This document discusses various pathologies of the ureter, bladder, and urethra. It begins by describing common congenital anomalies of the ureter including double and bifid ureters as well as ureteropelvic junction obstruction. It then discusses non-neoplastic conditions of the bladder such as vesical diverticula, cystitis, and various metaplastic lesions. Neoplastic conditions covered include urothelial carcinoma and adenocarcinomas of the bladder. Finally, it briefly mentions primary carcinoma of the urethra.

1. PATHOLOGY OF URETER,
BLADDER, AND URETHRA
By
Ali Faris

2. OBJECTIVES:
 Congenital Anomalies of the ureter :
* Double and bifid ureters
* Ureteropelvic junction (UPJ) obstruction
 non-neoplastic conditions of the bladder : Vesical diverticula, Cystitis, and Metaplastic
lesions of the bladder
 Neoplastic conditions of bladder: Urothelial carcinoma and Adenocarcinomas of the
bladder.
 Urethra: primary carcinoma

3. The renal pelvis, ureters, bladder, and urethra (except the terminal portion) are lined by "Urothelium".
Beneath the mucosa are the lamina propria and, deeper yet, the muscularis propria (detrusor muscle),
which makes up the bladder wall.

4. URETER
 The main pathological lesions involving the ureter include:
 Congenital Anomalies:
* Double and bifid ureters
* Ureteropelvic junction (UPJ) obstruction
 Obstructive Lesions: as a result of calculi, tumours, blood clots
 Primary malignant tumours:
 Primary malignant tumours of the ureter follow patterns similar to those arising in the
renal pelvis, calyces, and bladder, and a majority are urothelial carcinomas. Primary
tumors of the ureter are rare.

5. DOUBLE AND BIFID URETERS
 Double ureters are almost invariably
associated with totally distinct double renal
pelves or with the anomalous development
of a large kidney having a partially bifid
pelvis terminating in separate ureters.
 Double ureters may pursue separate
courses to the bladder but commonly are
joined within the bladder wall and drain
through a single ureteral orifice.
 Most are unilateral and of no clinical
significance.

6. URETEROPELVIC JUNCTION (UPJ)
OBSTRUCTION
 a congenital disorder, results in
hydronephrosis.
 It usually manifests in infancy or childhood,
much more commonly in boys.
 It is the most frequent cause of
hydronephrosis in infants and children.
 Grossly: the renal pelvis is markedly
dilated, but the ureter is not, indicating
that the point of obstruction is at the
ureteropelvic junction.

7. URETEROPELVIC JUNCTION (UPJ)
OBSTRUCTION

8. RETROPERITONEAL FIBROSIS
 It is an uncommon cause of ureteral narrowing or obstruction,
 characterized by a fibrous proliferative inflammatory process encasing the retroperitoneal
structures and causing hydronephrosis.
 The disorder occurs in middle to old age.
 The affected sites include: the pancreas, retroperitoneum, and salivary glands, to mention a
few.
 Causes:
1. The majority of cases have no obvious cause and are considered primary, or idiopathic (Ormond
disease).
2. At least a proportion of these cases are related to the newly described entity in which elevations of
serum IgG4 are associated with fibroinflammatory lesions that are rich in IgG4-secreting plasma cells.
3. Other cases are associated with drug exposures (ergot derivatives, adrenergic blockers), or malignant
disease (lymphomas, urinary tract carcinomas).

9. 2. RETROPERITONEAL FIBROSIS

10. bladder
Neopla
sms
Adenocarcinomas
Urothelial
carcinoma
Non-
neoplastic
lesions of the
bladder
Metaplastic Cystitis
Vesical
diverticula

11. BLADDER OR VESICAL DIVERTICULUM
 Consists of a pouchlike evagination of the
bladder wall.
 Diverticula may be congenital but more
commonly are acquired lesions that arise
as a consequence of persistent urethral
obstruction caused, for example, by
benign prostatic hyperplasia.
 Although most diverticula are small and
asymptomatic, they sometimes lead to
urinary stasis and predispose to infection.

12. CYSTITIS
 Cystitis takes many forms.
 Most cases stem from nonspecific acute or chronic
inflammation of the bladder.
 Etiology:
1. The common etiologic agents of bacterial cystitis are
coliform bacteria.
2. Patients receiving cytotoxic antitumor drugs, such as
cyclophosphamide, sometimes develop hemorrhagic
cystitis.
3. Adenovirus infection also causes a hemorrhagic cystitis.
 Several distinct variants of cystitis are defined by
either morphologic appearance or causation
(Interstitial cystitis, Malakoplakia, Polypoid cystitis).

13. INTERSTITIAL CYSTITIS (I.E., CHRONIC
PELVIC PAIN SYNDROME)
 is a persistent, painful form of chronic cystitis
occurring most frequently in women.
 It is characterized by intermittent, often severe
suprapubic pain, urinary frequency, urgency,
hematuria and dysuria without evidence of
bacterial infection.
 There are cystoscopic findings of fissures and
punctate hemorrhages (glomerulations) in the
bladder mucosa.
 The histologic findings are nonspecific.
 Late in the course, transmural fibrosis may
ensue, leading to a contracted bladder.

14. No epithelium and
plenty of ulceration. Not high powered,
therefore can't
see mast cells.
Difficult to treat
due to
unknown
etiology.

15. Ulcerating, no
PMN, mast
cells, chronic
inflammation.
Difficult to know
how to treat
these patients.
Sometimes
steroids are
given.

16. MALAKOPLAKIA
 Malakoplakia: from Greek Malako "soft" + Plako "plaque"
 Most commonly occurs in the bladder.
 Results from defects in phagocytic or degradative function of macrophages, such that
phagosomes become overloaded with undigested bacterial products. The macrophages have
abundant granular cytoplasm filled with phagosomes stuffed with particulate and
membranous bacterial debris.
 In addition, laminated mineralized concretions resulting from deposition of calcium in
enlarged lysosomes, known as Michaelis-Gutmann bodies, typically are present within the
macrophages.

17. POLYPOID CYSTITIS
 Is an inflammatory condition resulting from irritation to the bladder mucosa in which the urothelium is thrown
into broad bulbous polypoid projections as a result of marked submucosal edema.
 Polypoid cystitis may be confused with papillary urothelial carcinoma both clinically and histologically.

18. METAPLASIA
 Various metaplastic lesions may occur in the bladder:
1. Cystitis glandularis: Nests of urothelium (Brunn nests) may grow downward into the
lamina propria, and their central epithelial cells may variously differentiate into a
cuboidal or columnar epithelium lining.
2. Cystitis cystica: cystic spaces filled with clear fluid lined by flattened urothelium.
 Maybe there are goblet cells resembling intestinal mucosa (intestinal or
colonic metaplasia).
 As a response to injury, the urothelium often undergoes squamous
metaplasia, which must be differentiated from normal glycogenated
squamous epithelium, commonly found at the trigone in women.

19. METAPLASIA (BRUNN NESTS)
Solid nests of benign urothelial cells often with
regular contour.
Cells have normal cytology and orderly
arrangement.

20. METAPLASIA (CYSTITIS GLANDULARIS)
similar to cystitis cystica but with luminal cuboidal or columnar cells surrounded by
urothelial cells

21. METAPLASIA (CYSTITIS CYSTICA)
May appear grossly as pearly or
luminescent cysts with intact surface
urothelium.
Well-defined nests of urothelium with a centrally dilated
lumen (like von Brunn's nests but with a hole in the
middle).

22. INTESTINAL METAPLASIA
identical to typical cystitis glandularis but with presence of goblet cells

23. METAPLASIA
Both cystitis cystica and glandularis

25. NEOPLASMS
 Bladder cancer accounts for approximately 7% of cancers and 3% of cancer deaths in the
United States.
 The vast majority of bladder cancers (90%) are urothelial carcinomas.
 Carcinoma of the bladder is more common in men than in women, in industrialized than
in developing nations, and in urban than in rural dwellers.
 About 80% of patients are between the ages of 50 and 80 years.
 PATHOGENESIS OF BLADDER CANCER
 Bladder cancer, with rare exceptions, is not familial.
 Some of the most common factors implicated in the causation of urothelial carcinoma
include:
1. cigarette smoking
2. various occupational carcinogens
3. Schistosoma haematobium infections in areas where it is endemic, such as Egypt.

26. PATHOGENESIS OF BLADDER CANCERS
 Genetic Models for bladder carcinogenesis include:
1. A model for bladder carcinogenesis has been proposed in which the tumor is initiated by
deletions of tumor-suppressor genes on 9p and 9q, leading to formation of superficial
papillary tumors, a few of which may then acquire TP53 mutations and progress to
invasion.
2. A second pathway, possibly initiated by TP53 mutations, leads first to carcinoma in situ
and then, with loss of chromosome 9, progresses to invasion.
3. The underlying genetic alterations in superficial tumors include fibroblast growth factor
receptor 3 (FGFR3) mutations and activation of the Ras pathway.

27. MORPHOLOGY
 Two distinct precursor lesions to invasive urothelial
carcinoma are recognized:
1. Noninvasive papillary neoplasms (maybe low or high
grade)
2. Flat noninvasive carcinoma in situ (uniformly high
grade).
 In about half of the patients with invasive bladder
cancer, no precursor lesion is found; in such cases, it
is presumed that the precursor lesion was
overgrown by the high-grade invasive component.

28. NON INVASIVE PAPILLARY UROTHELIAL
NEOPLASMS
 The most common precursor lesion to invasive urothelial carcinoma.
 Demonstrate range of atypia and are graded to reflect their biologic behavior
 The most common grading system classifies tumors as follows:
1. Papilloma.
2. Papillary urothelial neoplasm of low malignant potential (PUNLMP).
3. Low grade papillary urothelial carcinoma.
4. High grade papillary urothelial carcinoma
 These exophytic papillary neoplasms are to be distinguished from inverted urothelial
papilloma, which is entirely benign and not associated with an increased risk for subsequent
carcinoma.

29. NON INVASIVE PAPILLARY UROTHELIAL
NEOPLASMS

30. CARCINOMA IN SITU (CIS)
 CIS is defined by the presence of cytologically
malignant cells within a flat urothelium (Fig. 17–18).
 Like high-grade papillary urothelial carcinoma, CIS
tumor cells lack cohesiveness. This leads to the
shedding of malignant cells into the urine, where
they can be detected by cytology.
 CIS commonly is multifocal and sometimes involves
most of the bladder surface or extends into the
ureters and urethra.
 On cystoscopic examination it may appear only as a
flat area of erythema or granularity. It is often
multifocal
 CIS is often asymptomatic.
 Without treatment, 50% to 75% of CIS cases
progress to muscle-invasive cancer

31. A urothelial CIS is shown. The atypical cells form a
disorganized epithelial layer that occupies the full
thickness of the urothelium but does not invade
through the basement membrane .
For the urothelium, any malignant cells above the
basement membrane qualify as CIS.
CARCINOMA IN SITU (CIS)

32. INVASIVE UROTHELIAL CANCER
 Invasive urothelial cancer associated with papillary urothelial cancer (usually of high grade) or
CIS may superficially invade the lamina propria or extend more deeply into underlying muscle.
 Underestimation of the extent of invasion in biopsy specimens is a significant problem.
 The extent of invasion and spread (staging) at the time of initial diagnosis is the most
important prognostic factor.
 Almost all infiltrating urothelial carcinomas are of high grade.

34. JUST KIDDING

35. OTHER EPITHELIAL BLADDER TUMORS
 Squamous cell carcinomas:
 resembling squamous cancers occurring at other sites
 Make up about 3% to 7% of bladder cancers in the United
States but are much more common in countries where urinary
schistosomiasis is endemic.
 Pure squamous cell carcinomas are nearly always associated
with chronic bladder irritation and infection.
 Mixed urothelial carcinomas with areas of squamous
carcinoma are more frequent than pure squamous cell
carcinomas.
 Most are invasive, fungating tumors or are infiltrative and
ulcerative
 The level of cellular differentiation varies widely, from well
differentiated lesions producing abundant keratin to
anaplastic tumors with only focal evidence of squamous
differentiation.
Squamous cell carcinoma : showing area of keratinization
(sample taken from Al kindy college of medicine pathology
lab)

36. SQUAMOUS CELL CARCINOMAS:
Gross: large necrotic mass that is typically invasive Keratin production

37. OTHER EPITHELIAL BLADDER TUMORS
 Adenocarcinomas of the bladder are rare and are histologically identical to adenocarcinomas
seen in the gastrointestinal tract.
 Some arise from urachal remnants in the dome of the bladder or in association with extensive
intestinal metaplasia.

38. STAGING OF BLADDER CANCERS
 Grading: tumor grade is the description of a tumor based on how abnormal the tumor cells
and the tumor tissue look under a microscope.
 Staging: cancer stage refers to the size and/or extent (reach) of the original (primary) tumor
and whether or not cancer cells have spread in the body.
 According to the TNM staging system (Tumor, Lymph node, Metastasis),The majority of
bladder cancers fall into one of the following categories:

39. STAGING OF BLADDER CANCERS (TNM)

40. CLINICAL FEATURES
 Bladder tumors most commonly present with painless hematuria.
 Patients with urothelial tumors, whatever their grade, have a tendency to develop new tumors after
excision, and recurrences may exhibit a higher grade.
 The risk of recurrence is related to several factors, including tumor size, stage, grade, multifocality,
mitotic index, and associated dysplasia and/or CIS in the surrounding mucosa.
 Most recurrent tumors arise at sites different than that of the original lesion, yet share the same
clonal abnormalities as those of the initial tumor, thus, these are true recurrences that stem from
shedding and implantation of the original tumor cells at new sites.
 Whereas high-grade papillary urothelial carcinomas frequently are associated with either concurrent
or subsequent invasive urothelial carcinoma.
 lower-grade papillary urothelial neoplasms often recur but infrequently invade

41. TREATMENT
 The treatment for bladder cancer depends on tumor grade and stage and on whether the lesion is
flat or papillary.
 For small localized papillary tumors that are not high grade, the initial transurethral resection is
both diagnostic and therapeutically sufficient.
 Patients with tumors that are at high risk for recurrence or progression typically receive topical
immunotherapy consisting of intravesical instillation of an attenuated strain of the tuberculosis
bacillus called Bacille Calmette-Guérin (BCG).
 BCG elicits a typical granulomatous reaction, and in doing so also triggers an effective local
antitumor immune response.
 Patients are closely monitored for tumor recurrence with periodic cystoscopy and urine cytologic
studies for the rest of their lives.
 Radical cystectomy typically is reserved for (1) tumor invading the muscularis propria; (2) CIS or
high-grade papillary cancer refractory to BCG; and (3) CIS extending into the prostatic urethra and
down the prostatic ducts, where BCG cannot contact the neoplastic cells.
 Advanced bladder cancer is treated using chemotherapy, which can palliate but is not curatives

42. TUMORS OF THE URETHRA
 Primary carcinoma of the urethra is an uncommon
lesion
 Tumors arising within the proximal urethra tend to
show urothelial differentiation and are analogous to
those occurring within the bladder,
 whereas lesions found within the distal urethra are
more often squamous cell carcinomas.
 Adeno carcinomas are infrequent in the urethra and
generally occur in women.
 Some neoplastic lesions of the urethra are similar to
those described in the bladder, arising through
metaplasia or, less commonly, from periurethral
glands.
 Cancers arising within the prostatic urethra are dealt
with in the section on the prostate.

43. REFERENCES
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Philadelphia, PA: Saunders/Elsevier, 668-671.
 Klatt, Edward C., 1951- author. (2015). Robbins and Cotran atlas of pathology.
Philadelphia, PA :Elsevier/Saunders, 343-349
 Husain A. Sattar., (2011). Fundamentals of pathology. 1st ed.). 135
 Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic
basis of disease (Ninth edition.). Philadelphia, PA: Elsevier/Saunders. 959-969
 Harsh Mohan, (2015). Textbook of PATHOLOGY 7th ed.). Philadelphia, PA 19106,
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