Cytology of Pleural, Pericardial and Peritoneal Cavity Effusions
INTRODUCTIONEffusions accumulate within body cavities either because of a disease process either within the cavity, or within the surrounding tissue. While there are only four body cavities in which fluid can accumulate (the right or left pleural cavities, the peritoneal cavity and the pericardial cavity), there are numerous causes for effusions. Correct cytologic interpretation of effusions is aided by knowledge of medical history, current clinical setting, radiographic findings and the chemical composition of the effusion. Regardless of the underlying diagnosis, clinicians appreciate the contribution of cytology in the evaluation of fluids obtained from pleural, pericardial or peritoneal cavities. Optimal fixation and slide preparation can contribute to better evaluation of body fluids from any of these body compartments. Diagnostic sensitivity can sometimes be improved when cytology and cell block preparation are used in tandem.
Fluid accumulations are classified into four categories: hydrostatic, infectious, noninfectious inflammatory, and malignant. Furthermore, effusions may be transudative or exudative, a distinction that is made by chemical analysis of the fluid. Transudates have low protein and low cell count since they are basically an ultrafiltration of plasma. Transudates are classically caused by cardiac failure or protein/electrolyte imbalance. Exudates, in contrast, have high cellularity often because of an active inflammatory process affecting the body cavity.
Hydrostatic causes of effusion reflect an imbalance of intravascular pressure, plasma oncotic pressure or increased capillary permeability, resulting in the flow of plasma constituents into a body cavity. Fluid is copious relative to the cellular content and protein level in the fluid is low. Cytology samples of this type of fluid yield small numbers of benign mesothelial cells, inflammatory cells and possibly blood, reflecting a traumatic tap. Mesothelial cells are easily identified as benign with little or no reactive change. As mentioned above, cardiac failure is a classic cause of a hydrostatic effusion. Effusions can also arise from oncotic imbalance, as may be seen with peritoneal ascites in liver failure.
Infectious effusions can occur in any of the body cavities and can be due to the direct effects of invading organisms or as a byproduct of the inflammation. Inflammatory cells and mesothelial cells constitute the majority of formed elements. The characteristic of the inflammation may provide clues to the offending organism. For instance, a high concentration of lymphocytes may indicate tuberculosis. Gram and acid fast stains may be useful. Occasional fungal infections may be present. ThinPrep slide preparations allow for the application of special stains to identify these organisms. Mesothelial cells show a continuum of reactive changes, a feature useful in their cytologic evaluation. Clues from cytology may direct the pathologist to request additional testing, culture, or raise a differential diagnosis for the clinician to consider.
Noninfectious inflammatory effusions indicate an underlying condition, either autoimmune (rheumatoid arthritis, systemic lupus) or reactive to a stimulus such as tissue necrosis or radiation therapy. Inflammation is variable and mesothelial cells may show a spectrum of atypia, which is usually in a continuum, signaling a benign condition.
Malignant effusions are of foremost concern in the cytologic evaluation of a body cavity effusion. The cytologist must be cognizant of the history of past and present disease and can be aided by knowledge of the chemical constituents of the fluid and its appearance (clear, bloody, partially clotted) as a preliminary to microscopic examination. The key to diagnosing a malignant effusion is the identification of a separate cell population distinct from the background benign mesothelial cells. These may exist as a uniform population of malignant cells (in the case of mesotheliomas) or as a second or foreign population against a backdrop of reactive mesothelia (in the case of metastatic tumors).
The most common tumors to appear in the pleural cavity in men are metastatic adenocarcinoma of the lung followed by metastatic gastrointestinal tumors. In women, metastatic beast carcinoma is most common followed by lung and ovarian tumor metastases. In peritoneal effusions, the most common metastatic tumor in men is from the gastrointestinal tract followed by pancreas and lung tumors. In women, the most common metastasis is from the ovaries followed by gastrointestinal and pancreatic metastases 14. Pericardial effusions may also occur due to metastatic malignancy involving the pericardial tissue.
Experienced cytologists recognize that there are no hard and fast rules in the cytology of cells from these sites and that consideration of clinical information along with cytologic criteria is necessary to achieve the best diagnosis. At times, special stains, immunohistochemistry, flow cytometry and gene rearrangement studies may be necessary to arrive at a definitive diagnosis.
Several factors may complicate cytologic evaluation. The presence of inflammation and reactive mesothelia may create the illusion of a continuum between benign and malignant populations, thus obscuring their presence. Loculation in the cavity may isolate malignant cells out of reach of the needle aspiration. Clotted fluid may entrap malignant cells so that they are not available for cytologic evaluation. The cytologist may find it difficult to make a definitive diagnosis when only a small number of malignant cells are present. Repeated aspiration of fluid may be necessary to arrive at an accurate diagnosis. Despite these drawbacks, cytologic evaluation is still requested by clinicians as an essential part of the total work up of all effusions.
Cytologic features of adenocarcinoma include three dimensional, rounded groups of 20 or more cells, the presence of so-called tumor "cannon-balls", papillary or acinar formations. Certain metastatic tumors may have other distinctive features such as psammoma bodies, signet cells or mucin production. Lymphomas are a less common cause of effusions in adults but, along with leukemias, is the most common cause of malignant effusions in children. The characteristic single cell, monomorphic pattern of lymphoid malignancies facilitates differentiation from carcinoma, but specific cell type may be difficult to determine without patient history, histologic correlation and/or ancillary studies.
Mesothelial tumors, less common than adenocarcinomas, can arise in any body cavity but occur most often in the pleural cavity. Patient history, especially exposure to asbestos, in combination with radiographic information is a necessary supplement to the cytologic diagnosis.
Features of mesothelioma include a uniform population of malignant cells, which on close inspection may be on a continuum with benign, and/or reactive mesothelial cells. The cells may appear singly or in large aggregates of 20 to 100 cells. They possess a uniform dense cytoplasm and enlarged, atypical nuclei. Due to the peripheral ruffled cytoplasm, sheets and aggregates display intercellular "windows", or clear spaces, between neighboring attached cells. These criteria need to be used in concert to improve the accuracy of the diagnosis. Morphology may sometimes offer limited value in this differential diagnosis, since mesotheliomas can display glandular and papillary features similar to adenocarcinoma. Mesotheliomas can also present as single cells or in small groups. The pathologist may then need to resort to a battery of immunohistochemical stains to complete the diagnostic evaluation. Clinicians should be warned that these studies are not always helpful and that the pathologic workup should not impede additional diagnostic testing including thorascopic, mediastinal or open biopsy, if necessary, in order to establish a diagnosis.
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