URINE CYTOLOGY

Introduction:Introduction:

Simple, safe, and inexpensive method that may uncover Simple, safe, and inexpensive method that may uncover a hidden urothelial cancer.a hidden urothelial cancer.

Primarily used for diagnosis of symptomatic patients.Primarily used for diagnosis of symptomatic patients. Detection of cancer in high-risk patients Detection of cancer in high-risk patients Follow-up of patients with history of urinary tract Follow-up of patients with history of urinary tract

neoplasia. neoplasia. Patients with low-grade noninvasive tumors can be Patients with low-grade noninvasive tumors can be

followed up cytologically. followed up cytologically. Patients with negative cytologic findings have a very low Patients with negative cytologic findings have a very low

risk of recurrence.risk of recurrence. High-grade cytologic abnormalities predict an aggressive High-grade cytologic abnormalities predict an aggressive

tumor coursetumor course

A positive cytology should always be confirmed A positive cytology should always be confirmed histologically before definitive therapy.histologically before definitive therapy.

False-positive diagnoses are commonly seen in cases of False-positive diagnoses are commonly seen in cases of stones, chemotherapy, radiation, viruses, reactive or stones, chemotherapy, radiation, viruses, reactive or degenerative changes, benign prostatic hyperplasia, degenerative changes, benign prostatic hyperplasia, prostatitis, and pseudopapillary clusters. prostatitis, and pseudopapillary clusters.

False-negative diagnosis may be of more clinical False-negative diagnosis may be of more clinical consequence.consequence.

Cytologic diagnosis of papillomas and well-differentiated Cytologic diagnosis of papillomas and well-differentiated papillary transitional cell carcinoma (TCC) can be difficult papillary transitional cell carcinoma (TCC) can be difficult or impossible because the cells are nearly normal-or impossible because the cells are nearly normal-appearing.appearing.

Transitional cells are among the most pleomorphic, benign epithelial cells in the body, ranging from little basal cells somewhat larger than a lymphocyte (approximately 10 µm) to huge multinucleated superficial (umbrella) giant cells (100 µm or larger).The cells vary from triangular to polyhedral to rounded, or caudate to columnar.Single, mononuclear parabasal-sized cells usually predominate in voided specimens.

Multinucleated Multinucleated umbrella cells, groups umbrella cells, groups of cells, and of cells, and pseudopapillary pseudopapillary aggregates are more aggregates are more commonly seen in commonly seen in catheterized urine.catheterized urine.

Columnar transitional cells are a normal and relatively common finding in specimens obtained by instrumentation of the bladder.They also can arise from the urethra, particularly of men, as well as in cystitis cystica.Usually benign, but can also be seen in well-differentiated papillary neoplasms.

Reactive changes in transitional cells caused by inflammation, stones, hyperplasia, radiation/chemotherapy, viral or bacterial cystitis, drugs, or even catheterization/instrumentation.Features include high N/C ratio, prominent nucleoli, darker and coarser chromatin (still evenly distributed).

•Other cells: Renal tubular cells (associated with kidney disease), Squamous cells (common finding in urine), Prostatic cells (normally found after prostatic massage), Seminal vesicle cells (uncommon in urine, but can be strikingly atypical in appearance especially in older man), Endometriosis can present in women with cyclic hematuria and suprapubic pain, RBC’s, inflammatory cells, giant cells, histiocytes, sperms and crystals.

DegenerationDegeneration (caused by (caused by inflammation, inflammation, stones, trauma, stones, trauma, etc); bizarre etc); bizarre transitional cells transitional cells with darkly with darkly condensed coarse condensed coarse or pyknotic or pyknotic chromatin.chromatin.

Relative advantages and disadvantages of urine specimen types.

Benign LesionsBenign Lesions

Urolithiasis: Increase Urolithiasis: Increase in cellularity even in in cellularity even in voided urine voided urine specimens, including specimens, including mechanical avulsion mechanical avulsion of pseudopapillary of pseudopapillary groups of transitional groups of transitional epithelium epithelium

Significant cellular Significant cellular atypia, the nuclei may atypia, the nuclei may be enlarged and be enlarged and pleomorphic, irregular pleomorphic, irregular in size and shape, in size and shape, with an increased N/C with an increased N/C ratio, hyperchromatic, ratio, hyperchromatic, coarse chromatin.coarse chromatin.

,,

•Cystitis: Cystitis is usually caused by fecal flora, particularly Escherichia coli, and also Proteus, Klebsiella, Enterobacter, Streptococcus faecalis, Staphylococcus, and Pseudomonas.

•The urine specimen contains polymorphonuclear leukocytes, histiocytes, red blood cells, and necrotic debris

•Atypical transitional cells, with irregular outlines, enlarged hyperchromatic nuclei, prominent nucleoli, and coarse chromatin with clearing.

•Malignancy usually has more necrosis, but usually less inflammation, than cystitis. However, inflammation does not rule out cancer.

•Brunn’s nests (solid buds of transitional cells), cystitis cystitica (small cysts lined with transitional cells) and glandularis (cysts lined with metaplastic glandular cells) are normally a result of chronic inflammation and may follow each other.

•Infections: Fungal infection can be isolated finding or part of a systemic infection. Most common types of fungi include Blastomyces, Cryptococcus, Aspergillus, and Candida.

•Parasites include trichomonas, ameba and schistosomiasis.

•Virus infections:

•Herpes (multinucleation, molding, margination with or without nuclear inclusion).

•Cytomegalovirus (cytomegaly, basophilic nuclear inclusion, thick nuclear membrane, with or without intracytoplasmic or intranuclear satellite inclusions).

•Human polyoma virus: DNA virus related to HPV and JC virus family. The cells have enlarged dark nuclei mimicking cancer, particularly carcinoma in situ ("decoy cells") and sometimes short, cytoplasmic tails (known as "comet cells")

•The most characteristic feature is the presence of a large, round, homogeneous, opaque blue/black viral inclusion in the nucleus

•Malakoplakia: Granulomatous disease, grossly, soft yellow plaques, about 3 to 4 cm in diameter, occur in the bladder.

•Cytologically Giant cells, known as von Hansemann histiocytes, abundant granular, periodic acid-Schiff (PAS)-positive cytoplasm.

•Radiation and Chemotherapy Effect:

•Cellular and nuclear enlargement, N/C ratio is not increased overall. Cytoplasmic and nuclear vacuolizations are common. Degenerative changes are common as well.

Some histiocytes Some histiocytes contain characteristic contain characteristic Michaelis-Gutmann Michaelis-Gutmann bodies. Round, bodies. Round, laminated, usually laminated, usually basophilic, but basophilic, but occasionally occasionally eosinophilic, calcified eosinophilic, calcified cytoplasmic inclusions cytoplasmic inclusions about 5 to 10 µm in about 5 to 10 µm in diameter. diameter.

•Urothelial Neoplasms:

•They occur three times as often in males, usually in patients over 50 years of age. Risk factors include aromatic amines, phenacetin, cyclophosphamide, alkylating agents, schistosomiasis, smoking etc.

•WHO/ISUP classification system for urothelial neoplasm:•Flat Lesions

•Dysplasia

•CIS

•Papillary Lesions

•Papilloma

•Papillary urothelial neoplasm of LMP

•Low grade urothelial carcinoma

•High grade urothelial carcinoma

Papillomas: Papillomas: Extremely rare and Extremely rare and occur almost occur almost exclusively in young exclusively in young patients. These patients. These cannot be recognized cannot be recognized cytologically unless cytologically unless an intact papillary an intact papillary frond is identifiedfrond is identified

•Papillary urothelial neoplasm of low malignant potential and low grade urothelial neoplasia:

•The cytologic features of these two lesions are similar.

•Cytologic Criteria: Cytoplasmic homogeneity, high nuclear to cytoplasmic ratio, irregular borders.

•Architectural criteria: Papillary fragments with fibrovascular cores (diagnostic but rare).

•Cell clusters without cores (not specific: also seen with urolithiasis, catheterization).

•Irregular cell clusters (more commonly associated with UC than smooth cell clusters).

•Dysplasia:

•Diagnosis of dysplasia is of limited value in cytology, because almost all patients have a coexisting high grade lesion.

•High grade urothelial carcinoma:

•High nuclear to cytoplasmic ratio, marked nuclear hyperchromasia, coarsely granular chromatin, irregular nuclear outline, large nucleoli (some cases).

•The background may contain necrotic debris, blood, and inflammatory cells.

•The sensitivity of urine cytology for high grade UC is 79% and specificity is greater than 95%.

•Differential diagnosis includes, polyoma virus, stones, normal upper tract brushings/washings, treatment effect, non-specific reactive changes.

•Other Malignant Lesions:

•Squamous cell carcinoma:

•Rare and strongly associated with Schistosoma hematobium. A definite diagnosis of squamous cell carcinoma should be deferred to biopsy or resection.

•Cytoplasmic keratinization, pearls, bridges, angulated hyperchromatic nuclei.

•The differential diagnosis includes condyloma accuminatum of the bladder, metastatic squamous cell carcinoma and a squamous cell carcinoma of the gynecologic tract.

•Adenocarcinoma:

•Strongly associated with bladder exstrophy and urachal remnants.

•Glandular differentiation is common in otherwise typical urothelial carcinoma, therefore the definitive diagnosis of pure adenocarcinoma is left to biopsy.

•Clear cell carcinoma:

•Small clusters of obviously malignant cells , abundant clear cytoplasm, large irregular nuclei, vesicular chromatin, large nucleoli.

•Small cell carcinoma:

•Very rare aggressive tumor although the prognosis is better than for those with SCC in other sites.

LymphomaLymphoma

• Rare but can Rare but can potentially be potentially be diagnosed with diagnosed with urine cytology.urine cytology.

•Prostatic Carcinoma:

•Almost always occurs in patients with poorly differentiated (gleason score > or = 8)

•Prominent nucleoli and relatively abundant cytoplasm. Clinical history is very important in order to avoid confusion with high grade urothelial carcinoma.

Renal cell carcinoma:Renal cell carcinoma:

Isolated cells Isolated cells moderate amount moderate amount of clear or granular of clear or granular cytoplasm, round to cytoplasm, round to irregular nuclei, irregular nuclei, prominent nucleoli.prominent nucleoli.

•Diagnosing difficult or borderline specimens: common patterns:

•It is advisable to use atypical as sparingly as possible by classifying them as either benign or suspicious.

•Common patterns that can be applied to atypical urines.

•Cell clusters in voided urine-diagnose as negative

•Cytologic or architectural criteria for a low grade lesion-diagnose as negative.

•Rare small highly atypical cells-diagnose as suspicious.

•Degenerated atypical cells with intact nuclear outlines-diagnose as suspicious.

•Rare mildly atypical cells-try to diagnose as negative.

•Ancillary studies:

•DNA aneuploidy (FCA, image analysis)

•Bard bladder tumor antigen test (BTA).

•Nuclear matrix protein test (NMP 22 test).

•Telomerase assays.

•Microsattellite instability assays.

•Hyaluronidase and hyaluronic acid assays.

•Growth factors: acid fibroblast growth factor, basic FGF, autocrine motility factor, epidermal growth factor, transforming growth factor-beta.

•Cell adhesion molecules, FISH etc.

•Summary:

•Most urines are negative.

•The value urine cytology for High grade lesions in undisputed,

•Clusters of urothelial cells per se are of limited use for the diagnosis of UC in voided urines.

•The term dysplasia should be avoided.

•Upper tract lesions should be diagnosed conservatively.

•Separating high risk from low risk patterns may be of value in reducing the number of atypical diagnoses.

•Still looking for a highly accurate ancillary study to reduce cystoscopies.