Bladder & urothelial tract

High grade urothelial carcinoma

• Combined cytologic term to include invasive high grade papillary urothelial carcinoma, noninvasive high grade papillary urothelial carcinoma and carcinoma in situ
• Diagnostic criteria based on The Paris System consensus:
  • At least 5 - 10 abnormal cells
  • High N/C ratio (0.7 or greater; nucleus occupies more than 70% of the cytoplasm)
  • Moderate to severe hyperchromatic nuclei (however, nuclear hypochromasia has been reported) (APMIS 2018;126:705)
  • Marked irregular nuclear membrane
  • Coarse / clumped chromatin
• Other cytomorphologic features:
  • Individual and cohesive clusters of tumor cells
  • Pleomorphic nuclei
  • Marked variation in tumor cell size and shapes (i.e. oval, round, elongated, plasmacytoid - comet cells)
  • Scant, pale or dense cytoplasm
  • Jet black and smooth or glassy chromatin (Cancer Cytopathol 2018;126:64)
• Background of necrosis and inflammation
• Prominent nucleoli can be seen in high grade urothelial carcinoma and reactive urothelial cells

Low grade urothelial neoplasia

• Combined cytologic term to include low grade papillary urothelial neoplasms (i.e. urothelial papilloma, papillary urothelial neoplasm of low malignant potential and low grade papillary urothelial carcinoma) and flat, low grade intraurothelial neoplasia
• Definitive cytologic diagnosis can only be made in the presence of this feature (Acta Cytol 1996;40:676):
  • 3 dimensional papillary clusters with nuclear overlapping of tumor cells around fibrovascular cores
• Cytologic diagnosis may be considered in the presence of the following features (Diagn Cytopathol 2014;42:555):
  • 3 dimensional clusters without fibrovascular cores
  • Increased number of monotonous singe cells (e.g. cercaria shaped cells with elongated tails and eccentrically placed nuclei) that are not umbrella cells
  • Note: these cases should still be categorized as negative for high grade urothelial carcinoma with optional comment suggestive of low grade urothelial neoplasia
• Cytologic diagnosis may be considered in the presence of the following features, which can also be associated with high grade urothelial carcinoma, in the absence of other high grade urothelial carcinoma characteristics (Cancer 1994;74:1621, Mod Pathol 1996;9:225):
  • Cytoplasmic homogeneity
  • Slightly irregular nuclear contours
  • Increased N/C ratio
  • Note: these cases should still be categorized as negative for high grade urothelial carcinoma with optional comment suggestive of low grade urothelial neoplasia

Other malignancies: primary, metastatic and miscellaneous lesions

Primary nonurothelial tumors

• Epithelial malignancies
  • Squamous cell carcinoma
    • Essentially similar to squamous cancers arising in other sites
    • Cellular specimen in clusters and singly
    • Tumor cells with:
      • Cytoplasm: abundant, polygonal, dense, keratinized (characteristically orangeophilic), intercellular bridges, low N/C ratio
      • Nuclei: hyperchromatic, nuclear enlargement, irregular nuclear contours, frequently pyknotic
    • Tadpole cells, fiber cells, squamous pearls and cell-in-cell arrangements may be seen
    • Background: hyperkeratosis, parakeratosis, squamous metaplasia, anucleated squamous cells (ghost cells), keratin debris, necrosis, inflammatory cells
    • Nonkeratinizing squamous cell carcinoma: dense cytoplasm, relatively uniform tumor cells, high N/C ratio, prominent nucleoli
    • Well differentiated squamous cell carcinoma: may present as minimally atypical cells (corresponding to ASCUS or LSIL in Pap) (Diagn Cytopathol 2005;33:394, Diagn Cytopathol 2012;40:798)
    • Note: definitive diagnosis of squamous cell carcinoma should be deferred to resection specimens as urothelial carcinoma with squamous differentiation cannot be excluded on urine cytology
  • Adenocarcinoma
    • Variable cellularity
    • Adenocarcinoma, not otherwise specified
      • Clusters of cells
      • Tumor cells with:
        • Cytoplasm: finely vacuolated
        • Nuclei: eccentrically placed, irregular nuclear contours, prominent nucleoli
    • Enteric (colonic type) adenocarcinoma (Cancer 1998;84:335)
      • Clusters of cuboidal to columnar cells and single degenerated cells
      • Tumor cells with:
        • Cytoplasm: scant, may be vacuolated, contains mucin
        • Nuclei: elongated, vesicular or hyperchromatic, irregular nuclear contours, noticeable or prominent nucleoli
      • Background: necrosis and mucin
    • Mucinous (colloid) adenocarcinoma
      • 3 dimensional clusters
      • Tumor cells with:
        • Cytoplasm: scant to moderate amount, lacy, occasional vacuoles
        • Nuclei: bland appearing, crowded, conspicuous nucleoli
      • Background: mucin
    • Signet ring cell carcinoma (Pathol Res Pract 1987;182:130, Acta Cytol 2009;53:309, Acta Cytol 2012;56:177)
      • Tumor cells with:
        • Cytoplasm: clear or finely vacuolated, large cytoplasmic mucin vacuole
        • Nuclei: crescent shaped (due to nucleus being pushed to the periphery by cytoplasmic vacuole), hyperchromatic
    • Clear cell adenocarcinoma (Diagn Cytopathol 1996;14:150, Korean J Pathol 2012;46:210, Am J Pathol 2014;184:584)
      • Tumor cells with:
        • Cytoplasm: abundant, vacuolated, clear or granular
        • Nuclei: centrally located, vesicular chromatin, irregular nuclear contours, prominent nucleoli
      • Singly or in clusters with hobnail appearance
  • Neuroendocrine tumors
    • Small cell carcinoma (Acta Cytol 2000;44:403, Diagn Cytopathol 2000;23:92, Diagn Cytopathol 1996;14:292, Cancer 1997;79:356, Cell J 2014;16:95)
      • Similar to small cell carcinoma arising in other sites
      • Hypercellularity
      • Tumor cells in various arrangements: singly, linear pattern, rosettes, loose or tight clusters
      • Tumor cells with:
        • Cytoplasm: scant, high N/C ratio
        • Nuclei: slightly enlarged (small to medium sized), round to ovoid, hyperchromatic, smudged chromatin, molding (may be minimal in liquid based preparations), crush artifact (may be less in liquid based preparations), absent or inconspicuous nucleoli (Diagn Cytopathol 2001;24:46)
      • Frequent mitosis and apoptosis
      • Background: hemorrhage, necrotic debris (may be clumped or clings to tumor cells in liquid based preparations), inflammation
      • Note: small cell carcinoma is commonly seen in combination with urothelial carcinoma; both cell populations may be seen
  • Large cell neuroendocrine carcinoma (Acta Cytol 2010;54:303)
    • Similar to large cell neuroendocrine carcinoma arising in other sites
    • Arranged in rosette pattern
    • Tumor cells with nuclear molding, finely or coarsely granular, hyperchromatic nuclei

• Nonepithelial malignancies
  • Sarcoma
    • Leiomyosarcoma (Diagn Cytopathol 2004;31:281, J Cytol 2017;34:171)
      • Individual or sheets of atypical spindle cells
      • Tumor cells with:
        • Cytoplasm: moderate amount, ill defined cytoplasmic borders, low N/C ratio
        • Nuclei: large, spindled, hyperchromatic, irregular nuclear contours, occasional nucleoli
    • Angiosarcoma (Cytopathology 1999;10:137)
      • Individual cells and in small clusters
      • Rather monomorphic spindled or epithelioid tumor cells with:
        • Cytoplasm: moderately abundant, granular to dense, intracellular lumina containing erythrocytes may be seen
        • Nuclei: large, round to oval, eccentrically placed, irregular nuclear membrane, hyperchromatic, prominent cherry-red nucleoli
    • Note: confirmatory workup by histologic and immunohistochemical evaluation is required
  • Hematologic malignancy
    • Lymphoma / leukemia (Leuk Lymphoma 2002;43:187, Cytopathology 2013;24:412, Diagn Cytopathol 2017;45:354, Diagn Cytopathol 2017;45:1125, J Am Soc Cytopathol 2015;4:107)
      • Cytomorphology dependent on specific type of lymphoma or leukemia
      • Singly, do not form aggregates
      • Tumor cells with high N/C ratio, coarse to vesicular chromatin, prominent nucleoli may be seen
      • Tumor diathesis may been present in the background
    • Plasmacytoma / myeloma (Acta Cytol 2003;47:787, Acta Cytol 2006;50:339)
      • Cytomorphology ranges from mature to immature neoplastic plasma cells
      • Tumor cells with eccentric nuclei, clock face chromatin and perinuclear hof (halo)
      • Binucleation common
    • Note: confirmatory flow cytometry and biopsy are essential
  • Melanoma (Acta Cytol 2001;45:631, Diagn Cytopathol 2014;42:1091)
    • Individual to sheets and clusters
    • Tumor cells with:
      • Cytoplasm: abundant, dark brown melanin pigment may be present
      • Nuclei: large, round to ovoid, eccentrically located, irregular nuclear contours, prominent nucleoli, occasional nuclear pseudoinclusions

Direct extension and metastatic tumors to urinary bladder

• Direct extension
  • Prostatic adenocarcinoma (Cancer 1998;84:335, Am J Clin Pathol 2000;113:29, Acta Cytol 2013;57:184)
    • Uniform, cuboidal cells arranged in clusters, some may show acinar formation
    • Tumor cells with:
      • Cytoplasm: abundant, dense, granular
      • Nuclei: round, smooth nuclear membrane, fine evenly distributed chromatin, may be eccentrically placed, prominent nucleoli OR hyperchromatic
    • Background usually clean
      • Note: prostatic adenocarcinoma detected in urine cytology has high Gleason scores and presents at advanced clinical stage
  • Colorectal adenocarcinoma (Cancer 1998;84:335)
    • Elongated or columnar cells in glandular arrangement
    • Tumor cells with:
      • Cytoplasm: frequent vacuolation
      • Nuclei: degenerated, hyperchromatic, angulated, irregular nuclear contours, coarse chromatin, inconspicuous nucleoli
    • Background tumor necrosis
    • Note: correlation with clinical history is necessary
  • Squamous cell carcinoma of uterine cervix
    • Similar to squamous cell carcinoma arising in other sites
    • Note: clinical history with ancillary studies are important to establish tumor origin
• Metastatic tumors
  • Renal cell carcinoma (Acta Cytol 1983;27:383, Cancer 1998;84:335)
    • For clear cell renal cell carcinoma: tumor cells in clusters with large nuclei, evenly distributed chromatin, prominent nucleoli and granular, vacuolated cytoplasm
    • Multinucleated cells with distinct nucleoli or large vacuolated cells with eccentric nuclei may be seen
    • Granular eosinophilic cells with pyknotic nuclei may be degenerative changes caused by urine
    • Note: primary renal cell carcinoma involving the renal pelvis may be seen in upper urinary tract specimens
    • Note: metastasis to bladder is very rare; most frequently reported type for bladder metastasis is clear cell renal cell carcinoma
  • Breast carcinoma
    • For metastatic lobular carcinoma: small tumor cells in linear arrangement or in small clusters, eccentrically placed nucleus, small nucleolus and vacuolated cytoplasm with occasional targetoid mucin
    • For metastatic ductal carcinoma: tumor cells are arranged in cellular sphere or morula
    • Note: metastatic breast carcinoma is more frequently lobular than ductal
  • Gastric carcinoma
    • Tumor cell shows signet ring morphology

Nonepithelial benign tumors and tumor-like conditions

• Nonepithelial benign tumors
  • Pheochromocytoma / paraganglioma (Diagn Cytopathol 2017;45:350)
    • Individual and nests of epithelioid cells
    • Tumor cells with:
      • Cytoplasm: moderate to abundant, finely granular
      • Nuclei: relatively regular and smooth nuclear contours, fine chromatin, inconspicuous nucleoli
    • Occasional spindle sustentacular cells present in association with the tumor cells
• Tumor-like lesions
  • Nephrogenic adenoma (Diagn Cytopathol 1988;4:210, Acta Cytol 1986;30:41)
    • Cuboidal to low columnar cells in singly or in papillary clusters
    • Lesional cells with:
      • Cytoplasm: scant, slightly increased N/C ratio, clear or slightly basophilic, vacuolated
      • Nuclei: no to minimal atypia, round to ovoid, fine chromatin, smooth to slightly irregular nuclear membrane, small central nucleolus
    • Background: neutrophils or lymphocytes
  • Amyloidosis (Acta Cytol 2005;49:319)
    • Amorphous, waxy material
      • Stained light green by Papanicolaou method
      • Positivity with direct fast scarlet (DFS), showing yellow-green birefringence under polarized light
  • Inflammatory pseudotumor (pseudosarcomatous fibromyxoid tumor) (Acta Cytol 1999;43:257, Acta Cytol 2003;47:1069)
    • Atypical spindle cells
    • May present in papillary clusters

Contributed by Bonnie Choy, M.D.

A voided urine from a 55 year old man with hematuria shows cells with high nuclear to cytoplasmic ratios, nuclear hyperchromasia and pleomorphism. What is the correct diagnosis?

1. Benign urothelial cells
2. High grade urothelial carcinoma
3. Low grade urothelial carcinoma
4. Polyoma virus infected urothelial cells

B. High grade urothelial carcinoma. Based on The Paris System for Reporting Urinary Cytology, the diagnostic criteria for high grade urothelial carcinoma include high N/C ratio, moderate to severe hyperchromatic nuclei, markedly irregular nuclear membrane and coarse chromatin. The voided urine contains cells meeting the diagnostic criteria for high grade urothelial carcinoma. While urothelial cell with polyoma (BK) viral cytopathic effect show high N/C ratio, other features of high grade urothelial carcinoma are not seen.

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Reference: Cytology-neoplastic

A bladder washing from a 70 year old man with hematuria. Tumor cells are present and immunohistochemistry was performed on the cell block. The tumor cells are positive for NKX3.1 and negative for GATA3, PAX8 and CDX2. What is the correct interpretation?

1. Colonic adenocarcinoma
2. Nephrogenic adenoma
3. Prostatic adenocarcinoma
4. Urothelial carcinoma

C. Prostatic adenocarcinoma. Nonurothelial carcinomas can involve the urinary bladder either by direct extension from adjacent organs or metastasis from distant site. The tumor cell shows NKX3.1 positivity. GATA3, PAX8 and CDX2 are negative. This immunoprofile supports the diagnosis of prostatic adenocarcinoma.

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Reference: Cytology-neoplastic