Renal agenesis and duplication, and positional abnormalities of the upper tract are the result of growth failure or abnormal branching of the ureteric duct from the mesonephric duct.

Total failure of the ureteric duct to develop results in renal agenesis. Bilateral renal agenesis is rare, with a reported incidence of 3.5/10⁵ live births,¹²,¹³ while unilateral agenesis is more frequently encountered¹² and in one series was detected in 1/1,200 of children on screening.¹⁴ Renal agenesis may also arise when there is failure of the ureteric duct to fuse with the metanephros, and where the ureteric duct may persist to form a blind diverticulum part way along the length of the ureter.

During elongation of the ureteric duct, with associated renal ascent, splitting of the ampullary bud may occur. In cases where this splitting occurs early in nephrogenesis or if two separate ampullary buds form along the length of the mesonephric duct, then double renal pelves and ureters will form, giving rise to a duplex collecting system (Fig. 4-2). Typically the vesicoureteral orifice of the upper pole ureter in a duplex system lies medial and caudal to the lower pole orifice, although exceptions to this rule have been reported. When splitting of the ureteric duct is a late event, a bifid ureter forms with two renal pelves, which drain into separate ureters that fuse to terminate in a single vesicoureteral orifice¹⁵,¹⁶ (Fig. 4-3). The site of the junction of bifid ureters depends on timing of the branching of the ureteric
duct; however, in the majority of cases, this is in the lower third of the ureter and may be sited in the bladder wall.¹⁷

During embryogenesis the developing ureteric duct migrates distally along the mesonephric duct to fuse with the bladder, and the vesicoureteral orifice migrates to its normal trigonal position. If the ureteric duct develops in close proximity to the bladder, then migration of the vesicoureteral orifice extends beyond the trigone in both the caudal and lateral planes. Often the ectopic ureter is inserted more directly into the bladder wall with loss of the valve mechanism and resulting vesicoureteral reflux.¹⁸ In extreme cases the ureteral orifice extends beyond the bladder, and the ureter terminates in the urethra or the genital structures that develop from the mesonephric duct.¹⁶ In females ureteral ectopia is associated with a duplex system in 80% of cases, while in males there is usually a single renal outflow tract.¹⁸ Further, as the ureteric duct takes its origin from the mesonephric duct, upper tract abnormalities are often associated with other malformations of the urogenital system and are found in the prune belly and VATER syndromes and trisomy 21.

Clinical features of congenital abnormalities of the upper tract are variable although there is often reflux and urinary stasis leading to urinary tract infection, lithiasis, and fistula formation. Ureteral duplications are often asymptomatic although cyclic abdominal pain may occasionally be a presenting feature.¹⁷ Ultrasonography is valuable in the demonstration of malformations in utero and in neonates. The role of the pathologist may be to define the anatomic basis of a functional deficiency.

Ureteropelvic Junction (UPJ) obstruction refers to the significant functional impairment of urinary flow from the renal pelvis to the ureter leading to hydronephrosis (Fig. 4-4). The majority of cases are congenital and occur in the pediatric age group. More rarely the obstruction may be secondary to postoperative or inflammatory strictures, renal stones, and urothelial neoplasms, including fibroepithelial polyps.¹⁹,²⁰ Rarely UPJ obstruction is associated with renal parenchymal neoplasia. There is also a reported association with congenital renal abnormalities in 15% to 20% of patients,²¹ with agenesis and cystic renal dysplasia in the contralateral kidney,²² and with vasculitis.²³ Functional obstruction has also been reported due to extrinsic compression by an aberrant lower pole vessel. This is seen in 16% to 20% of patients with UPJ obstruction with a median age of 67 months at presentation.²⁴ UPJ obstruction is more likely to be unilateral in adults, while pediatric cases are more frequently bilateral.

Congenital UPJ obstruction affects 13,000 newborns annually in the United States with hospitalization rates of 2.4/100,000 for patients aged ≤18 years. The highest incidence is in children <3 years of age with hospital admission rates of 9.3/100,000 being reported,¹⁹ and in this age group there is a male predominance.²⁵ Ethnicity appears not to be a significant factor although slightly higher hospitalization rates for UPJ obstruction have been noted for patients of Hispanic origin.¹⁹

Transport of urine from the renal papilla to the bladder is active and dependent on smooth muscle contraction, with some modulation by the autonomic nervous system.²⁶ In many cases of clinical UPJ obstruction, no identifiable lesion is seen and the impairment is functional.²⁷ Earlier studies have demonstrated abnormalities at both a cellular and ultrastructural level, and in particular increased interstitial collagen has been implicated,²⁸ although this is likely to be a secondary effect. Folds in the muscle or overlying mucosa, or the development of kinks or strictures that lead to reorientation of muscle bundles into a predominantly longitudinal pattern, have also been suggested as a pathogenic mechanism for UPJ obstruction.²⁹,³⁰ Recent reports utilizing S100 protein, CKIT protooncogene protein (CD117), and synaptophysin immunohistochemistry suggest a defect in innervation as the cause of UPJ obstruction.³¹ The UPJ is not normally innervated, and in cases of obstruction it is apparent that this segment extends for a longer distance down the proximal ureter.³² Defective innervation is supported by a finding of increased vasoactive intestinal peptide and decreased levels of synaptophysin and nerve growth factor receptor in UPJ obstruction.³² Transforming growth factor beta 1 (TGF-β1) has recently been shown to be increased in UPJ obstruction; however, this may be a secondary effect leading to the promotion of extracellular matrix formation and collagen synthesis.³³

Prior to the advent of ultrasound investigations, UPJ obstruction was usually diagnosed during investigations for
azotemia, urinary tract infection, or hematuria. The majority of cases are now discovered by the detection of renal pelvis dilatation on prenatal or perinatal ultrasound, and it is recommended that a dilatation of ≥5 mm be further investigated.³⁴ Asymptomatic cases of UPJ obstruction are usually treated conservatively, and in those patients with good renal function, the outcome is favorable whether the treatment is conservative or surgical. While patients with moderate impairment may benefit from pyeloplasty, those with poor function usually have minimal recovery following pyeloplasty.²⁷

The gross surgical specimen in congenital UPJ obstruction is usually funnel shaped (Fig. 4-5), and thickening of the portion of the renal pelvis in the vicinity of the UPJ may be present. The histologic findings are variable and nonspecific, and occasionally no abnormality is seen. The mucosa is usually normal although projections resembling mucosal folds may be present.³⁵ There is occasionally hypertrophy of the smooth muscle layer³² although this is more commonly thinned, and segmental loss of smooth muscle has also been reported.³⁶ Interstitial fibrosis is the most common finding although this is variable and may be associated with a mild diffuse chronic inflammatory infiltrate (Fig. 4-6). On electron microscopy, increased interstitial collagen is usually observed.

Ureteral diverticula are rare and may be congenital or acquired. Symptoms are nonspecific; however, dysuria and hematuria may be presenting features.³⁷ Congenital diverticula are related to sites of weakness within the ureteral wall and are most commonly found adjacent to the ureteropelvic and vesicoureteral junctions. Other abnormalities of the urinary tract may be found in conjunction with congenital diverticula.³⁸

Acquired diverticula are probably secondary to chronic infection or ureteral obstruction.³⁹,⁴⁰ Occasionally multiple diverticula may be present, and it has been suggested that these are acquired, being the result of chronic infection.⁴¹ It is recommended that treatment of small acquired diverticula should be directed toward management of the predisposing condition,³⁶ although larger diverticula may require surgical resection.

Histologically, congenital diverticula contain all three layers of the ureteral wall, while acquired diverticula usually have a thinned mucosal layer.³⁷

Paraureteral diverticula originate within the bladder wall, adjacent to the ureteral orifice, and are due to a failure of normal muscle development or a defect in Waldeyer fascia.⁴² In some cases, these can expand to involve the ureter with vesicoureteral reflux or outflow obstruction.⁴³ There is occasionally coexisting renal dysplasia, and an association with pelvicalyceal duplication has been reported.⁴⁴,⁴⁵ Treatment is surgical and consists of diverticulectomy with or without ureteral reimplantation.⁴³

Ureterocele is the cystic dilatation of the distal ureter that projects into the bladder (Fig. 4-7). This most commonly occurs in Caucasian females,⁴⁶ and there is an annual hospitalization rate of 1/10⁵ in the pediatric age group, with 92% of hospital admissions being children under the age of 2 years.⁴⁷ The pathogenesis is uncertain and persistence of Chawalla membrane has been suggested, as has abnormality of the ureteral muscularis.⁴⁸ It has been estimated that there is an association with a duplex system in 95% of cases in females and 44% of cases in males.⁴⁷ Ureterocele associated with duplex ureter usually occurs in the upper pole ureter and is situated more inferiorly than ureterocele that arises from a single ureter. Previously ureteroceles arising in association with duplex ureters have been designated ectopic ureterocele; however, this term is now limited to those
ureteroceles that extend beyond the bladder into the bladder neck or urethra.⁴⁹ If a ureterocele burrows between the bladder mucosa and muscularis to lie intramurally, the term cecoureterocele is applied.

Ureterocele is associated with dilatation of the proximal ureter and often results in reflux and hydronephrosis. Larger ureteroceles may also obstruct the contralateral ureter or the normal ipsilateral ureter in a duplex system. Obstruction of renal outflow from ureterocele may lead to cystic renal dysplasia or renal scarring, and in 10% of cases hypertension develops.⁵⁰

The histologic features of ureterocele relate to chronicity. The surface mucosa of ureterocele originates from the bladder, while the cyst lumen is lined by ureteral mucosa⁵¹ (Fig. 4-8). The muscularis may show hypertrophy or be attenuated and atrophic, with interstitial edema and variable interstitial fibrosis.

Treatment of ureterocele consists of early prophylactic antibiotic therapy, to minimize the effect of urinary tract infection. Endoscopic puncture may be undertaken as an emergency procedure, followed by surgical excision of the ureterocele and ureteral reconstruction.⁵²

Megaureter is dilation of the ureter. This is considered to be primary if it is the result of a defect of intrinsic smooth muscle. It is most commonly seen in the pediatric age group and is characterized by a ureteral diameter of >7 mm. Megaureter is not a specific diagnosis and may be associated with reflux or outflow obstruction, although a significant proportion is nonrefluxing and nonobstructed. These three categories of megaureter are further subdivided into primary and secondary groups⁵³ (Table 4-1). The pathogenesis of megaureter is dependent on the type; however, there is an association with abnormalities of the urinary tract, particularly cystic renal dysplasia.⁵⁴

Rarely congenital nonrefluxing megaureter is associated with ureteral dysplasia where the muscularis has poorly formed myocytes, with absent or poor organization into muscle bundles. There is usually pronounced interstitial fibrosis with a variable infiltrate of lymphocytes and plasma cells.⁶⁴,⁶⁵ On ultrastructural examination there is thinning of myofilaments, wide separation of cell membranes, a decrease in numbers of nexuses, and an increase in collagen fibers and ground substance.⁶⁵

It has been shown that ureteral dysplasia is evident at 11 weeks’ gestation, and as there is an association with urinary outflow obstruction early in nephrogenesis, cystic renal dysplasia frequently occurs.⁶³ The pathogenesis of ureteral dysplasia is unknown although muscle contractility studies show decreased amplitude of contractions and decreased response to adrenergic drugs.⁶⁶ On imaging there is dilatation of the involved ureteral segment, which is usually sited in the distal ureter. In severe cases interstitial fibrosis leads to ureteral obstruction, although, in most cases this obstruction is functional rather than anatomical.⁶⁷

Treatment of ureteral dysplasia involves resection of the dysplastic segment with ureteral reimplantation.⁶⁸

Ureteral stricture may be either congenital or secondary to trauma and inflammation. The pathogenesis of congenital stricture is uncertain and may be associated with failure of complete recanalization of the ureter, which undergoes temporary obliteration during fetal development.⁶⁹,⁷⁰ An alternative theory is that congenital ureteral stricture is due to external compression of the ureter by fetal vessels leading to incomplete smooth muscle development.⁷¹ This latter theory accords with the histologic findings, which consist of segmental absence of muscle and narrowing of the ureteral lumen. Congenital ureteral stricture may occur in isolation or may be a component of multiple organ syndromes.⁷² There is also an association with ipsilateral and contralateral cystic renal dysplasia, solitary kidney, and blind ending of the contralateral ureter.

Secondary ureteral stricture is a recognized complication of ureteral endoscopy and pelvic surgery, with an incidence ranging from 0.5% to 3%.⁷³ Other secondary causes of ureteral stricture are trauma, ureteral infections, including tuberculosis and inflammation in adjacent organs, radiation, ureteral lithiasis; vasculitis and ischemia, amyloidosis, and endometriosis.⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹

Primary tumors of the ureter, especially urothelial carcinoma, usually present with ureteral stricture, and hydronephrosis and stricture may also be seen in association with extraureteral tumors that involve the ureter by direct infiltration or metastatic spread (Fig. 4-12).

Ureteral valves are a rare cause of ureteral outflow obstruction with <60 cases being reported.⁸⁰ The majority of cases occur in males in the pediatric age group, with hydronephrosis being the most frequently associated finding. In many cases there is also an association with abnormalities of the kidney and ureters.¹¹

The pathogenesis of ureteral valves is debated; however, it has been suggested that they represent a persistent Chawalla membrane or an exuberant form of the ureteral folds seen in normal fetal development.¹¹,⁸¹

Specific criteria for the diagnosis of ureteral valves have been proposed; (i) The leaflets should be covered by mucosa and contain smooth muscle, (ii) There should be ureteral obstruction proximal to the fold but not distal to it, and (iii) There should be no other evidence of either functional or mechanical obstruction.⁸¹ The requirement for the identification of smooth muscle in the leaflet is debated, while others require smooth muscle in the leaflet base.¹¹ Valves may occur throughout the length of the ureter, with 50% reported from the proximal ureter, 17% the mid ureter, and 33% the distal ureter. Histologically, ureteral valves may form leaflets or an annular ring of mucosal-covered connective tissue.

Management of valve leaflets is surgical with most treated by ureteroureterostomy, ureteropyelostomy, or longitudinal ureterotomy.¹¹

Ureteral folds are rarely detected on excretory urography, and these occasionally have a corkscrew appearance.¹⁰ These folds consist of lamina propria and smooth muscle and probably represent persistent fetal ureteral tortuosity.¹⁰,⁸² Most cases of ureteral folds are not associated with outflow obstruction, although rarely hydronephrosis may be a presenting feature.⁸³

Infection of the upper urinary tract is usually secondary to lower tract infection and may be associated with urinary tract obstruction, voiding dysfunction, and urinary tract abnormalities (ureteral duplication, megaureter, and UPJ obstruction). Other significant contributing factors include catheterization, instrumentalization, and urinary tract lithiasis, while ureteral infection may occur secondary to pyelonephritis.

The most common pathogenic bacterial organism in the urinary tract is Escherichia coli although Proteus, Klebsiella, Enterococcus, Pseudomonas, and Serratia are frequently encountered. Struvite lithiasis is often associated with Proteus and less commonly Morganella infection.⁸⁴

Mycobacterium infection of the ureter (Fig. 4-13A and B) is usually secondary to renal infection and may result in the development of stricture leading to hydronephrosis. Mycobacterium tuberculosis is most frequently involved, although M. avium, M. kansasii, and M. bovis infections are also well described.

Upper tract fungal infections are usually associated with systemic disease or localized renal infection in an immunocompromised patient. A wide variety of fungi have been reported as renal pelvis and ureteral pathogens with Candida being the most commonly seen. This may form a fungal bezoar within the renal pelvis and, as is reported for Aspergillus and Coccidioides, may result in ureteral stricture formation.⁸⁵,⁸⁶ There is a single case report of extragenital granuloma inguinale presenting as a soft tissue neoplasm involving the ureter.⁸⁷

While more commonly occurring in the urinary bladder, renal parenchyma, and genital tract, occasional cases of malacoplakia of the renal pelvis and ureter (Fig. 4-13C) have been reported.⁸⁸, ⁸⁹, ⁹⁰ There is a female predominance with ages of patients ranging from 24 to 78 years (mean 66 years).⁸⁸,⁹¹ In the majority of cases, there were no reported preexisting conditions although an association with concurrent acute inflammation and immunosuppression has been noted,⁸⁹,⁹² and there is a single case report of malacoplakia in a transplant ureter.⁹³

Malacoplakia of the renal pelvis and/or ureter usually presents as an exophytic tumor-like lesion on imaging and may be mistaken for urothelial carcinoma.⁹⁴ Urinary cytology has also been shown to be diagnostic in rare instances.⁹⁵ Disease may be bilateral or unilateral and is often associated with urinary obstruction and hydronephrosis.⁹⁴ Malacoplakia has also been reported as a cause of secondary UPJ obstruction.⁹⁶ On occasion inflammation may be limited to the renal pelvis or ureter; however, there is usually concurrent malacoplakia in the urinary bladder or renal parenchyma, and it has been suggested that involvement of the urinary outflow tract is a secondary feature.⁹⁷

Grossly the lesion may be solitary or multifocal and is soft friable and exophytic ranging from white to pale yellow in color.

Histology shows typical features of malacoplakia with early lesions resembling xanthogranulomatous inflammation without Michaelis-Gutmann bodies, while later lesions may be associated with interstitial fibrosis.⁹²,⁹⁸ On ultrastructural examination both histiocytes and urothelial cells contain cytoplasmic multilamellar bodies.⁹⁹

Few reports have identified organisms within foci of malacoplakia although E. coli has been isolated,⁸⁶ and treatment usually involves either localized or radical resection with adjuvant antibiotic therapy. Occasionally antibiotic treatment alone, or in combination of ureteral stenting, is successful.⁸⁸,⁸⁹,¹⁰⁰

Renal lithiasis is a common problem, especially in Western countries, and is increasing in frequency. Within the United States, it is estimated that 13% of males and 7% of females will be diagnosed with a renal stone and that the likelihood of recurrence is up to 50% on a 5-year follow-up.¹⁰¹,¹⁰² The advent of nonsurgical treatments has led to a decline in hospitalization for renal lithiasis although in 2000, 62/100,000 population were treated as inpatients for upper tract stones in the United States, with the rates being highest for the 55- to 64-year age group.¹⁰¹

Stone composition is variable (Table 4-2) and in the majority of instances stones form as the result of metabolic disorders, dietary factors, and/or urinary tract abnormalities, although medications such as adenosine, ephedrine, indinavir, and triamterene have been implicated. There is a strong
genetic predisposition to some forms of nephrolithiasis, and genes associated with cystinuria, hyperoxaluria, and X-linked nephrolithiasis have been identified.¹⁰³ In many cases multiple genetic loci are involved and this reflects the many and diverse causes of hypercalciuria. A separate pathogenesis is described for struvite stones, which form as a result of chronic bacterial infection of the urinary tract, with the presence of urea-splitting bacteria being necessary for the generation of inorganic carbonate and phosphate.¹⁰⁴

The natural history of stones within the renal pelvis and ureter is dependent on stone type and the metabolic environment. In general terms calyceal stones are asymptomatic
when small, but if untreated, almost 50% will become symptomatic in 5 years.¹⁰⁵ Larger stones within the renal pelvis may present with urinary tract infection, pain, hematuria, dysuria, and obstruction, especially at the UPJ¹⁰⁶ (Fig. 4-14).

Ureteral stones (Fig. 4-15) are often symptomatic, and impaction, with urinary outflow obstruction, may be a presenting feature. Stones >5 mm in diameter usually require intervention as they are unlikely to pass spontaneously,¹⁰⁵ and complications include localized mucosal ulceration and edema, leading to scarring and stricture formation, or ureteral perforation.

The pressure effect of renal stones on the mucosa of the renal pelvis is compounded by recurrent acute or chronic inflammation. This results in mucosal ulceration, reactive hyperplasia of adjacent urothelium, granulation tissue formation, and fibrosis. Chronic inflammation predisposes to reactive epithelial changes with a predominance of squamous metaplasia. Other benign mucosal changes reported from the renal pelvis in association with renal lithiasis are pyelitis follicularis, pyelitis cystica, polypoid pyelitis, xanthogranulomatous pyelitis, encrusted pyelitis, and fibroepithelial polyposis.¹⁰⁷ Similar changes are seen in the ureter with chronic inflammation being associated with squamous metaplasia, ureteritis follicularis, ureteritis cystica, and polypoid ureteritis.¹⁰⁷

Renal lithiasis is a recognized risk factor for renal pelvic and ureteral malignancy.¹⁰⁸ The risk of developing malignancy is enhanced by recurrent urinary tract infections and is most commonly associated with struvite staghorn calculi. In some series the risk of malignancy increased with chronicity, while in others the risk remained stable over a 10-year follow-up.¹⁰⁹ Urothelial carcinoma (UC) is the tumor most frequently associated with lithiasis, although squamous cell carcinoma (SCC) occurs in 20% of cases and has been found in 2% of patients with recurrent staghorn calculi.¹¹⁰ In addition to these tumors, verrucous carcinoma, sarcomatoid SCC, small cell (neuroendocrine) carcinoma, and adenocarcinoma have been reported.¹¹¹, ¹¹², ¹¹³

Although the kidney is the most common organ to be involved in many of the forms of systemic vasculitis,¹¹⁴ reports of vasculitis of the renal pelvis and ureter are rare and are usually confined to single cases. Vasculitis of the urinary outflow tract often occurs as part of multisystem disease and presents as UPJ obstruction or ureteral stenosis, which may be unilateral or bilateral, with secondary hydronephrosis.

Renal pelvic or ureteral vasculitis has been reported as part of the polyarteritis group of systemic vasculitis (classic polyarteritis nodosa,¹¹⁵ polyarteritis nodosa associated with hepatitis B,¹¹⁶ and acute febrile mucocutaneous lymph node syndrome),²³ as well as with Henoch-Schőnlein hypersensitivity angiitis¹¹⁷. In these cases ureteral stenosis was associated with typical clinical and pathologic systemic features. Renal pelvic and ureteral vasculitis has also been noted in Churg-Strauss syndrome¹¹⁸ and Wegener granulomatosis¹¹⁹ in patients with established pulmonary disease. Limited Wegener granulomatosis, involving the urogenital tract, has also been associated with ureteral vasculitis.¹²⁰

Ureteral angiitis as part of the systemic manifestation of rheumatic connective tissue disease occurs rarely and has
been noted in cases of systemic sclerosis,¹²¹ systemic lupus erythematosus,¹²² and dermatomyositis.¹²³

Hemorrhage into the renal pelvis may be associated with subepithelial hematoma (Antopol-Goldman lesion).¹³⁶ Often misdiagnosed as renal pelvic neoplasia, 25 cases of subepithelial hematoma have been reported. There is a female predominance with the ages of patients ranging from 24 to 84 years.¹³⁶, ¹³⁷, ¹³⁸ In several cases the cause of the hematoma could not be determined, while in others it was shown to be secondary to trauma, hypertension, analgesic abuse, or coagulopathy. In five cases subepithelial hematomas were associated with congenital renal abnormalities.¹³⁶, ¹³⁷, ¹³⁸ Histologic findings are nonspecific and consist of subepithelial hemorrhage, which may be associated with peripelvic hemorrhage, renal cortical infarction, or hydronephrosis.¹³⁸ The majority of cases have been treated by nephrectomy or partial nephrectomy; however, once the diagnosis is established, conservative therapy is advocated.¹³⁸

Hemorrhage into the renal pelvis, in the absence of subepithelial hematoma or neoplasia, has been associated with coumadin anticoagulant therapy¹³⁹ and has been recognized as a complication of retrograde endopyelotomy.¹⁴⁰

Retroperitoneal fibrosis is typically a diffuse fibrous process that involves the aorta, vena cava, and structures of the retroperitoneum. It may be primary or idiopathic or in approximately 25% of cases is secondary to autoimmune diseases, malignancy, trauma and surgery, chronic infection, drugs (methysergide, pergolide, ergotamine, methyldopa, hydralazine, and beta-blockers), and radiation.¹⁴¹ There is a prevalence of 1 to 2 cases per 200,000 with a male predominance, and although pediatric cases are well recognized,¹⁴² the majority of patients are 50 to 60 years of age at diagnosis.¹⁴³

The pathogenesis of retroperitoneal fibrosis is uncertain, and the association of secondary forms of the disease with hyperimmune states suggests an autoimmune etiology. There is also a reported association with asbestosis, autoimmune thyroid disease including Riedel thyroiditis, Wegener granulomatosis, mediastinal fibrosis, polyarteritis nodosa, systemic lupus erythematosus, sclerosing cholangitis and primary biliary cirrhosis, UC, and sclerosing lymphoma.¹⁴⁴

Clinical features are nonspecific and relate to the structure encased in fibrous tissue. Often there is ureteral involvement, and in neglected cases renal failure is a common complication. Laboratory results are similarly nonspecific
with elevated C-reactive protein and erythrocyte sedimentation rate, as well as positive antinuclear antibodies being the most frequent findings.

Macroscopically, retroperitoneal fibrosis consists of white fibrous plaques that encase retroperitoneal structures. The fibrosis is usually diffuse; however, in occasional cases the fibrosis is confined to single organs, and localized ureteral (Fig. 4-17A) and perirenal retroperitoneal fibrosis has been reported.¹⁴⁵ On microscopic examination (Fig. 4-17B) the lesions consist of sheets of fibroblasts showing variable cellularity. There is frequently an associated inflammatory infiltrate consisting predominantly of lymphocytes and plasma cells. In older lesions the inflammatory cell infiltrate is less prominent, and there is hyalinization, occasionally with dystrophic calcification.¹⁴¹ Vascular changes resembling vasculitis, with intramural inflammatory cells and fibrinoid necrosis, are often present.

In the majority of cases, there is both a symptomatic and clinical response to steroids with a resulting decrease in the volume of fibrous tissue.¹⁴¹ Stenting of ureters is frequently necessary, and in cases refractile to steroids, surgical intervention, consisting of ureteral replacement and autotransplantation of the kidney may be required. Often the disease relapses and long-term follow-up is necessary.¹⁴³ In cases of secondary retroperitoneal fibrosis, treatment of the primary disease process may lead to a reduction in the volume of fibrous tissue.

Topical chemotherapeutic agents such as triethylenethiophosphoramide (thiotepa) and mitomycin C are used to treat superficial urothelial cancer of the upper tract and may produce urothelial atypia.¹⁴⁶,¹⁴⁷ Reactive urothelial atypia may also be caused by chemotherapeutic agents given systemically to treat neoplastic and nonneoplastic disorders. Among these, cyclophosphamide is known to have significant effects on urothelium and can reactivate polyoma virus infection, which morphologically can also mimic carcinoma. busulfan, adriamycin, epirubicin, ethoglucid, cisplatin, and mitoxantrone are other agents known to cause urothelial changes.¹⁴⁷

Thiotepa and mitomycin C cause a pronounced necroinflammatory process and mucosal denudation accompanied by enlargement, vacuolization, and multinucleation of urothelial cells. These changes can last for several weeks after treatment.¹⁴⁷ Cyclophosphamide produces variable cellular and nuclear enlargement, with binucleation and multinucleation. In these cases, usually there are large, bizarre nuclei resembling those seen after radiotherapy. Nuclei are often eccentric, irregular in outline, and hyperchromatic, with coarse chromatin mimicking carcinoma cells. However, unlike carcinoma, there is loss of chromatin texture with nuclear pyknosis. Cyclophosphamide may also cause hemorrhagic pyelitis and ureteritis, in addition to cystitis. The histologic changes include vascular ectasia with severe edema and hemorrhage of the lamina propria, usually associated with necrosis of the epithelial lining, and mucosal ulceration.¹⁴⁸

Biopsies from patients with stents or strictures and after instrumentation can have atypical changes mimicking urothelial CIS. In contrast to urothelial CIS, reactive atypia displays cellular and nuclear enlargement with prominent nucleoli and mitotic activity in the absence of significant pleomorphism and chromatin abnormalities. Immunohistochemistry (CK20, P53, and CD44) may be helpful however, correlation with morphology is critical due to overlap in immunoprofile in reactive versus neoplastic conditions.

Endometriosis, the benign proliferation of ectopic endometrial mucosa, involves the urinary tract in 2% of reported cases.¹⁴⁹ In most of these instances, endometriosis is confined to the urinary bladder; however, in 16% of cases one or both ureters are also involved.¹⁵⁰ In most cases of urinary tract endometriosis, symptoms of dysuria, frequency, recurrent urinary tract infection, and/or renal angle pain are reported, although endometriosis confined to the ureter is asymptomatic in 60% of patients.¹⁵¹

In endometriosis diffusely spread within the pelvis and in the urinary tract, lesions are more commonly found on the left side, and it has been speculated that this is a reflection of the direction of flow of peritoneal fluid that carries regurgitated endometrial tissue to ectopic sites.¹⁴⁹

In 65% of cases involving the ureters, endometriosis is superficial within the overlying peritoneal tissues, and in a further 30% of cases, the endometriotic deposits lie adjacent to the ureter. Intramural endometriosis is present in only 5% of lesions, and these are usually associated with ureteral stenosis.¹⁵⁰,¹⁵²

The histologic features of ureteral endometriosis are similar to those seen in other organs. Recognizable endometrial epithelium and stroma may be present, or there may be recent hemorrhage and/or aggregates of hemosiderin and hemosiderin-laden macrophages (Fig. 4-18). In the latter instance CD10 immunohistochemistry is often useful for detecting small foci of residual endometrial stroma. Rarely, Müllerianosis with endocervicosis or endosalpingiosis can be seen as ureteric lesions. In some cases there is associated endometriosis.¹⁵³

Rarely endometrioid adenocarcinoma may arise in ureteral endometriosis, and in one reported case there was no evidence of residual endometriosis in the genital tract or elsewhere in the urinary tract.¹⁵⁴

Management of endometriosis of the ureter is dependent on the site of the lesion. Peritoneal deposits are amenable to laparoscopic excision, while intramural endometriosis may require ureteral resection and anastomosis.¹⁵³,¹⁵⁵

Primary localized amyloidosis is rarely seen in the urinary tract with <50 reported cases involving the renal pelvis and ureter.¹⁵⁶, ¹⁵⁷, ¹⁵⁸ There is a male predominance, and patients are usually >50 years of age, with pyrexia, hematuria, and flank pain being common presenting features.¹⁵⁶ On imaging, ureteral stricture and hydronephrosis are frequent findings. This may be unilateral or bilateral and in most cases mimics invasive UC.¹⁵⁷ Although urinary cytology may provide evidence of the correct diagnosis,¹⁵⁷ most cases are diagnosed following surgery.

Histologically, amyloid deposits are interstitial and most commonly involve the lamina propria and muscularis. The amyloid is usually of the AL type, as demonstrated by congophilia with resistance to permanganate treatment, and on immunohistochemistry consists of lambda light chains. Rarely osseous metaplasia may occur.¹⁵⁹ Management usually involves surgical resection of the involved segment.