1. Journal Reading

2. Mahual B. Amin, and Jesse K. McKenney
An Approach to the Diagnosis of Flat Intraepithelial Lesions of the Urinary Bladder Using the World Heath Organization/ International Society of Urological Pathology Consensus Classification System
Mahual B. Amin, and Jesse K. McKenney
Review Article
Advances in Anatomic Pathology, Vol9, No 4, pp ,July, 2002

3. Histological Prespective
Melicow and Hollowell, intraepithelial lesions of the urinary bladder in 1952
Hyperplasia, metaplasia, papillary
excrescences and bowenoid changes
Koss ,in 1952, discovered carcinoma in situ with features of Paget’s disease
clinically unimpressive case with dramatic
adverse outcome

4. Evolution of WHO/ISUP Classification for Flat Lesions with Atypia

5. The WHO/ISUP Classification for Flat Lesions with Atypia

6. The WHO/ISUP Classification for Flat Lesions with Atypia
Reactive atypia:
(1) Nuclear abnormalities occurring in
acutely or chronically inflamed urothelium.
(2) Nuclei are usually enlarged , uniformly,
fine vesicular nuclear chromatin, central
prominent nucleoli, mitotic figures.

7. The WHO/ISUP Classification for Flat Lesions with Atypia
Atypia of unknown significance:
(1) Severity of atypia is out of proportion to
the extent of inflammation, dysplasia
cannot be confidently excluded.
(2) Patient should be followed up after
inflammation subsides.

8. The WHO/ISUP Classification for Flat Lesions with Atypia
Dsyplasia ( low-grade intraurothelial neoplasia)
(1) Appreciable cytologic and architectural
changes felt to be preneoplastic.
(2)Short of the diagnostic threshold for
carcinoma in situ.

9. The WHO/ISUP Classification for Flat Lesions with Atypia
Carcinoma in situ ( high-grade intraurothelial neoplasm)
(1) Encompresses lessions previously designated
as severe dysplasia and possibly even moderate
dysplasia.
(2) Large, irregular, hyperchromatic nuclei present
within part of, or most often involving the
entire urothelium.

10. The WHO/ISUP Classification for Flat Lesions with Atypia
Carcinoma in situ ( high-grade intraurothelial neoplasm)
(3)Need not to be full thickness cytologic
atypia, N/C may not be high, and an
umbrella cell layer may be present.
(4)Should not be subclassified

11. Diagnostic Approach to Bladder Biopsy Specimens

12. Diagnostic Approach to Bladder Biopsy Specimens
Normal urothelium: 3~6 layers
Denudation: reactive condition( trauma or
infection ) or CIS
Hyperplasia: entire flat intrapeithelial
lesions

13. Diagnostic Approach to Bladder Biopsy Specimens
Polarity:
Perpendicularly to the basement membrane with orderly organization of basal cells, intermediate cells and superficial umbrella cells.
Loss of cytoplasmic clearing( increased eosinphilia)

14. Diagnostic Approach to Bladder Biopsy Specimens
Nuclear megaly:
(1) Normal urothelium in the specimen
(2) Stromal lymphocytes
(3) CIS: 5x lymphocytes
dysplasia and normal: 2x lymphocytes

15. Diagnostic Approach to Bladder Biopsy Specimens
Nuclear atypia:
(1) Dysplasia :nuclear border, nuclear
chromatin abnormalities.
(2) CIS: nuclear pleomorphism, frequent mitoses
including atypical mitoses or surface
mitoses, prominent nucleoli (single or
multiple)

16. Reative Atypia Nucleomegaly
Single, prominent nucleolus, evenly distributed vesicular chromatin.
Nuclear pleomorphism is lacking
Maintain the polarity, mitoses in basal and middle layer, no atypical mitoses
Intraurothelial acute and chronic inflammatory cells

18. Urothelial Dysplasia
Nuclear abnormalities, in the absence of inflammation or disproportionate to the amount of inflammation.
Falling below the threshold of CIS
Thickness is often normal (4~7 layers)
Loss of polarity (nuclear parallel to long axis) and clouded
Increased cytoplasmic eosinophilia, nucleomegaly, irregular nuclear counters, altered chromatin distribution.

19. Urothelial Dysplasia Nucleoli are not usually conspicuous
Mitoses is variable
Lamina propria is usually unaltered, but may contain increased inflammation, neovascularity,or both.
Denudation with atypical cells clining to the the submucosa is not a common feature.

20. Urothelial Dysplasia

21. CIS Unequivocal severe cytologic atypia
Denuded, diminished, normal thickness or hyperplastic
Alteration or complete loss of polarity, marked crowding, pleomorphism and mitoses
The lamina propria is frequently hypervascualr and inflamed reflecting the erythematous appearance witnessed on cystoscopy

22. CIS Nuclear anaplasia is generally obvious,
Varied cytologic and architectural patterns

24. Large Cell , Pleomorphism
Loss of polarity, nucleomegaly, marked variation in nuclear shape and size, but retain abundant eosinophilic cytoplasm

25. Large Cell CIS, Non-pleomorphism
Rather monomorphic and mimic reactive urothelial atypia
Markedly enlarged nulcei with high-grade cytologic features diagnostic for CIS.

26. Small Cell CIS
Nuclear feature identical to large cell CIS wtihout pleomorphism.
Absence of signficant cytoplasm (nuclei are still marked enlarged)

27. Clinging CIS
Partially denuded urothelium with a patchu, usually single layer of residual urothelial cells meeting the morphologic criteria for CIS.

28. Cancerization of Normal Urothelium
Pagetoid growth:
Clusters or isolated single cells with features of CIS within the normal urothelium

29. Cancerization of Normal Urothelium
Undermining or overriding growth

31. CIS Rare cases have glandular differentiation
Do not include the particular pattern of CIS into the report.
(1) Pognostic implications are not known
(2) Lead to confusion

32. Panel: CK20, p53, and CD44( standard isoform) CK20:
The Role of Immunohistochemistry in The Diagnosis of Flat Urothelial Lesions with Atypia
Panel: CK20, p53, and CD44( standard
isoform)
CK20:
(1) only in superficial umbrella cells
(2) strong positive of whole layer in CIS.

33. The Role of Immunohistochemistry in The Diagnosis of Flat Urothelial Lesions with Atypia
(1) nuclear staining is absent in normal
(2) diffuse nuclear staining in the whole
layer in the CIS.
CD44:
(1) limited in basal and parabasal cells in normal
(2) increased reactivity in whole layer in reactive
(3) absent in neoplastic cells in CIS.

34. The Role of Immunohistochemistry in The Diagnosis of Flat Urothelial Lesions with Atypia
Limited and preliminary studies suggest a potential adjuctive role of IHC.
Not use in evaluation of the dysplasia
Adjunct tools in :
(1) pathologist strongly favors the diagnosis of CIS
(2) with no known history of papillary lesion(de
novo or primary CIS)
(3) In confirming unusual morphologic
presentations of CIS such as the cancerization.

35. An Analysis of Cytokeratin 20, p53, and CD44 Antigens
Discriminatory Immunohistochemical Staining of Urothelial Carcinoma in Situ and Non-neoplastic Urothelium
An Analysis of Cytokeratin 20, p53, and CD44 Antigens
Jesse K. McKenney, M.D., Sangeeta Desai, M.D., Cynthia Cohen, M.D., and
Mahul B. Amin, M.D.
Am J Surg Pathol 25(8): 1074–1078, 2001.

36. An Analysis of Cytokeratin 20, p53, and CD44 Antigens
Discriminatory Immunohistochemical Staining of Urothelial Carcinoma in Situ and Non-neoplastic Urothelium
An Analysis of Cytokeratin 20, p53, and CD44 Antigens
Jesse K. McKenney, M.D., Sangeeta Desai, M.D., Cynthia Cohen, M.D., and
Mahul B. Amin, M.D.
Am J Surg Pathol 25(8): 1074–1078, 2001

37. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Innate vagaries of normal urothelium and histologic sectioning.
(1) the thickness varies
(2) the sections are thick, the urothelium
may appear hyperchromatic compo
unded with tangential cut.
(3) renal pelvis, urethra, and the
bladder neck:
slightly larger cells with diminshed cytologic
clearing

38. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Inflammatory atypia:
Presence of acute or significant chronic inflammation warrants caution in interpresentation

39. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Therapy associated atypia:
(1)Radiation:
(a) full-thickness atypia mimicking CIS,
(b) often multinucleated giant cells with bizarre
nuclei not typical of intraurothelial neoplasm.
(c) the cytoplsam is usually prominent and
shows degenration with vacuolization.
(d) atypical fibroblasts and radiation
vaculopathy.

40. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Therapy associated atypia:
(2)Intravesical chemotherapy:
Severe urothelial atypia but is often limited only the superficial urothelial cells.

41. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Extensive denudation:
(1)Main cause: trauma due to instrumentation, prior therapy and CIS(denuding cystitis)
(2)Deeper sectioning : may found atypical cells
(2)If no atypical cells, association with neovascularity and chronic inflammation in the lamina propria must included in the report and correlation with urine cytology findings.

42. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Truncated papillae of treated papillary carcinoma:
(1)Mitomycin C and thiotepa therapy destroy the tips of the papilla of papillary transitional carcinoma.
(2)Mistaken as CIS or dysplastic
changes instead of residual
papillary urothethlial carcinoma

43. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Carcinoma in situ involving von Brunn’s nests:
(1)Over-diagnosis of invasion
(2)In general, von Brunn’s nests have
a round contour and lack retraction
artifact or surrounding stromal
cahnges.
(3)In the presence of inflammation,
the basement membrane may be
obscured and distorted,
simulating invasion.

44. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Carcinoma in situ with microinvasion
(1) Under-diagnosis of invasion
(2) Desmoplasia or retraction artifact is useful in recognizing invasion, but stromal response may be absent.

45. Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypia
Polyoma virus infection
(1)Immunocompromised patients with human plyoma virus,large homogeneous inclusions in enlarged nuclei of urothelial cells, so- called “decoy cells”
(2)Mimicking the malignancy (CIS)

46. Clinical and Biological Relevance of Dysplasia and Carcinoma in Situ
(1)Clinically or cystoscopical silent
(2)Patient with bladder neoplasia: 22% to 86%
(3)Patient with invasive carcinoma: 100%S
(4)Smith et al, Althausen et al: dysplasia in the patient with TCC is a marker for progression (increased recurrence and invasion)
(5)Cheng et al shows 19% and 15% of primary dysplasia with progression.(muscle invasion)

47. Clinical and Biological Relevance of Dysplasia and Carcinoma in Situ
CIS
(1)S/S: frequency, dysuria, nocturia and suprapubic fullness, erythematous or granular appearance in cystoscope.
(2)A precursor to invasive carcinoma.
(3)The prognosis of the primary DCIS is better than CIS with prior or concomitant papillary bladder neoplasm.
(4)Cheng et al followed 138 patients and found 35% had disease progression and 20% died of bladder cacner.