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1. PATHOLOGYAND STAGING OF BLADDER
TUMORS
Dr Vipin Sharma ( Mch 1 st year)

2. • Layers of the bladder
 urothelium 3-7 layers thick
 BM
 lamina propria -muscularis mucosa, blood vessels, lymphatic,
nerves
 muscularis propria - inner longitudinal, middle circular, and outer
longitudinal
 serosa

3. Layers of bladder

4. • Hyperplasia :-increase in no of cell layers without nuclear or
architectural abnormalities.
Atypical hyperplasia: -Increase in no of cells with nuclear or
architectural changes
 Metaplasia: - change in epithelium with squamous or adenomatous
development.
Epithelial dysplasia:-Epithelial changes that are intermediate
between normal urothelium and CIS (severe dysplasia)
- 15% risk of developing high grade TCC

5. classification
• Benign tumors of bladder
• Epithelial metaplasia ,leucoplakia ,inverted papilloma ,nephrogenic adenoma
, leiomyoma ,cystitis cystica ,cystitis glandularis
• Urothelial cancer
• Non urothelial malignancy
• Sarcoma ,signet ring cell carcinoma ,squamous cell carcinoma ,prostatic
urethral cancer

6. Histologic Type of Tumors of the Urinary Bladder According to the World
Health Organization 2004 Classification

7. Inverted Papilloma
-Benign proliferative lesion
-Associated with
-Chronic inflammation
-Bladder outlet obstruction.
-Located throughout the bladder
-Most common - Trigon
-Less than 1% of all bladder tumors.

8. Inverted Papilloma
-Demonstrate an inverted growth pattern
-“Anastomosing islands of histologically and cytologically normal
urothelial cells invaginating from the surface urothelium into the lamina
propria.
-No muscularis propria invasion”
 Differential diagnosis :
Urothelial cancer with an inverted growth pattern.
 Fluorescent in-situ hybridization (FISH) -differentiate
- 1 % incidence of recurrence

9. - PAPILLOMA
• Delicate stalks lined by normal appearing urothelium.
• -Recurrence is common.
• -Do not progress or invade the bladder
NEPHROGENIC ADENOMA
 Chronic irritation of the urothelium.
-Trauma,
-Previous surgery,
-Renal transplantation,
-Intravesical chemotherapy,
-Stones,
-Catheters,
-Infection.

10. • Nephrogenic adenoma arises from nests of displaced
mesonephric tissue in the urothelium that is activated with
mucosal injury
• May be vascular  gross hematuria
• Incidence: Male = female
• -Involve the mucosa and sub mucosa of the bladder.
• -Covered by cuboidal cells with clear or eosinophilia cytoplasm.
• -Infiltration by inflammatory cells.
Nephrogenic Adenoma

11. Cystitis Cystica and Glandularis
-A common finding in normal bladders
-Associated with
– Inflammation and Chronic obstruction
-Cystic nests lined by columnar or cuboidal cells
-Associated with proliferation of Von Brunn nests
-Rarely transform in to Adenocarcinoma
-Regular endoscopic evaluation recommended
• Presenting features:
• Irritative voiding Symptom sand Hematuria
• Treatment
• Eliminate the cause of irritation
• Transurethral resection

12. Von Brunn nest with cystitis cystica

13. Cystitis Glandularis
• Associated with pelvic lipomatosis
• May occupy the majority of the bladder.
• May develop in to or coexist with intestinal metaplasia (usually benign).
• Leiomyoma
• Most common non epithelial benign tumor
• Most commonly in women of childbearing age
• Histologically similar to leiomyomas of the uterus
• Appear as smooth indentations of the bladder

14. Cystitis Glandularis

15. Urothelial carcinoma
• Most common malignancy of urinary tract
• Second most common cause of death among genitourinary tumor
• Initially 80% urothelial tumor is non muscle invasive(NMIBC)
• NMIBC are large comparative to muscle invasive tumors
• NMIBC includes CIS ,PUNLMP ,low and high grade urothelial cancer
(sup. cancer)

17. Molecular mechanisms
Normal urothelium
Induction of cancer Progression of cancer
Activation of proto-oncogenes
Loss of tumor suppressor genes
Abnormal expression of,
Growth factors
Adhesion molecules
Angiogenic factors
Carcinogens from occupation,
Smoking, infection, radiation,
chemotherapy
Carcinoma of bladder

18. Tumor suppressor genes
Low grade papillry CIS and muscle invasive High grade papillary
and Muscle invasive
TP53 mutations (17p13) Uncommon Hallmark- 60% Hallmark- >50%
PTEN (10q23) Rare Hallmark Hallmark- 30-35%
RB gene (13q14) Rare Hallmark Hallmark-37%
Deletions of Ch regions 9P16, 9p21 Hallmark Absent in pure CIS 70-80%
Loss of heterozygosity (LOH) of Ch 9 >50% Rare Rare

19. proto oncogenes
Low grade papillry CIS and muscle invasive High grade papillary
and Muscle invasive
Alterations in the
fibroblast growth factor receptor–3
(FGFR-3) - 4p16
Hallmark-75% Infrequent-20% Common
Deletions -9p14, 9q11-13, 9q33-34 Hallmark Absent in pure CIS 70-80%
H RAS mutations- (11p15) 15% 10-15% 10-15%
Point mutations in PIK3CA (3q26) 16% Rare Rare
Over expression of C-Erb B2 (7q) Uncommon 10-14% 10-14%

20. CIS
papillary,flat
high-grade tumors in which the surface epithelium contains cancer cells
• Spread – Distal ureters and prostatic urethra on the surface or in a
pagetoid manner
•Urine cytology - 80- 90 % positive
• 40 - 83% progress to muscle-invasive cancer
• Endoscopically, - reddish with heaped-up mucosa can be
mistaken
for inflammatory changes or
radiation cystitis.

21. • Muscle invasive
• Histology:
• Invading urothelium shows irregular nests, single cell
infiltration or tentacular finger-like projections .
• Stromal response
-desmoplasia,
-retraction or
-inflammation.
• Assess level of invasion for staging.
• Presence and status of involvement of muscularis propria
should be reported in TURBT specimen for adequate staging.

22. HISTOLOGIC VARIANTS OF UROTHELIAL
CARCINOMA
• Nested pattern
• Small tubular pattern
• Microcytic pattern
• Inverted pattern
• With squamous differentiation
• With glandular differentiation
• Micro papillary
• Sarcomatoid
• Clear cell
• With syncitiotrophoblasts
• With unusual stromal reaction

23. NESTED VARIANT OF UROTHELIAL CARCINOMA
• The nested variant of urothelial carcinoma is a rare
but aggressive cancer
• male-to-female ratio of 6 : 1
• confused with benign lesions
- von Brunn nests that are in the lamina propria, cystitis cystica, inverted
papillomas.
• There is little nuclear atypia in the nested variant of urothelial carcinoma

24. Nested variant
• Tumor cells will often
contain areas with large
nuclei and mitotic figures

25. CLEAR CELL VARIANT OF UROTHELIAL CARCINOMA
• 70% -will have foci of clear cells within the tumor.
• cells contain glycogen-rich vacuoles and may be confused with
metastatic clear cell carcinoma of the kidney.
• Clar cell variant does not portend a significantly worse prognosis for
urothelial cancers

26. GLANDULAR OR ADENOCARCINOMA DIFFERENTIATION
• Mixed tumor differentiation is most common with squamous cell
cancer,
• Glandular differentiation occurs in only 6% of urothelial cancer cases.
• Glandular differentiation is defined as the presence of two glandular
spaces within the tumor
• Mucin production can occur, and tumor cells seem to be floating in
the mucin.

27. PLASMACYTOID TUMOR
• A plasmacytoid tumor - recognized by the WHO classification
system since 2011.
• Plasmacytoid cells with the centric nuclei
that often invade through the bladder wall
and into the perivesical adipose tissue at
the time of diagnosis.
• diagnosed at an advanced stage .
• Onset of hematuria is delayed - sessile and non-papillary tumor
growth pattern.

28. MICROPAPILLARY
• Incidence - 0.7-2.2%
• M:F - 10:1
• occurs at older age – 65 yrs
• Present at advanced stage
• Associated with conventional urothelial ca in 80%
• Histology similar to papillary serous ca of ovary
• Angiolymphatic invasion is common
• High progression from Non-muscle invasive -Muscle invasive -
Metastatic

29. TREATMENT OF MICROPAPILLARY
• Surgical resection- Treatment of choice
• TURBT & BCG is ineffective
• Neo-adjuvant Chemo – not effective
• Locally advanced disease – poor prognosis
4 year survival -22%

30. NON UROTHELIAL MALIGNANCY
• Sarcoma
• Signet ring cell ca
• Small cell ca
• Sq cell ca
• Prostatic urethral ca
• adenocarcinoma

31. SCC
• Risk factor for bladder SCC
- Smoking
- Stones/FBs
- Schistosomiasis haematobium
- Chronic UTIs
- Chronic indwelling catheter
- BCG
- Diverticula (bladder)

33. Adeno carcinoma
• Risk factors for adenocarcinoma of the bladder
- Urachal cyst/remnant,
- Cystitis glandularis,
- CIS,
- Chronic inflammation,
- Ureterosigmoidostomy,
- Bladder augment,
- Exstrophy of bladder.

34. ADENOCARCINOMA
• <2% of primary bladder cancers
• Majority represent Mets from GI tract, breast, lung , colon
primary
• Usually arise in trigon or in dome (urachal)
• Most common type of bladder Ca in exstrophy & associated
with pelvic lipomatosis
• Develop in response to chronic inflammation and irritation

35. • Classifications of adenocarcinomas of the GU tract
• 1) primary vesical
• 2) urachal
• 3) metastatic
• Most are poorly differentiated and invasive
• More often associated with cystitis glandularis than CIS
• Generally poor prognosis due to advanced stage at presentation.

36. URACHAL ADENOCARCINOMA
• Located at the dome of the bladder
• 90% of masses occur close to the bladder
• Midline, infraumbilical, soft-tissue mass with calcification (
Stippled ) considered to be urachal adenocarcinoma until
proved otherwise.
• Usually adenocarcinomas but can also be TCC, SCC, or even
sarcomas
• Present with bloody or mucoid discharge from umbilicus
• Present as palpable mass after forming mucocele.
• POOR PROGNOSIS

37. SIGNET CELL CARCINOMA:
• 1/3 urachal origin and 2/3 directly extend into the bladder
• Rare variant of adenocarcinoma
• High-grade, high-stage tumors at presentation
• Poor prognosis
• Carcinoembryonic antigen (CEA)- Elevated
• The prognostic significance – unclear
• Treatment is radical cystectomy
• Survival < 20 months

38. SMALL CELL CARCINOMA
• < 1% all primary bladder tumors
• Derived from neuroendocrine stem cells or dendritic cells
• Stain +ve for Enolase
• May be mixed with elements of TCC
• Very aggressive with early vascular and muscle invasion
• Small cell carcinoma of lung or prostate- Metastasized to the bladder-
should be evaluated
Small cell carcinoma of the bladder should be considered and treated as
metastatic disease, even if there is no radiologic evidence of disease
outside the bladder.
Chemo radiation

39. sarcoma:
• Leiomyosarcoma > rhabdomyosarcoma
• M:F ratio is 2 : 1,
• Presentation- sixth decade of life.
• Rhabdomyosarcoma- MC in young children.
• Produce polyploidy lesions at the base of the bladder, described as
botryoides tumors
•pelvic radiation and systemic chemotherapy
•Not smoking related.
• The majority of sarcomas are high grade , and more
than 75% are confined to bladder muscle
•Gross painless hematuria and local irritative
symptoms

40. INVESTIGATION & TREATMENT
• Transurethral resection of tumor-Diagnostic
• Metastasis at presentation
• Abdominal and chest imaging
• grade- Primary prognostic factor
• -Angio-lymphatic invasion poor prognosis
• Radical Cystectomy with negative margin - For localized disease
• Chemotherapy - Active regimens are lacking
• - Doxorubicin, Ifosphamide, and Cisplatin are
effective

41. Prostatic Urethral Ca
• Associated with urothelial Ca in 90% of cases
• Only 3% of urothelial Ca patients will have prostatic urethral Ca
• Risk factors CIS of the bladder neck
H/o intravesical chemo
 Route of spread- Direct or pagetoid
• Diagnosis : Transurethral resection of prostatic
urethra
• Treatment : Non invasive-Transurethral
resection of prostate
Prostatic ductal ca- complete transurethral
prostatectomy plus BCG

42. GRADING SYSTEM OF UROTHELIAL CARCINOMAS (ISUP)
• Most high grade lesions are muscle-invasive
• Grade correlates with prognosis
• Stage correlates with survival
• Low grade - loss of suppressor genes on chromosome 9q
• -high grade- abnormalities in p53, RB, p16 (suppressor genes)

43. PAPILLOMA - GRADE 0
-benign
-but must r/o concomitant TCC
- WELL-DIFFERENTIATED - GRADE 1
-PUNLMP when mucosally confined
MODERATELY-DIFFERENTIATED - GRADE 2
- Thickened urothelium, a few mitotic figures, slight anaplasia
- moderate disturbance of base-to-surface cellular maturation
POORLY-DIFFERENTIATED - GRADE 3
- Frequent mitotic figures
-HIGH-GRADE
-p53, RB, chromosome 9p abnormalities found in CIS

44. TNM
• Primary Tumor (T)
• TX Primary tumor cannot be
assessed
• T0 No evidence of primary tumor
• Ta Non invasive papillary carcinoma
• Tis Carcinoma in situ: “flat tumor”
• T1 Tumor invades subepithelial
connective tissue
• T2 Tumor invades muscularis
propria
• pT2a Tumor invades superficial
muscularis propria (inner half)
• pT2b Tumor invades deep
muscularis propria (outer half)
• T3 Tumor invades perivesical
tissue:
• pT3a Microscopically
• pT3b Macroscopically (extravesical
mass)
• T4 Tumor invades any of the
following: prostatic stroma ,
seminal vesicles, uterus, vagina,
pelvic wall, abdominal wall
• T4a Tumor invades prostatic
stroma, uterus, vagina
• T4b Tumor invades pelvic wall,
abdominal wall

45. • Regional Lymph Nodes (N)
• NX Lymph nodes cannot be assessed
• N0 No lymph node metastasis
• N1 Single regional lymph node metastasis
in the true pelvis
• (hypogastric, obturator, external iliac, or
presacral lymph node)
• N2
• Multiple regional lymph node metastasis
in the true pelvis (hypogastric, obturator,
external iliac, or
• presacral lymph node metastasis)
• N3 Lymph node metastasis to the common
iliac lymph
• Distant Metastasis (M)
• M0 No distant metastasis
• M1 Distant metastasis
• Anatomic Stage/Prognostic Groups
• Group T N M
• Stage 0a Ta N0 M0
• Stage 0is Tis N0 M0
• Stage I T1 N0 M0
• Stage II T2a N0 M0
• T2b N0 M0
• Stage III T3a N0 M0
• T3b N0 M0
• T4a N0 M0
• Stage IV T4b N0 M0
• Any T N1-3 M0
• Any T Any N M1

46. Prognostic Factors (Site-Specific Factors)
• Presence or absence of extranodal extension
• Size of the largest tumor deposit in the lymph nodes
 Grade
 Multiplicity
 Papillary versus sessile
 Lympho-vascular invasion
 Status of the remaining urothelium

47. summary
• Papilloma- diff urothelial cancer with an inverted growth pattern
• Nephrogenic adenoma-infiltration by inflammatory cells.
• Cystitis cystica- regular endoscopic evaluation
• Leiomyoma -most common non epithelial benign tumor, women ,
smooth indentation
• CIS- reddish with heaped-up mucosa
• CLEAR ceinverted LL VARIANT- glycogen-rich vacuoles
• GLANDULAR OR ADENOCARCINOMA DIFFERENTIATION- tumor cells
seem to be floating in the mucin.

48. • Plasmacytoid- advanced stage,hematuria delayed ,poor
• Micropapillary - angiolymphatic invasion
• Adenocarcinoma- trigon or in dome (urachal), stippled calcification
• Signet cell carcinoma-survival < 20 months
• Small cell carcinoma consider as metastatic
• Sarcoma - polyploidy ,high grade ,muscle wall

49. REFERENCE CAMPBELL-WALSH UROLOGY
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