Transcript Journal Reading

Journal Reading

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 222232,July, 2002
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
Evolution of WHO/ISUP Classification for
Flat Lesions with Atypia
The WHO/ISUP Classification for Flat
Lesions with Atypia
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.
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.
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.
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.
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
Diagnostic Approach to Bladder
Biopsy Specimens
Diagnostic Approach to Bladder
Biopsy Specimens

Normal urothelium: 3~6 layers
 Denudation: reactive condition( trauma or
infection ) or CIS
 Hyperplasia: entire flat intrapeithelial
lesions
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)
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
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)
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
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.
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.
Urothelial Dysplasia
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
CIS

Nuclear anaplasia is generally obvious,
 Varied cytologic and architectural patterns
Large Cell , Pleomorphism

Loss of polarity, nucleomegaly, marked
variation in nuclear shape and size, but
retain abundant eosinophilic cytoplasm
Large Cell CIS, Non-pleomorphism

Rather monomorphic and mimic reactive
urothelial atypia
 Markedly enlarged nulcei with high-grade
cytologic features diagnostic for CIS.
Small Cell CIS

Nuclear feature identical to large cell CIS
wtihout pleomorphism.
 Absence of signficant cytoplasm (nuclei are
still marked enlarged)
Clinging CIS

Partially denuded urothelium with a patchu,
usually single layer of residual urothelial
cells meeting the morphologic criteria for
CIS.
Cancerization of Normal
Urothelium
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Pagetoid growth:
Clusters or isolated single cells with features
of CIS within the normal urothelium
Cancerization of Normal
Urothelium
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Undermining or overriding growth
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
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.
The Role of Immunohistochemistry in The
Diagnosis of Flat Urothelial Lesions with
Atypia

P53:
(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.
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.

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.

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
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
Problems and Pitfalls in the Diagnosis
of Flat Lesion with Atypia

Inflammatory atypia:
Presence of acute or significant chronic
inflammation warrants caution in
interpresentation
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.
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.
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.
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
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.
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.
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)
Clinical and Biological Relevance
of Dysplasia and Carcinoma in
Situ

Dysplasia:
(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)
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.