Non-gynecologic cytology encompasses all cytological specimens other than cervical Pap tests. It is a rapidly growing area driven by minimally invasive sampling techniques, liquid-based preparations, and the increasing need for molecular testing on small samples.
Effusion Fluids
Pleural, peritoneal (ascitic), and pericardial effusions are the most common non-gynecologic cytology specimens. Fluid (50-500 mL) is collected by thoracentesis, paracentesis, or pericardiocentesis and sent to the laboratory for cell count, chemistry, microbiology, and cytology. Cytology preparation includes centrifugation, smear preparation, and cell block for IHC.
Reactive mesothelial cells are the most common finding — they show mild atypia, may be mistaken for malignancy by inexperienced observers. Malignant effusions most commonly result from metastatic carcinoma (lung, breast, ovarian, gastric, pancreatic) or lymphoma. The diagnosis requires definitive identification of malignant cells, which may be single or in clusters, with nuclear enlargement, high N/C ratio, irregular nuclear contours, and prominent nucleoli. IHC on cell blocks identifies the primary site: calretinin and WT1 for mesothelioma; MOC-31, Ber-EP4, and Claudin-4 for carcinoma; mammaglobin and GATA3 for breast; PAX8 for ovarian.
Mesothelioma — malignant mesothelioma cells show dense, “busy” cell clusters with scalloped borders, nuclear pleomorphism, and a two-cell population (epithelioid and sarcomatoid). IHC: calretinin+, WT1+, D2-40+, claudin-4-.
Urine Cytology
Urine cytology screens for urothelial carcinoma in patients with hematuria, irritative voiding symptoms, or history of bladder cancer. Voided urine (first morning specimen or random) is the standard sample; catheterized urine and bladder washings are used for specific indications.
High-grade urothelial carcinoma — cells with high N/C ratio, irregular nuclear membranes, hyperchromasia, and coarse chromatin. Nuclear pleomorphism is marked. Necrosis and mitotic figures may be present. Sensitivity for high-grade tumors is 70-90%; sensitivity for low-grade tumors is only 20-40%. The Paris System for Reporting Urinary Cytology standardizes terminology into seven categories (nondiagnostic, negative, atypical, suspicious, high-grade urothelial carcinoma, low-grade urothelial neoplasm, other malignancies). High-grade urothelial carcinoma requires definitive cytologic criteria; the “atypical” category should be used sparingly (<10% of cases).
Respiratory Cytology
Sputum cytology examines spontaneously expectorated or induced sputum for malignant cells. Sensitivity is 40-70% for central lung tumors (squamous cell, small cell) but <20% for peripheral adenocarcinomas. Three morning specimens are recommended.
Bronchoalveolar lavage (BAL) — saline is instilled and aspirated from a bronchial segment or subsegment. BAL cytology diagnoses infections (Pneumocystis jirovecii, CMV, fungi), diffuse lung diseases (sarcoidosis, hypersensitivity pneumonitis, pulmonary alveolar proteinosis — characteristic eosinophilic material), and malignancy.
Endobronchial brushing and washing collect cells from visible endobronchial lesions. Sensitivity for central tumors is 70-85%.
Cerebrospinal Fluid (CSF) Cytology
CSF cytology diagnoses leptomeningeal carcinomatosis, primary CNS lymphoma, and infections. CSF (10-20 mL) is processed by cytocentrifugation or ThinPrep. Leptomeningeal metastasis — malignant cells from solid tumors (breast, lung, melanoma) or lymphoma in CSF. Sensitivity of a single specimen is 50-60%; three consecutive specimens increase sensitivity to 85-90%. Primary CNS lymphoma — large B-cell lymphoma cells with prominent nucleoli, often with a background of reactive lymphocytes.
Gastrointestinal Cytology
Bile duct brushings — endoscopic retrograde cholangiopancreatography (ERCP) brushings of biliary strictures diagnose cholangiocarcinoma. Sensitivity is 40-70%; specificity exceeds 95%. Ancillary FISH (UroVysion probe set) increases sensitivity. Pancreatic cyst fluid — CEA level (>192 ng/mL) and cytology diagnose mucinous cystic neoplasms. Esophageal and gastric brushings — now largely replaced by endoscopic biopsy.
Analytic Considerations
Non-gynecologic cytology is more challenging than gynecologic cytology because specimens are more variable, cellularity is lower, and reactive atypia (from inflammation, chemotherapy, radiation) mimics malignancy. Clinical correlation is essential — the cytopathologist must know the patient’s age, sex, clinical presentation, imaging findings, and prior therapy to avoid false-positive interpretation. Cell blocks and ancillary IHC are critical for definitive diagnosis. Liquid-based cytology has improved specimen adequacy and enabled molecular testing from these samples.
