract cancer subsequently experience bladder involvement.78,89,91-93 In contrast, the incidence of upper urinary tract tumors is low (0.7% to 4%) among patients with primary bladder cancer.85 Patients with multiple bladder tumors are at high risk for development of upper tract cancer. The location of bladder involvement is also important; those with cancer in the trigone are at approximately sixfold higher risk for a synchronous tumor in the upper tract.91,92 Patients with synchronous or prior history of bladder carcinoma have worse prognosis than those patients without bladder involvement.81,83,92

173

Comparison of upper tract and bladder cancer revealed that the former was more likely to have advanced tumor stage, higher grade, lymphovascular invasion, and lymph node metastasis. Among patients with non–muscle-invasive urothelial carcinoma, those with bladder involvement were more likely to experience higher recurrence and lower cancer-specific survival rates than those with renal pelvicalyceal tumor, but not ureteral tumor.94 Patients with stage Ta bladder cancer with two or more recurrences are also at high risk for development of upper urinary tumor.95 In pT2 and pT3 tumors, there was no difference in outcome between the three tumor locations (urinary bladder, ureteral, and renal pelvicalyceal). In pT4 tumors, patients with ureteral and pelvicalyceal tumors were more likely to experience recurrence and mortality than those with bladder involvement. However, an earlier study of 425 patients did not show outcome difference between different locations.94 Overall, 60% of cases of upper tract carcinoma are invasive at diagnosis compared with 15% to 25% of bladder tumors.61,74 In patients who had undergone nephroureterectomy for upper tract carcinoma, pathologic stage was an independent predictor of cancer-specific survival.78,96 The gross appearance is similar to that in the bladder (Fig. 3.23), except that large papillary tumors frequently fill the ureters and cause obstruction, resulting in hydronephrosis (Fig. 3.24). Large tumors of the pelvis may extensively invade the renal parenchyma in an ill-defined infiltrative manner (Fig. 3.25), and may extend into paracortical fat, eliciting a

Fig. 3.23 Papillary urothelial carcinoma of the renal pelvis.

Fig. 3.24 Papillary hydronephrosis.

urothelial

carcinoma

of

the

ureter

causing

174

CHAPTER 3

Renal Pelvis and Ureter

Fig. 3.25 Infiltrative urothelial carcinoma of the pelvis replacing most of the kidney. Fig. 3.28 Noninvasive papillary urothelial carcinoma, high grade (grade 3 of 3).

Fig. 3.26 Papillary urothelial carcinoma filling the lumen of the ureter.

scirrhous response. In large tumors, little evidence may remain of mucosal origin in the pelvis, and extensive histologic sampling is required. Gross fat extension or invasion into renal parenchyma should be documented.97,98 Grade and stage are the most important prognostic factors in urothelial carcinoma of the upper tract.35,61,77 The grading scheme is identical to that applied in the bladder (see detailed discussion in Chapter 5) (Figs. 3.26 through 3.28). Both 1973 and 1998 International Society of Urologic Pathology/2004 World Health Organization (WHO) grading systems have been used in recent years. The WHO 2016 recommends the distinction of low and high grades in an effort to standardize terminology and definitions, eliminates ambiguity in diagnostic categories in the WHO 1973 system, and better defines the high-risk group.36,99 The American Joint Committee on Cancer recommends low grade and high grade, and in squamous cell and adenocarcinoma, GX, G1–3 (Table 3.3).77 Histopathology of urothelial carcinoma of the renal pelvis and ureter (Fig. 3.29) has the same spectrum as urothelial carcinoma of the urinary bladder, including squamous and glandular differentiation, and sarcomatoid (Fig. 3.30), lymphoepithelioma-like,

Fig. 3.27 Noninvasive papillary urothelial carcinoma, low grade (grade 2 of 3) (A and B).

CHAPTER 3 Renal Pelvis and Ureter

TABLE 3.3

175

The 2017 American Joint Committee on Cancer TNM Staging for Carcinoma of the Renal Pelvis and Ureter77

Primary tumor (T) TX T0 Ta Tis T1 T2 T3

T4

Primary tumor cannot be assessed No evidence of primary tumor Papillary noninvasive carcinoma Carcinoma in situ Tumor invades the subepithelial connective tissue Tumor invades the muscularis (For renal pelvis only) tumor invades beyond muscularis into peripelvic fat or the renal parenchyma T3 (For ureter only) tumor invades beyond muscularis into periureteric fat Tumor invades adjacent organs or through the kidney into the perirenal fat

Regional lymph nodes (N)a NX N0 N1 N2

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single lymph node 2 cm in greatest dimension Metastasis in a single lymph node >2 cm or multiple lymph nodes

Distant metastasis (M) M0 M1

No distant metastasis Distant metastasis

a

Laterality does not affect the N classification. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.

Fig. 3.29 Invasive urothelial carcinoma involving the muscularis propria wall.

plasmacytoid, micropapillary, inverted, microcystic, and small cell variants. Approximately 25% harbor histologic variants, and some of these are associated with worse prognosis (see Chapter 6).100-102 Rare variants, including those with trophoblastic differentiation and osteoclast-type giant cells, have also been reported.103-106 For some entities, immunohistochemical studies may be of diagnostic help. In addition to grade and stage, other histologic factors are prognostically important, including concomitant carcinoma

Fig. 3.30 Sarcomatoid urothelial carcinoma of the ureter.

in situ, sessile tumor growth pattern, tumor size, tumor necrosis, lymphovascular invasion, lymph node involvement, tumor architecture, positive surgical margins, and histologic variants. Extranodal extension is an independent predictor of poor clinical outcome in patients with upper tract urothelial carcinoma with lymph node metastasis.36,61,107,108 Immunophenotypically, upper tract urothelial carcinoma is similar to its counterpart in bladder, staining for GATA3, S-100P, uroplakin III, thrombomodulin, cytokeratins 7 and 20, p63, and highmolecular-weight cytokeratin.109 PAX2 and PAX8, nephric cell lineage transcription factors that play key roles in renal organogenesis, are often expressed in upper tract urothelial carcinoma, but are usually nonreactive in bladder urothelial carcinomas.110 Cytology for detection or surveillance in the upper urinary tract is challenging, with sensitivity and specificity of 54% and 56%, respectively.48,50,111 Patients with clinical low-grade tumors on biopsy run the risk of upgrading, particularly with positive urine cytology. The predictive value of biopsy can be improved by extensive ureteroscopic sampling.112 Fluorescence in situ hybridization analysis of chromosomes 3, 7, 9, and 17 abnormalities provides superior sensitivity compared with cytology for the detection of upper urinary tract urothelial carcinoma while maintaining a similar specificity.113 Genetic factors play a role in carcinogenesis of upper tract urothelial carcinoma. The risk is significantly increased in patients with family history of hereditary nonpolyposis colon cancer (Lynch syndrome), with upper tract tumors developing at a younger age and more likely in the ureter, with an almost equal gender ratio.114-116 Although some believe these tumors have high-grade potential, similar to that in the general population, others report that patients with microsatellite instability (MSI) more often have low-grade, low-stage cancer with an inverted growth pattern and good prognosis.117,118 Another group found no pathologic difference in invasion depth or growth type, but noted higher grade than with non MSI-H tumors.119 When cancer arises in the upper tract, it is more common in the ureter among patients with Lynch syndrome than the general population (51% versus 45%, respectively), and the likelihood is greater for high-grade tumor (88% and 74%, respectively).118,120 High incidence of MSI (21%) was initially reported in sporadic tumors of the upper tract,121 although others reported a lower incidence (7%).86,122 High MSI was associated with better prognosis.119,123 These tumors often display

176

CHAPTER 3

TABLE 3.4

Renal Pelvis and Ureter

Four Clusters of Gene Expression126

Subtypes of UUT-UC

Cluster 1

Cluster 2

Cluster 3

Cluster 4

Mutation

No PIK3CA mutation Nonsmokers High grade NMIUC High recurrence Favorable survival

100% FGFR3 mutations

100% FGFR3 mutations; 71% PIK3CA mutations; no TP53 mutations High tobacco use

No PIK3CA mutation; 62% KMT2D mutations; 50% TP53 mutations High tobacco use High grade MIUC Carcinoma in situ Short survival

Tobacco history Grade Stage Recurrence Survival

Enriched low grade NMIUC No bladder recurrence

Bladder recurrence

MIUC, Muscle-invasive urothelial carcinoma; NMIUC, non-muscle-invasive urothelial carcinoma; UUT-UC, upper urinary tract-urothelial carcinoma. From Moss TJ, Qi Y, Xi L, et al. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol 2017;72:641-649.

inflammation, suggesting likely response to immune checkpoint inhibitors, similar to bladder cancer.121 Patients identified as high risk for Lynch syndrome should undergo DNA sequencing for patient and family counseling.118 Screening of patients with Lynch syndrome is important to predict development of new primary tumors.116 Cytogenetic studies of sporadic tumors show that genetic changes in upper tract urothelial carcinoma are similar to those in the urinary bladder.124 Promoter hypermethylation was an independent predictor of progression-free survival in patients with upper tract urothelial carcinomas.125 Nevertheless, important differences exist between sporadic and inherited forms.124,126 Different molecular subgroups in bladder and upper urinary tract cancers have been described. Several pathways other than MMR (mismatch repair) are differentially deregulated, including TP53 signaling and level of genomic instability. Higher rate of TP53 mutations and related pathways lead to important genomic instability, alterations of copy numbers, and dysfunction of the cell cycle and apoptosis. FGFR3 (fibroblast growth factor receptor 3) is commonly mutated in high-grade tumors, with higher rates than in the bladder. Up to 60% of high-grade tumors display FGFR3 mutations. Four major different tumor clusters with different outcomes have been identified (Table 3.4).126

Fig. 3.31 Squamous cell carcinoma of the renal pelvis. the probe indicates the course of the ureter.

Squamous Cell Carcinoma Approximately 10% of renal pelvic tumors are squamous cell carcinoma, with a lower percentage of cases of ureteral involvement.40,100 Calculi, horseshoe kidney, and chronic infection are risk factors.127 The relationship with squamous metaplasia is controversial, perhaps owing to the rarity of squamous cell carcinoma of the upper urinary tract. Epstein-Barr virus infection is not implicated.128 The most common presenting symptoms are flank pain and gross hematuria. Most squamous cell carcinomas of the renal pelvis and ureters are high stage; extensive infiltration of the renal parenchyma is common (Fig. 3.31), and survival at 5 years is rare.63 The histopathology of this tumor is similar to squamous cell carcinoma in the bladder. This tumor should be distinguished from metastatic squamous cell carcinoma, which usually is straightforward when clinical and pathologic features are considered.

Fig. 3.32 Mucinous adenocarcinoma of the renal pelvis.

Adenocarcinoma Primary adenocarcinoma of the upper tract is rare, and reports consist of single cases or small series of cases (Fig. 3.32). Most occur in adults, but rare pediatric cases have been described.129 Calculi, chronic inflammation, and infection appear to be predisposing

conditions.101 Most patients present with advanced cancer, similar to those with squamous cell carcinoma, and have a poor prognosis. Intestinal metaplasia and villous adenoma may be precursors based on common coexistence, and noninvasive carcinoma is sometimes

CHAPTER 3 Renal Pelvis and Ureter

177

Fig. 3.33 Mucinous adenocarcinoma of the ureter infiltrating the lamina propria (A and B). The tumor cells display signet ring cell features.

found in the adjacent mucosa.130 Variants of adenocarcinoma have been described, and the prognostic significance of subclassification is uncertain. The prognosis is generally poor.63 Papillary architecture and resemblance to mucinous adenocarcinoma of the colon (Fig. 3.33) are common.

Metastases Neoplastic involvement of ureters may occur by direct local extension or metastasis.131 Contiguous ureteral involvement is more frequent and is usually caused by carcinoma of the cervix, prostate, or bladder. Metastatic involvement is less common, and breast and colon are the most common sites of primaries. Ureteral involvement is rarely the initial manifestation. When distant metastasis occurs, the lung is the most common site of metastasis for patients with urothelial carcinoma of upper tract.132

Mesenchymal Neoplasms Mesenchymal neoplasms are uncommon in the ureter and pelvis. Fibroepithelial polyp is most common, followed by benign and malignant smooth muscle tumors. A variety of additional tumors have been reported as single cases including hemangioma, neurofibroma, and malignant schwannoma.

Fibroepithelial Polyp Fibroepithelial polyp is more common in the ureters and renal pelvis than in the bladder. It is an uncommon benign mesenchymal tumor of the renal pelvis and ureter. Approximately 70% of patients are male, and it occurs at all ages from infancy to old age (mean, approximately 40 years).133 Fibroepithelial polyp is the most common benign polypoid lesion of the ureter in children. Colicky flank pain and hematuria are the most common symptoms. The cause is uncertain.134 Grossly, fibroepithelial polyp consists of single or multiple slender smooth-surfaced vermiform polyps that usually arise from a common base. The ureteropelvic junction is a common site, and the polyp may cause obstruction at that narrow point. Rarely, it is bilateral. Microscopically, the polyp is covered by normal urothelium, which may be focally eroded. The core of the polyp is composed of loose edematous and vascular stroma with few inflammatory cells (Fig. 3.34).1

Fig. 3.34 Fibroepithelial polyp consisting of a fibrovascular core with scattered inflammatory cells and a covering of normal urothelium.

Leiomyoma and Leiomyosarcoma Smooth muscle tumors of the ureter and pelvis are much rarer than those of the kidney, and patients have an approximately equal frequency of benign and malignant tumors. Patients present with hematuria, pain, or mass, findings indistinguishable from those of urothelial neoplasms.135,136 Grossly, small tumors may form polypoid masses (Fig. 3.35), whereas larger tumors are often infiltrative. Histologically, they resemble their counterparts elsewhere.1 Hemangioma Hemangioma of the ureter and renal pelvis is an uncommon polypoid tumor (Fig. 3.36) consisting of hypervascular fibrous stroma covered by normal urothelium. Occurring in children and adults, this lesion may be multiple and frequently causes obstruction.137 Other Tumors Other sarcomas, such as osteogenic sarcoma, extraosseous Ewing sarcoma, liposarcoma, rhabdomyosarcoma, and malignant schwannoma are rare. Malignant melanoma may arise in the mucosa of the

178

CHAPTER 3

Renal Pelvis and Ureter

Fig. 3.36 Hemangioma of the ureter. Fig. 3.35 Leiomyosarcoma of ureter, gross appearance.

renal pelvis. Carcinosarcoma, combining squamous or urothelial carcinoma with heterologous sarcoma, such as osteogenic sarcoma, chondrosarcoma, or rhabdomyosarcoma, is rare. Choriocarcinomatous differentiation may be seen in coexisting urothelial carcinoma. Pure choriocarcinoma of the renal pelvis has been reported. Inflammatory myofibroblastic tumor involving the ureter is rare (see

detailed discussion in Chapters 5 and 6). Obstruction caused by secondary infiltration by malignant lymphoma occurs in approximately 16% of cases of disseminated lymphoma.101,103-106,129 References are available at expertconsult.com

CHAPTER 3 Renal Pelvis and Ureter

References 1. Cheng L, Lopez-Beltran A, Bostwick DG. Bladder Pathology. 1st ed. Hoboken, NJ: Wiley-Blackwell, 2012. 2. Bohnenpoll T, Kispert A. Ureter growth and differentiation. Semin Cell Dev Biol. 2014;36:21–30. 3. Blake J, Rosenblum ND. Renal branching morphogenesis: morphogenetic and signaling mechanisms. Semin Cell Dev Biol. 2014;36:2–12. 4. Ruano-Gil D, Coca-Payeras A, Tejedo-Mateu A. Obstruction and normal recanalization of the ureter in the human embryo. Its relation to congenital ureteric obstruction. Eur Urol. 1975;1:287–293. 5. Matsuno T, Tokunaka S, Koyanagi T. Muscular development in the urinary tract. J Urol. 1984;132:148–152. 6. Ferguson DR. Urothelial function. BJU Int. 1999;84:235–242. 7. Tan PH, Chiang GS, Tay AH. Pathology of urinary tract malformations in a paediatric autopsy series. Ann Acad Med Singapore. 1994;23:838–843. 8. Inamoto K, Tanaka S, Takemura K, Ikoma F. Duplication of the renal pelvis and ureter: associated anomalies and pathological conditions. Radiat Med. 1983;1:55–64. 9. Solomon BD, Bear KA, Kimonis V, et al. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A. 2012;158A:3087–3100. 10. Woods AG, Brandon DH. Prune belly syndrome. A focused physical assessment. Adv Neonatal Care. 2007;7:132–143, quiz 144–135. 11. Gomez Huertas M, Culianez Casas M, Molina Garcia FS, Carrillo Badillo MP, Pastor Pons E. Complementary role of magnetic resonance imaging in the study of the fetal urinary system. Radiologia. 2016;58:101–110. 12. Petit T, Ravasse P, Fououes Y, Delmas P. Retroperineoscopic excision of a single blind ectopic ureter in childhood. Surg Endosc. 2002;16:1105–1106. 13. Reisner DC, Elgethun MT, Heller MT, Klepchick PR, Hartman MS. Congenital and acquired disorders of ureteral course. Curr Probl Diagn Radiol. 2017;46:151–160. 14. Horasanli K, Bayar G, Acinikli H, Kutsal C, Kirecci SL, Dalkilic A. Lower urinary tract dysfunction in pediatric patients after ureteroneocystostomy due to vesicoureteral reflux: long-term follow-up. Low Urin Tract Symptoms. 2018 [Epub ahead of print], DOI: 10.1111/luts.12213. 15. Davidovits M, Cleper R, Eizenberg N, Hocherman O, Mashiach R. Outcomes of prenatally diagnosed solitary functioning kidney during early life. J Perinatol. 2017;37:1325–1329. 16. Sugarman J, Anderson J, Baschat AA, et al. Ethical considerations concerning amnioinfusions for treating fetal bilateral renal agenesis. Obstet Gynecol. 2018;131:130–134. 17. Choi H, Oh SJ. The management of children with complete ureteric duplication: selective use of uretero-ureterostomy as a primary and salvage procedure. BJU Int. 2000;86:508–512. 18. el Ghoneimi A, Miranda J, Truong T, Monfort G. Ectopic ureter with complete ureteric duplication: conservative surgical management. J Pediatr Surg. 1996;31:467–472. 19. Donmez MI, Yazici MS, Abat D, Kara O, Bayazit Y, Bilen CY. Laparoscopic upper pole heminephrectomy in adults for treatment of duplex kidneys. Urol J. 2015;12:2074–2077. 20. Mahmood H, Hadjipavlou M, Das R, Anderson C. Robotic partial nephrectomy for duplex kidney with ectopic ureter draining in the vagina in an adult patient with urinary incontinence. BMJ Case Rep. 2017;2017, DOI: 10.1136/bcr-2016-218576. 21. Kaefer M, Misseri R, Frank E, Rhee A, Lee SD. Refluxing ureteral reimplantation: a logical method for managing neonatal UVJ obstruction. J Pediatr Urol. 2014;10:824–830. 22. Eccles MR, Bailey RR, Abbott GD, Sullivan MJ. Unravelling the genetics of vesicoureteric reflux: a common familial disorder. Hum Mol Genet. 1996;5 Spec No: 1425–1429.

178.e1

23. Lee SK, Joseph VT. Vesico-ureteric reflux in Singapore children—a survey of surgically treated children. Ann Acad Med Singapore. 1984;13:593–598. 24. Autorino R, Eden C, El-Ghoneimi A, et al. Robot-assisted and laparoscopic repair of ureteropelvic junction obstruction: a systematic review and meta-analysis. Eur Urol. 2014;65:430–452. 25. Chiarenza SF, Bleve C, Fasoli L, et al. Ureteropelvic junction obstruction in children by polar vessels. Is laparoscopic vascular hitching procedure a good solution? Single center experience on 35 consecutive patients. J Pediatr Surg. 2016;51:310–314. 26. Fogarty JD, Hafron JM, Melman A. Renal obstruction caused by herniation of renal pelvis and ureteropelvic junction through superior lumbar triangle hernia (Grynfeltt hernia). Urology. 2006;67:620–621. 27. Jude E, Deshpande A, Barker A, Khosa J, Samnakay N. Intravesical ureteric reimplantation for primary obstructed megaureter in infants under 1 year of age. J Pediatr Urol. 2017;13 47:e41–e47. 28. Tokunaka S, Gotoh T, Koyanagi T, Miyabe N. Muscle dysplasia in megaureters. J Urol. 1984;131:383–390. 29. Didier RA, Chow JS, Kwatra NS, Retik AB, Lebowitz RL. The duplicated collecting system of the urinary tract: embryology, imaging appearances and clinical considerations. Pediatr Radiol. 2017;47:1526–1538. 30. Shah H, Tiwari C, Shenoy NS, Dwivedi P, Gandhi S. Transurethral incision of ureteroceles in paediatric age group. Turk J Urol. 2017;43:530–535. 31. Gupta R, Gupta S, Khan D, Basu S. Bilateral single system orthotopic ureterocele with bilateral multiple calculi presented with retention of urine - an urological emergency. J Clin Diagn Res. 2017;11: PD01–PD02. 32. Lazarou G, Andrikopoulou M, Cho S. Management of infected urethral diverticulum with urethral dilation. Female Pelvic Med Reconstr Surg. 2015;21:e17–e18. 33. Di Paola G, Mogorovich A, Manassero F, Ali G, Selli C. Pseudodiverticula of ureter: radiologic and histologic findings. Urology. 2009;73:268–269. 34. Oswald J, Brenner E, Schwentner C, et al. The intravesical ureter in children with vesicoureteral reflux: a morphological and immunohistochemical characterization. J Urol. 2003;170:2423–2427. 35. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and bladder tumours. Eur Urol. 2016;70:106–119. 36. Moch H, Humphrey PA, Ulbright TM, Reuter VE. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC) Press, 2016. 37. Epstein JI, Amin MB, Reuter VE. Biopsy Interpretation of the Bladder. 3rd ed. Philadelphia, PA: Lipppincott & Wilkins, 2016. 38. Ghali F, Pattison E, Pais VM, Jr. Keratinized squamous metaplasia of the upper urinary tract resulting in recurrent renal colic. Clin Nephrol. 2015;84:251–253. 39. Ganeshappa A, Krambeck A, Grignon DJ, Lingeman JE. Endoscopic management of keratinizing desquamative squamous metaplasia of the upper tract: a case report and review of the literature. J Endourol. 2009;23:1277–1279. 40. Holmang S, Lele SM, Johansson SL. Squamous cell carcinoma of the renal pelvis and ureter: incidence, symptoms, treatment and outcome. J Urol. 2007;178:51–56. 41. Sung MT, Lopez-Beltran A, Eble JN, et al. Divergent pathway of intestinal metaplasia and cystitis glandularis of the urinary bladder. Mod Pathol. 2006;19:1395–1401. 42. Sidharth, Maskey P, Chalise PR, et al. Primary mucinous adenocarcinoma of the renal pelvis and ureter. Nepal Med Coll J. 2011;13:229–230. 43. Chang CP, Wang SS, Wen MC, Ou YC. Mucinous adenocarcinoma of the renal pelvis masquerading as xanthogranulomatous pyelonephritis. Urology. 2013;81:e40–e41.

178.e2

CHA P T E R 3

Renal Pelvis and Ureter

44. Winston D, Yates JK, Munver R, Fromer D. A rare presentation of nephrogenic adenoma: multiple upper tract lesions in a female patient. Can J Urol. 2011;18:6064–6065. 45. Devine P, Ucci AA, Krain H, et al. Nephrogenic adenoma and embryonic kidney tubules share PNA receptor sites. Am J Clin Pathol. 1984;81:728–732. 46. Baker PM, Young RH. Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: a report of 4 cases. Hum Pathol. 2000;31:678–683. 47. Shapiro EY, Lipsky MJ, Cha DY, McKiernan JM, Benson MC, Gupta M. Outcomes of intrarenal Bacillus Calmette-Guerin/interferon-alpha2B for biopsy-proven upper-tract carcinoma in situ. J Endourol. 2012;26:1645–1650. 48. Rosenthal DL, Wojcik EM, Kurtycz DFI. The Paris System for Reporting Urinary Cytology. New York, NY: Springer International Publishing, 2016. 49. Li B, Haridas B, Jackson AR, et al. Inflammation drives renal scarring in experimental pyelonephritis. Am J Physiol Renal Physiol. 2017;312:F43–F53. 50. Zheng X, Si Q, Du D, et al. The Paris System for urine cytology in upper tract urothelial specimens: a comparative analysis with biopsy and surgical resection. Cytopathology. 2018;29:184–188. 51. Dong H, Dawes S, Philip J, Chaudhri S, Subramonian K. Malakoplakia of the urogenital tract. Urol Case Rep. 2015;3:6–8. 52. Yu M, Robinson K, Siegel C, Menias C. Complicated genitourinary tract infections and mimics. Curr Probl Diagn Radiol. 2017;46:74–83. 53. Ballesteros Sampol JJ. Urogenital malacoplakia. Report of 4 cases and review of the literature. Arch Esp Urol. 2001;54:768–776. 54. Machairiotis N, Stylianaki A, Dryllis G, et al. Extrapelvic endometriosis: a rare entity or an under diagnosed condition? Diagn Pathol. 2013;8:194. 55. Antonelli A, Simeone C, Zani D, et al. Clinical aspects and surgical treatment of urinary tract endometriosis: our experience with 31 cases. Eur Urol. 2006;49:1093–1097. discussion 1097-1098. 56. Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, Robboy SJ. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol. 2001;20:133–139. 57. Liu H, Zhang G, Niu Y, Jiang N, Xiao W. Retroperitoneal fibrosis: a clinical and outcome analysis of 58 cases and review of literature. Rheumatol Int. 2014;34:1665–1670. 58. Salvadori M, Tsalouchos A. Immunoglobulin G4-related kidney diseases: An updated review. World J Nephrol. 2018;7:29–40. 59. Clevenger JA, Wang M, MacLennan GT, Montironi R, LopezBeltran A, Cheng L. Evidence for clonal fibroblast proliferation and autoimmune process in idiopathic retroperitoneal fibrosis. Hum Pathol. 2012;43:1875–1880. 60. Visser O, Adolfsson J, Rossi S, et al. Incidence and survival of rare urogenital cancers in Europe. Eur J Cancer. 2012;48:456–464. 61. Roupret M, Babjuk M, Comperat E, et al. European Association of Urology Guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol. 2018;73:111–122. 62. Redrow GP, Guo CC, Brausi MA, et al. Upper urinary tract carcinoma in situ: Current knowledge, future direction. J Urol. 2017;197:287–295. 63. Busby JE, Brown GA, Tamboli P, et al. Upper urinary tract tumors with nontransitional histology: a single-center experience. Urology. 2006;67:518–523. 64. Manel A, Combe M, Devonec M. Inverted papilloma of the pyeloureteral junction, current literature data. Prog Urol. 2000;10:282–286. 65. Luo JD, Wang P, Chen J, et al. Upper urinary tract inverted papillomas: Report of 10 cases. Oncol Lett. 2012;4:71–74. 66. Brown AL, Cohen RJ. Inverted papilloma of the urinary tract. BJU Int. 2011;107 Suppl 3:24–26. 67. Mbeutcha A, Roupret M, Kamat AM, et al. Prognostic factors and predictive tools for upper tract urothelial carcinoma: a systematic review. World J Urol. 2017;35:337–353. 68. Nuhn P, Novara G, Seitz C, et al. Prognostic value of prior history of urothelial carcinoma of the bladder in patients with upper urinary

69. 70. 71.

72. 73. 74.

75. 76. 77. 78. 79. 80. 81.

82.

83. 84.

85. 86.

87. 88.

tract urothelial carcinoma: results from a retrospective multicenter study. World J Urol. 2015;33:1005–1013. Lughezzani G, Burger M, Margulis V, et al. Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature. Eur Urol. 2012;62:100–114. Nishino Y, Yamamoto N, Komeda H, Takahashi Y, Deguchi T. Bacillus Calmette-Guerin instillation treatment for carcinoma in situ of the upper urinary tract. BJU Int. 2000;85:799–801. Thalmann GN, Markwalder R, Walter B, Studer UE. Long-term experience with bacillus Calmette-Guerin therapy of upper urinary tract transitional cell carcinoma in patients not eligible for surgery. J Urol. 2002;168:1381–1385. Campbell MT, Shah AY, Matin SF, Siefker-Radtke AO. Optimizing management of upper tract urothelial carcinoma. Urol Oncol. 2017;35:492–498. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30. Novara G, De Marco V, Dalpiaz O, et al. Independent predictors of metachronous bladder transitional cell carcinoma (TCC) after nephroureterectomy for TCC of the upper urinary tract. BJU Int. 2008;101:1368–1374. Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol. 2000;164:1523–1525. Rink M, Robinson BD, Green DA, et al. Impact of histological variants on clinical outcomes of patients with upper urinary tract urothelial carcinoma. J Urol. 2012;188:398–404. Amin M, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017. Holmang S, Holmberg E, Johansson SL. A population-based study of tumours of the renal pelvis and ureter: incidence, aetiology and histopathological findings. Scand J Urol. 2013;47:491–496. Grollman AP, Shibutani S, Moriya M, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A. 2007;104:12129–12134. Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial carcinoma of the renal pelvis: a clinicopathologic study of 130 cases. Am J Surg Pathol. 2004;28:1545–1552. Kang CH, Yu TJ, Hsieh HH, Yang JW, Shu K, Shiue YL. Synchronous bilateral primary transitional cell carcinoma of the upper urinary tracts: ten patients with more than five years of follow-up. Urology. 2004;63:380–382. Pignot G, Colin P, Zerbib M, et al. Influence of previous or synchronous bladder cancer on oncologic outcomes after radical nephroureterectomy for upper urinary tract urothelial carcinoma. Urol Oncol. 2014;32: 23.e21–28. Holmang S, Johansson SL. Synchronous bilateral ureteral and renal pelvic carcinomas: incidence, etiology, treatment and outcome. Cancer. 2004;101:741–747. Novara G, De Marco V, Gottardo F, et al. Independent predictors of cancer-specific survival in transitional cell carcinoma of the upper urinary tract: multi-institutional dataset from 3 European centers. Cancer. 2007;110:1715–1722. Catto JW, Yates DR, Rehman I, et al. Behavior of urothelial carcinoma with respect to anatomical location. J Urol. 2007;177:1715–1720. Audenet F, Colin P, Yates DR, et al. A proportion of hereditary upper urinary tract urothelial carcinomas are misclassified as sporadic according to a multi-institutional database analysis: proposal of patient-specific risk identification tool. BJU Int. 2012;110: E583–E589. Anderstrom C, Johansson SL, Pettersson S, Wahlqvist L. Carcinoma of the ureter: a clinicopathologic study of 49 cases. J Urol. 1989;142:280–283. Peyronnet B, Seisen T, Dominguez-Escrig JL, et al. Oncological outcomes of laparoscopic nephroureterectomy versus open radical nephroureterectomy for upper tract urothelial carcinoma: An European Association of Urology Guidelines systematic review.

CHAPTER 3 Renal Pelvis and Ureter

89.

90.

91.

92.

93. 94. 95. 96.

97.

98.

99. 100.

101.

102. 103. 104.

105. 106.

Eur Urol Focus. 2017: [Epub ahead of print], DOI: 10.1016/j. euf.2017.10.003. Zigeuner RE, Hutterer G, Chromecki T, Rehak P, Langner C. Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location. BJU Int. 2006;98:1181–1186. Li WM, Shen JT, Li CC, et al. Oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. Eur Urol. 2010;57:963–969. Cosentino M, Palou J, Gaya JM, Breda A, Rodriguez-Faba O, Villavicencio-Mavrich H. Upper urinary tract urothelial cell carcinoma: location as a predictive factor for concomitant bladder carcinoma. World J Urol. 2013;31:141–145. Palou J, Rodriguez-Rubio F, Huguet J, et al. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumor. J Urol. 2005;174:859–861, discussion 861. Kirkali Z, Tuzel E. Transitional cell carcinoma of the ureter and renal pelvis. Crit Rev Oncol Hematol. 2003;47:155–169. Rink M, Ehdaie B, Cha EK, et al. Stage-specific impact of tumor location on oncologic outcomes in patients with upper and lower tract urothelial carcinoma following radical surgery. Eur Urol. 2012;62:677–684. Canales BK, Anderson JK, Premoli J, Slaton JW. Risk factors for upper tract recurrence in patients undergoing long-term surveillance for stage Ta bladder cancer. J Urol. 2006;175:74–77. Holmang S, Johansson SL. Long-term follow-up of patients with tumours of the renal pelvis and ureter: how often is a bladder tumour diagnosed after five tumour-free years? Scand J Urol. 2014;48:65–72. Amin MB, Srigley JR, Grignon DJ, et al. Updated protocol for the examination of specimens from patients with carcinoma of the urinary bladder, ureter, and renal pelvis. Arch Pathol Lab Med. 2003;127:1263–1279. Lopez-Beltran A, Bassi PF, Pavone-Macaluso M, Montironi R. European Society of Uropathology, Uropathology Working Group. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. A joint proposal of the European Society of Uropathology and the Uropathology Working Group. Virchows Arch. 2004;445:103–110. Cheng L, MacLennan GT, Lopez-Beltran A. Histologic grading of urothelial carcinoma: a reappraisal. Hum Pathol. 2012;43:2097–2108. Perez-Montiel D, Wakely PE, Hes O, Michal M, Suster S. Highgrade urothelial carcinoma of the renal pelvis: clinicopathologic study of 108 cases with emphasis on unusual morphologic variants. Mod Pathol. 2006;19:494–503. Hayashi H, Mann S, Kao CS, Grignon D, Idrees MT. Variant morphology in upper urinary tract urothelial carcinoma: a 14-year case series of biopsy and resection specimens. Hum Pathol. 2017;65: 209–216. Lopez-Beltran A, Paner G, Blanca A, et al. Lymphoepithelioma-like carcinoma of the upper urinary tract. Virchows Arch. 2017;470:703–709. Hirsch MS, Nascimento AF. PAX8 distinguishes diffuse large B-cell lymphoma mimicking sarcoma. Case Rep Pathol. 2017;2017: 6714549. Cho MH, Kim SH, Park WS, et al. Bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review. World J Surg Oncol. 2016;14:270. Cuadra-Urteaga JL, Font A, Tapia G, Areal J, Taron M. Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component. Cancer Biol Ther. 2016;17:233–236. Castagnetti M, Angelini L, Alaggio R, Scarzello G, Bisogno G, Rigamonti W. Oncologic outcome and urinary function after radical cystectomy for rhabdomyosarcoma in children: role of the orthotopic ileal neobladder based on 15-year experience at a single center. J Urol. 2014;191:1850–1855.

178.e3

107. Mellouli M, Charfi S, Smaoui W, et al. Prognostic role of lymphovascular invasion in patients with urothelial carcinoma of the upper urinary tract. Urol J. 2017;14:5008–5012. 108. Roscigno M, Shariat SF, Freschi M, et al. Assessment of the minimum number of lymph nodes needed to detect lymph node invasion at radical nephroureterectomy in patients with upper tract urothelial cancer. Urology. 2009;74:1070–1074. 109. Amin MB, Trpkov K, Lopez-Beltran A, Grignon D. Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the bladder lesions: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014;38:e20–e34. 110. Tacha D, Zhou D, Cheng L. Expression of PAX8 in normal and neoplastic tissues: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol. 2011;19:293–299. 111. Messer J, Shariat SF, Brien JC, et al. Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma. BJU Int. 2011;108:701–705. 112. Margolin EJ, Matulay JT, Li G, et al. Discordance between ureteroscopic biopsy and final pathology for upper tract urothelial carcinoma. J Urol. 2018;199:1440–1445. 113. Mian C, Mazzoleni G, Vikoler S, et al. Fluorescence in situ hybridisation in the diagnosis of upper urinary tract tumours. Eur Urol. 2010;58:288–292. 114. Roupret M, Yates DR, Comperat E, Cussenot O. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol. 2008;54:1226–1236. 115. Koornstra JJ, Mourits MJ, Sijmons RH, Leliveld AM, Hollema H, Kleibeuker JH. Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol. 2009;10:400–408. 116. Phelan A, Lopez-Beltran A, Montironi R, et al. Inherited forms of bladder cancer: a review of Lynch syndrome and other inherited conditions. Future Oncol. 2018;14:277–290. 117. Moller P, Seppala T, Bernstein I, et al. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut. 2017;66:1657–1664. 118. Hartmann A, Dietmaier W, Hofstadter F, Burgart LJ, Cheville JC, Blaszyk H. Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability. Hum Pathol. 2003;34:222–227. 119. Crockett DG, Wagner DG, Holmang S, Johansson SL, Lynch HT. Upper urinary tract carcinoma in Lynch syndrome cases. J Urol. 2011;185:1627–1630. 120. Harper HL, McKenney JK, Heald B, et al. Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome. Mod Pathol. 2017;30:146–156. 121. Hartmann A, Zanardo L, Bocker-Edmonston T, et al. Frequent microsatellite instability in sporadic tumors of the upper urinary tract. Cancer Res. 2002;62:6796–6802. 122. Mongiat-Artus P, Miquel C, Van der Aa M, et al. Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract. Oncogene. 2006;25: 2113–2118. 123. Roupret M, Catto J, Coulet F, et al. Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma. J Med Genet. 2004;41. e91. 124. Sfakianos JP, Cha EK, Iyer G, et al. Genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2015;68:970–977. 125. Catto JW, Azzouzi AR, Amira N, et al. Distinct patterns of microsatellite instability are seen in tumours of the urinary tract. Oncogene. 2003;22:8699–8706. 126. Moss TJ, Qi Y, Xi L, et al. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2017;72:641–649. 127. Nachiappan M, Litake MM, Paravatraj VG, Sharma N, Narasimhan A. Squamous cell carcinoma of the renal pelvis, a rare

178.e4

128.

129.

130.

131.

CHA P T E R 3

Renal Pelvis and Ureter

site for a commonly known malignancy. J Clin Diagn Res. 2016;10: PD04–PD06. Ng KF, Chuang CK, Chang PL, Chu SH, Wallace CG, Chen TC. Absence of Epstein-Barr virus infection in squamous cell carcinoma of upper urinary tract and urinary bladder. Urology. 2006;68: 775–777. Elawdy MM, Taha DE, Osman Y, El-Hamid MA, El-Mekresh M. Non-transitional cell carcinoma of the upper urinary tract: a case series among 305 cases at a tertiary urology institute. Urol Ann. 2017;9:99–102. Rao DS, Krigman HR, Walther PJ. Enteric type adenocarcinoma of the upper tract urothelium associated with ectopic ureter and renal dysplasia: an oncological rationale for complete extirpation of this aberrant developmental anomaly. J Urol. 1996;156:1272–1274. Manach Q, Phe V, Parra J, Renard-Penna R, Comperat E, Bitker MO. Ureteral metastasis of prostatic adenocarcinoma: case report and literature review. Prog Urol. 2013;23:1443–1448.

132. Liu H, Hemminki K, Sundquist J, et al. Second primary cancers after cancer of unknown primary in Sweden and Germany: efficacy of the modern work-up. Eur J Cancer Prev. 2013;22:210–214. 133. Carey RI, Bird VG. Endoscopic management of 10 separate fibroepithelial polyps arising in a single ureter. Urology. 2006;67:413–415. 134. Li R, Lightfoot M, Alsyouf M, Nicolay L, Baldwin DD, Chamberlin DA. Diagnosis and management of ureteral fibroepithelial polyps in children: a new treatment algorithm. J Pediatr Urol. 2015;11:22.e21–22.e26. 135. Englund M, McCredie S, Robson S. Leiomyoma of the ureter. ANZ J Surg. 2017;87:E92–E93. 136. Aubert E, Millet I, Serre I, Taourel P. Leiomyosarcoma of the ureter: a rare case. Diagn Interv Imaging. 2012;93:60–63. 137. Ferrero Doria R, Garcia Victor F, Moreno Perez F, Gasso Matoses M, Diaz Calleja E. Cavernous haemangioma as the cause of ureteral pyelic junction obstruction. Arch Esp Urol. 2005;58:960–963.