Journal Reading

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 222-232,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 Pagetoid growth: Clusters or isolated single cells with features of CIS within the normal urothelium

Cancerization of Normal Urothelium 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

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.

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.

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.

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.

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

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 (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.