Ureteral narrowings are at ureteropelvic junction, crossing of external/common iliac artery and where ureters enter bladder; these are also sites of obstruction and stone impaction

Ureters enter bladder in oblique manner; bladder muscle contraction mechanically closes off ureteral orifice; defects cause reflux

Congenital abnormalities

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Diverticuli: cause urinary tract infections

Double/bifid ureters: associated with duplication of renal pelves

Hydroureter: may have neurogenic cause

Megaloureter: may have smooth muscle defect

Ureteropelvic obstruction:

Causes hydronephrosis

More common in males and on left side, 20% bilateral

May be associated with agenesis of contralateral kidney

May be due to abnormal organization of smooth muscle bundles

Inflammation of ureters

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Associated with long-standing chronic inflammation

Ureteritis cystica: fine cysts in mucosa composed of dilated Brunn’s nests with clear contents

Ureteral follicularis: fine granular mucosa due to multiple lymphoid follicles

Ureteritis glandularis: intestinal metaplasia in ureters

Granuloma inguinale: case report of extragenital granuloma inguinale presenting as a retroperitoneal mass resembling a soft tissue neoplasm and involving the ureter, Hum Path 1990;21:559

Micro: tiny mucin-containing microcysts and medium sized tubular structures resembling renal tubules and lined by cuboidal cells; cytologic atypia characterized by enlarged vesicular nuclei and prominent nucleoli; no mitotic figures; may have transmural involvement and appear infiltrative, Mod Path 2002;15:765, AJCP 1983;80:92

Micro images: image1, image2, image3, image4, image5, cytokeratin

Positive stains: CK7, AE1-AE3, mucin

Negative stains: CEA, p53, Ki-67 (<5%)

EM: epithelial cells with sparse microvilli and thick basal lamina

Ureteral obstructive lesions

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INTRINSIC

Stones (<= 5 mm), usually lodge at ureteropelvic junction, where ureters cross iliac artery, where ureters enter bladder

Strictures (congenital or due to sclerosing retroperitoneal fibrosis)

Tumors, blood clots, neurogenic causes

EXTRINSIC

Pregnancy, local inflammation, endometriosis, local tumors (ureteral obstruction is a major cause of death from cervical carcinoma)

Sclerosing retroperitoneal fibrosis

Adults 40+

70% idiopathic; others associated with ergot derivatives, beta blockers, adjacent inflammation, local tumors

Associated with mediastinal fibrosis, sclerosing cholangitis, Riedel thyroiditis

May have autoimmune origin

Micro: lymphocytes, plasma cells, eosinophils; variable granulomatous inflammation

Ileal conduits

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Ureteroileal anastomotic sites for ileal conduits in childhood show various chronic changes; microscopically show cystically dilated intestinal glands, urothelial lined cysts, mucus pools and intestinal epithelial lined cysts, Hum Path 1993,24:189

WHO/ISUP classification of urothelial neoplasms

Note: similar information is in bladder chapter/outline

WHO/ISUP - general

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Prior classification systems

Ash (1940) – classify as transitional cell carcinoma grades 1-4; grade 1 comparable to papilloma, grade 2 comparable to low grade; grades 3 (most) and 4 comparable to high grade

Mostofi (1960) – grade 1 called papilloma and not carcinoma

WHO/ISUP: World Health Organization / International Society of Urologic Pathologists consensus classification that is controversial for some lesions (low malignant potential)

Major changes from prior systems are that papillary urothelial carcinomas must exhibit atypia and carcinoma in situ need not be full thickness

WHO/ISUP grade correlates with tumor stage and recurrence

Website tutorial (click here), has further discussion; free but requires registration,

Classification:

Normal: flat mucosa with no overt thickness; includes slight disorganization of cells and nuclear pleomorphism, formerly termed mild dysplasia; size of normal urothelial cells is 3x lymphocytes, image1

Hyperplasia: flat or papillary

Flat lesions with atypia: reactive, unknown significance, dysplasia (LG IUN), CIS (HG IUN)

Papillary urothelial neoplasms: papilloma, inverted papilloma, low malignant potential, low grade, high grade

Invasive urothelial neoplasms: lamina propria invasion, muscularis propria invasion (for bladder)

Low grade neoplasms

Includes papilloma, inverted papilloma, low malignant potential, low grade papillary urothelial neoplasms,

urothelial carcinoma grade 1 of 3, some urothelial carcinomas grade 2 of 3

Hyperplasia

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Flat hyperplasia

Markedly thickened mucosa without cytologic atypia, image1

May be adjacent to low grade papillary urothelial neoplasm

By itself has no malignant potential and requires no treatment

Papillary hyperplasia

Slight tenting, undulating or papillary growth lined by urothelium of varying thickness, without atypia

Asymptomatic, found on routine follow-up cystoscopy of papillary urothelial neoplasms

Often has small dilated capillaries at base, but no well defined fibrovascular core; lacks discrete papillary fronds associated with papillary neoplasm, image1

Treatment: follow up if new, unknown if increased risk of papillary neoplasm in patient with prior history of papillary urothelial tumor

Papillary hyperplasia with atypia

Architectural pattern of papillary hyperplasia with atypia of overlying urothelium

80% male, age range 55 to 92 years

At diagnosis, 50% associated with flat carcinoma in situ, 30% with dysplasia

Prognostic implications: usually associated with high grade papillary urothelial carcinoma; also CIS and invasive urothelial carcinoma, Hum Path 2002;33:512

Flat lesions with atypia

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Reactive: inflammatory atypia; uniformly enlarged and vesicular nuclei, central prominent nucleoli, may have frequent mitotic figures; may have history of instrumentation, stones or therapy; not neoplastic, image1

Flat lesions of unknown significance: between reactive atypia and dysplasia, more pleomorphism and hyperchromasia than expected for the amount of inflammation present; should have close follow up and reevaluation after inflammation subsides, image1

Dysplasia

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Aka low grade intraurothelial neoplasia (LG IUN)

Low interobserver agreement on diagnosis, even among experts

Micro: appreciable cytologic and architectural changes indicative of neoplasia, but less than CIS, image1

Carcinoma in situ

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Aka high grade intraurothelial neoplasia (HG IUN)

Usually flat lesion, not papillary

Precursor of invasive cancer in some cases

May shed atypical cells into urine, making cytology valuable for diagnosis

Micro: flat lesion composed of cells with large, irregular, hyperchromatic nuclei, mitotic figures in mid to upper epithelium; atypia may not be full thickness

In bladder, nuclear area 5x lymphocytes vs. 2x lymphocytes for normal urothelium, Hum Path 2001;32:997

Also (but less important) loss of polarity, nuclear crowding, irregular thickness of urothelium

Note: high grade non-invasive papillary lesions are NOT designated carcinoma in situ to avoid confusion

Micro images: image1

Patterns: large cells with, or large cells without pleomorphism, small cell, clinging (single layer of atypical cells on denuded urothelium), cancerization of urothelium (pagetoid, undermining or overriding); pattern need not be included in surgical pathology report

Associated microinvasion (2 mm or less) demonstrates invasive cells with retraction artifact mimicking vascular invasion (77% of cases of microinvasion); also nests or irregular cords, rarely as isolated single cells with or without desmoplasia, AJSP 2001;25:356

Positive stains: typical pattern is CK20+, p53+, CD44-; E-cadherin positive (Hum Path 2002;33:996)

DD: denuding cystitis (cells may look malignant), reactive atypia (patchy CK20 in umbrella cells only, p53 weak/negative, CD44 diffusely or focally positive vs. CIS with intense CK20 and p53 positivity in 81% and 57% of cases, CD44 negative in all cases, AJSP 2001;25:1074)

Papillary urothelial neoplasms – not carcinoma

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Papilloma

Rare, benign, usually small and isolated in younger patients

May recur

Gross: soft, pink, delicate papillary structures, usually pedunculated

Micro: distinct papillary growth, small delicate stalk with central fibrovascular core lined by urothelium of normal thickness and cytology; no fusion of adjacent fronds; papillary fronds may appear detached due to sectioning of complex arborizing papillary structures; necrosis rare; minimal mitosis

Micro images: image #1; #2

Reference: Mod Path 2000;13:1315

Inverted urothelial papilloma

Adult and elderly men

Low risk of recurrence if completely excised

May be associated with urothelial carcinoma, rarely in the inverted urothelial papilloma itself

Gross: usually solitary, polypoid, pedunculated; at trigone, bladder neck or prostatic urethra

Micro: invagination of epithelium, no atypia, no papillae, minimal stroma

Epithelium may be insular, trabecular, pallisading, gland-like resembling cystitis glandularis; rarely neuroendocrine

DD: urothelial carcinoma invading into Brunn nests

Papillary urothelial neoplasms of low malignant potential

May arise in young patients

1/3 recur, 5% as higher grade; 10 year survival 95% or more

Are rarely associated with invasion or metastases

Some question distinguishing these lesions from low grade papillary urothelial carcinomas

Add to report "Patients with these tumors are at risk of developing new bladder tumors ("recurrence"), usually of a similar histology. However, since these subsequent lesions occasionally manifest as urothelial carcinoma, follow up is warranted."

Have lower MIB-1, p53, mitotic counts than low grade papillary carcinomas, and higher disease free survival (76 vs. 15 months), AJSP 2001;25:1528

Micro: orderly arrangement of cells within papillae with minimal architectural abnormalities and minimal nuclear atypia, regardless of cell thickness; thicker epithelium than papilloma, increase in nuclear size and hyperchromasia compared to papilloma; mitotic figures if present are usually confined to basal layer

Micro images: image #1; A and B; #2

Reference: Mod Path 2001;14:267, Mod Path 2000;13:1315

Benign tumors

Benign tumors-general

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Usually mesenchymal, such as leiomyoma or fibroepithelial polyp

Fibroepithelial polyps protrude into lumen, also seen in bladder, renal pelves, urethra; composed of loose vascularized connective tissue beneath mucosa

May be affected by neurofibromatosis, AJSP 1989;13:873

Leiomyoma

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Case reports: 43 year old man with flank pain and gross hematuria (Case of the Week #203)

Nephrogenic adenoma

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Mean age 52 years, range 15 to 94 years (entire urinary tract), M/F = 2:1

Ureter rare site (4% of all urinary tract tumors)

Micro: usually tubular or cystic pattern; also papillary; composed of small, hollow, round tubules; some solid, occasionally elongated; may have pseudoinfiltrative appearances; basement membrane around tubules may be appreciable but not prominent; tubules/cysts often have eosinophilic or basophilic secretion
Reference: Mod Path 1995;8:722

Malignant tumors

Urothelial carcinomas

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Urothelial carcinoma of renal pelvis and ureter often lumped together as “upper urinary tract”

Most malignancies of ureter are urothelial carcinomas

Most patients are women, age 50+, non-white

Cause obstruction, may be multiple, occur concurrently in lower urinary tract

Associated with smoking, occupational exposure to arylamines, analgesic nephropathy, Balkan nephropathy

Also associated with hereditary nonpolyposis colorectal cancer syndrome (HNPCC), characterized by mutations in DNA mismatch repair genes, detectable by microsatellite instability; associated with family history of colon cancer and higher grade urothelial carcinomas, Mod Path 2002;15:790

Case reports: micropapillary urothelial carcinoma (Archives 2000;124:1347), HNPCC (Archives 2003;127:E60)

Overall 5 year survival (including renal pelvis) is 75%

Tumor grade and stage are most important predictors of prognosis

Low grade, noninvasive papillary urothelial carcinomas are monoclonal - multiple synchronous tumors appear to be due to intramucosal seeding, Hum Path 1999;30:1197

Treatment: nephroureterectomy with excision of ipsilateral ureteral orifice and bladder cuff en bloc

Micro images: figure 1C/1D, image1, image2,

Positive stains: thrombomodulin (AJCP 1998;110:385)

Molecular image: microsatellite instability

Metastases

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Common site for ovarian cancer metastases (24% of patients) at autopsy, Hum Path 1988;19:57

Staging

Primary Tumor (T)

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TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

Ta: Papillary noninvasive carcinoma

Tis: Carcinoma in situ

T1: Tumor invades subepithelial connective tissue

T2: Tumor invades the muscularis

T3: Tumor invades beyond muscularis into periureteric fat

T4: Tumor invades adjacent organs, or through the kidney into the perinephric fat

Regional Lymph Nodes (N)

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Note: laterality does not affect the N classification

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension

N2: Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension

N3: Metastasis in a lymph node, more than 5 cm in greatest dimension

Distant Metastasis (M)

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M0: No distant metastasis

M1: Distant metastasis

Anatomic stage / prognostic groups

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Stage 0a: Ta N0 M0

Stage 0is: Tis N0 M0

Stage I: T1 N0 M0

Stage II: T2 N0 M0

Stage III: T3 N0 M0

Stage IV: T4 N0 M0 or Any T N1-3 M0 or M1

End of Ureters chapter