Chapter 4 Diagnostic pitfalls in effusion fluid cytology
FACTORS LEADING TO POTENTIAL DIAGNOSTIC PITFALLS
False positivity in up to 0.5% and false negativity in up to 30% of cases have been reported in effusion fluid cytology.1 Most of these discrepant diagnoses, especially false-positive results, could be prevented if the interpreter is conversant with the following factors responsible for potential diagnostic pitfalls in this area of cytopathology (Table 4.1).
A classical example in this category would be predominance of polyhedral cells in metastatic sarcoma, in contrast to spindle cells in other cytology specimens such as fine-needle aspiration biopsy (FNAB) smears.IMPROPER SPECIMEN PROCESSING
If staining, cell block preparation, immunostaining, and other specimen processing steps are not organized properly to address various objectives associated with interpretation of effusion cytology (see Chapter 3), it may lead to suboptimal results. This may range from improper collection or storage (see Chapter 14) to failure of making smears for proper staining such as Diff-Quik staining and cell block preparation. Additional factors such as improper orientation of immunostained cell block sections for evaluation of ‘subtractive coordinate immunoreactivity pattern’ (SCIP) (see Chapter 5) may further compromise the final interpretation.
THE MANY FACES OF REACTIVE MESOTHELIAL CELLS
Many of the false positives in effusion fluid cytology are caused by the atypical features of reactive mesothelial cells associated with a variety of underlying benign processes, including acute pancreatitis,2 tuberculosis,1 ovarian fibroma,1 pulmonary infarction,3 chemotherapy,4 and cirrhosis1 (see Table 3.2). These clinical conditions may induce remarkable changes in mesothelial cells, resulting in morphologic appearances overlapping those of malignant cells. This may lead to the pitfall of misinterpreting these floridly reactive mesothelial cells with atypical features as cancer cells (see Figures 2.9, 2.10, 4.5c).
Figure 4.9 Chronic inflammatory cells with a few reactive mesothelial cells (pleural fluid). a. With DQ stain, the typical nuclear morphology helps to interpret them as polymorphic lymphocytes, which is consistent with chronic inflammatory cells. b. With PAP stain, these chronic inflammatory cells may resemble cells of lymphoma (compare with Figure 4.12d) and round blue cell tumors, especially in children. RM, reactive mesothelial cell. [a, DQ-stained Cytospin smear; b, PAP-stained SurePath smear (a, 100×; b, 100×).]
Figure 4.5 Degenerative vacuoles in reactive mesothelial cells (ascitic fluid). Note relatively fuzzy boundaries of vacuoles (arrowheads in b,c) without any secretions (compare with Figure 4.7b). The secretory vacuoles containing mucin in neoplastic cells usually show secretion with a targetoid appearance (compare with Figure 4.7a). Some of these cells may have nuclear features overlapping with cancer cells (c) and may be misinterpreted as cancer cells, especially in patients with clinical history of adenocarcinoma. RM, reactive mesothelial cells. [a–c, PAP-stained SurePath preparation (a, 100× F1 (Focus 1) and F2 (Focus 2); b,c, 100× zoomed).]
PROLIFERATION-RELATED FEATURES5–25
The malignant cells may continue to proliferate even after they are exfoliated into a serous cavity fluid to give rise to ‘cell balls’ known as ‘proliferation spheres’ (see Chapter 3, Figures 3.9, 3.10, 4.1, 4.3). These proliferation spheres are three-dimensional, solid or hollow aggregates without a stromal core (Figure 3.10). They are unique to metastatic cancer cells in serous cavity fluids. In contrast, urine and cerebrospinal fluid are not conducive to proliferation of neoplastic cells; therefore, urothelial carcinoma in urine and metastatic cancer cells in cerebrospinal fluid do not form proliferation spheres.
The periphery of the proliferation spheres often shows a radial arrangement due to the rapid proliferation of their constituent cells, resulting in an increase in the size of these groups (see Figure 4.1). Acinar and glandular structures may also resemble proliferation spheres at lower magnification. However, these structures are smaller and a central space can usually be seen at higher magnification by adjusting the fine focus (Figure 4.2).
Proliferation spheres are not observed in recently developed malignant effusions because of lack of time necessary for proliferation, and so they are usually observed at a later stage. They continue to grow and may reach up to 0.5 mm in diameter, which are readily visible to the naked eye either in the fluid or on the slide. These are observed in effusions secondary to many types of malignancies, especially ductal carcinoma of the breast, epithelioid mesothelioma, and poorly differentiated small cell carcinoma of the lung.
Proliferation spheres are not formed in effusions secondary to cancers that lack significant intercellular cohesion. Examples of these include anaplastic gastric carcinoma (linitis-plastica type), non-cohesive type of adenocarcinoma of the lung, non-cohesive epithelioid mesothelioma, pleomorphic giant cell carcinoma of the pancreas, giant cell carcinoma of the lung, lobular carcinoma of the breast, adrenocortical carcinoma, and lymphomas. Irrespective of effusion duration, such effusions usually contain a high proportion of isolated cells (see Table 9.1(3)).
Some proliferation spheres may join together, especially during specimen processing, to form groups that may resemble a papillary configuration (Figure 4.4). Proliferation spheres simulating papillary structures are relatively common in effusion smears from a variety of neoplasms and do not denote a papillary architecture at the primary lesion. Consequently, papillary-like structures are not uncommon in effusions associated with non-papillary adenocarcinomas of colon and pancreas (see Table 9.1(10)).
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