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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 222-232,July, 2002

Histological PrespectiveHistological 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 Evolution of WHO/ISUP Classification for Flat Lesions with AtypiaFlat Lesions with Atypia

The WHO/ISUP Classification for Flat LesThe WHO/ISUP Classification for Flat Lesions with Atypiaions with Atypia

The WHO/ISUP Classification for Flat LesThe WHO/ISUP Classification for Flat Lesions with Atypiaions 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 LesThe WHO/ISUP Classification for Flat Lesions with Atypiaions 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 LesThe WHO/ISUP Classification for Flat Lesions with Atypiaions 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 LesThe WHO/ISUP Classification for Flat Lesions with Atypiaions 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 LesThe WHO/ISUP Classification for Flat Lesions with Atypiaions 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 Diagnostic Approach to Bladder Biopsy SpecimensBiopsy Specimens

Diagnostic Approach to Bladder Diagnostic Approach to Bladder Biopsy SpecimensBiopsy Specimens

Normal urothelium: 3~6 layersDenudation: reactive condition( trauma or

infection ) or CISHyperplasia: entire flat intrapeithelial

lesions

Diagnostic Approach to Bladder Diagnostic Approach to Bladder Biopsy SpecimensBiopsy 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 Diagnostic Approach to Bladder Biopsy SpecimensBiopsy 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 Diagnostic Approach to Bladder Biopsy SpecimensBiopsy 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 AtypiaReative Atypia

NucleomegalySingle, prominent nucleolus, evenly distribu

ted vesicular chromatin.Nuclear pleomorphism is lackingMaintain the polarity, mitoses in basal and

middle layer, no atypical mitosesIntraurothelial acute and chronic inflammat

ory cells

Urothelial DysplasiaUrothelial 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 DysplasiaUrothelial Dysplasia

Nucleoli are not usually conspicuousMitoses is variableLamina propria is usually unaltered, but ma

y contain increased inflammation, neovascularity,or both.

Denudation with atypical cells clining to the the submucosa is not a common feature.

Urothelial DysplasiaUrothelial Dysplasia

CISCIS

Unequivocal severe cytologic atypia Denuded, diminished, normal thickness or hyperpl

astic Alteration or complete loss of polarity, marked cro

wding, pleomorphism and mitoses The lamina propria is frequently hypervascualr an

d inflamed reflecting the erythematous appearance witnessed on cystoscopy

CISCIS

Nuclear anaplasia is generally obvious,Varied cytologic and architectural patterns

Large Cell , PleomorphismLarge Cell , Pleomorphism

Loss of polarity, nucleomegaly, marked variation in nuclear shape and size, but retain abundant eosinophilic cytoplasm

Large Cell CIS, Non-pleomorphismLarge Cell CIS, Non-pleomorphism

Rather monomorphic and mimic reactive urothelial atypia

Markedly enlarged nulcei with high-grade cytologic features diagnostic for CIS.

Small Cell CISSmall Cell CISNuclear feature identical to large cell CIS w

tihout pleomorphism.Absence of signficant cytoplasm (nuclei are

still marked enlarged)

Clinging CISClinging CIS

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

Cancerization of Normal UrotheliuCancerization of Normal Urotheliumm

Pagetoid growth:

Clusters or isolated single cells with features of CIS within the normal urothelium

Cancerization of Normal UrotheliuCancerization of Normal Urotheliumm

Undermining or overriding growth

CISCIS

Rare cases have glandular differentiationDo 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 DiThe Role of Immunohistochemistry in The Diagnosis of Flat Urothelial Lesions with Atypiagnosis of Flat Urothelial Lesions with Atypi

aa

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 DiThe Role of Immunohistochemistry in The Diagnosis of Flat Urothelial Lesions with Atypiagnosis of Flat Urothelial Lesions with Atypi

aa

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 DiThe Role of Immunohistochemistry in The Diagnosis of Flat Urothelial Lesions with Atypiagnosis of Flat Urothelial Lesions with Atypi

aa

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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof Flat Lesion with Atypia

Inflammatory atypia:

Presence of acute or significant chronic inflammation warrants caution in interpresentation

Problems and Pitfalls in the Diagnosis Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof 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 Problems and Pitfalls in the Diagnosis of Flat Lesion with Atypiaof Flat Lesion with Atypia

Polyoma virus infection(1)Immunocompromised patients with human plyoma vir

us,large homogeneous inclusions in enlarged nuclei of urothelial cells, so- called “decoy cells”

(2)Mimicking the malignancy (CIS)

Clinical and Biological Relevance Clinical and Biological Relevance of Dysplasia and Carcinoma in Sitof Dysplasia and Carcinoma in Sit

uu 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 patie

nt 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 Clinical and Biological Relevance of Dysplasia and Carcinoma in Sitof Dysplasia and Carcinoma in Sit

uu CIS(1)S/S: frequency, dysuria, nocturia and suprapubic fullne

ss, 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.