Bladder, ureter & renal pelvis
Cytology
Cytology-neoplastic


Topic Completed: 5 November 2020

Minor changes: 19 November 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Neoplastic urine cytology[TIAB]

Lucy Jager, M.D.
Bonnie Choy, M.D.
Page views in 2020 to date: 336
Cite this page: Jager L, Choy B. Cytology-neoplastic. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/bladdercytologyneoplastic.html. Accessed November 23rd, 2020.
Definition / general
  • Urine cytology is more sensitive in detecting high grade urothelial carcinoma than low grade (Diagn Cytopathol 2013;41:852, Urol Oncol 2014;32:27.e1)
    • Sensitivity: 10 - 43.6% for low grade, 50 - 85% for high grade
    • Specificity: 26.3 - 88% depending on type of urine sample collection
  • Rate of malignancy in urine cytology: 1.7 - 5.8% (Am J Clin Pathol 2007;127:946, Cytopathology 2011;22:329, Cancer Cytopathol 2013;121:15)
  • Bladder washings and upper urinary tract specimens have higher percentage of malignant cases when compared with voided urine specimens
  • Positive predictive value and specificity for urine cytology designated as positive for malignancy is very high
    • Specificity: 78 - 100%, majority > 90%
Essential features
  • The Paris System for Reporting Urinary Cytology is the recommended system to report results (Rosenthal: The Paris System for Reporting Urinary Cytology, 1st Edition, 2016)
  • Urine cytology cannot distinguish invasive high grade urothelial carcinoma from noninvasive high grade urothelial carcinoma or carcinoma in situ
  • Low grade urothelial neoplasia is a 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
  • Cell block can also be prepared from the residual specimen for ancillary studies
CPT coding
  • 88108: cytopathology, concentrated preparation (e.g. cytospin or Saccomanno)
  • 88112: cytopathology, enriched / concentrated preparation, nongynecologic (e.g. liquid based slide preparation: ThinPrep, SurePath)
  • 88305: cell block
  • 88342: immunohistochemical stain (qualitative), first stain
  • 88341: immunohistochemical stain (qualitative), second and subsequent stains
Sites
  • Urinary bladder, upper urinary tracts (renal pelvis, ureters), urethra
  • Urinary bladder diversion (ileal conduit, Indiana pouch, neobladder)
Case reports
Cytology description
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


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
Cytology images

Contributed by Bonnie Choy, M.D.
High grade urothelial carcinoma High grade urothelial carcinoma

High grade urothelial carcinoma

High grade urothelial carcinoma High grade urothelial carcinoma High grade urothelial carcinoma

High grade urothelial carcinoma

Low grade urothelial neoplasia

Low grade urothelial neoplasia


Squamous cell carcinoma

Squamous cell carcinoma

Small cell carcinoma

Small cell carcinoma

Prostatic adenocarcinoma

Prostatic adenocarcinoma

NKX3.1

NKX3.1

Colorectal adenocarcinoma

Colorectal adenocarcinoma

Renal cell carcinoma

Renal cell carcinoma

Molecular / cytogenetics description
Sample pathology report
  • Bladder, voided urine:
    • Specimen adequacy:
      • Satisfactory for evaluation
    • Interpretation:
      • Positive for malignancy
    • Diagnosis:
      • High grade urothelial carcinoma
Differential diagnosis
Board review style question #1

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
Board review answer #1
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
Board review style question #2

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
Board review answer #2
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
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