GENERAL FEATURES

Any neoplasm, including rare examples of central nervous system tumors,¹ may involve a serous cavity and manifest as a malignant effusion. Amongst these, metastatic adenocarcinoma is, by far, the most common cause of malignant effusions.² The serous cavity lining is rich in lymphatic channels. The lymphatic lacunae open through narrow gaps (stoma) in the lining with virtual extension of the lymphatic system into the serous cavities.³ Most of the carcinomas from various sites metastasize to serosa via the lymphatic vessels. Blockage in lymphatic channels by carcinoma cells leads to effusion. Primary carcinomas of organs covered with serosal membranes such as lung, intestines, liver, ovary, etc., can spread to serous cavities by direct extension, resulting in malignant effusions.

Cytopathologic evaluation of effusions from serous cavities is usually focused on the detection of malignant cells.² The sampling benefit of effusion cytology generally provides a higher yield of diagnostic material than biopsy of the serous lining. In contrast to a focal biopsy from a small area of an extensive serosal surface, an effusion represents cells exfoliated from the entire serosal surface (see Figure 1.12). In a series of 414 cases of malignant effusion, needle biopsy of the pleura was non-diagnostic in 13%; however, cytologic analysis of the effusions demonstrated higher diagnostic sensitivity.⁴

Figure 9.12 Primary peritoneal carcinoma, peritoneal fluid. The specimen shows a predominance of adenocarcinoma cells in papillary configurations (a,d) without stromal cores (g). Solitary neoplastic cells (red arrows NC in a,b,d,e) are easily distinguished from the rare reactive mesothelial cells (blue arrowheads RM in c,d,e). However, in PAP-stained preparation (d), reactive mesothelial cells (arrowhead RM in e) have significant morphologic overlap with neoplastic cells (red arrows NC in d,e). Mitotic figures (yellow arrow MF in a) and apoptotic cells (yellow arrows AP in d,f) are present concurrently. Some cells show degenerative vacuolation (a,b). These vacuoles may resemble secretory vacuoles and lead to misinterpretation as mucinous adenocarcinoma. The cancer cells do not show nuclear immunoreactivity for calretinin (h), but they are immunoreactive for BerEP4 (i). The neoplastic cells show nuclear (and cytoplasmic) immunoreactivity for WT-1(j). The patient had ascites with diffuse peritoneal involvement with omental caking. The ovaries were not enlarged. AP, apoptotic cancer cell; MF, mitotic figure; NC, neoplastic cell; RM, reactive mesothelial cell. [a–c, DQ-stained Cytospin smear; d–f, PAP-stained SurePath smear; g, HE-stained cell block section; h–j, immunostained cell block sections (a, 100×; b,c, 100× zoomed; d, 100×; e,f, 100× zoomed; h–j, 100×).]

With the proper approach, cytologic examination of effusion fluids, with or without ancillary tests, is a highly valuable method for diagnosing cancer. However, there may be a significant variation in interpretation of effusion cytology. This, in combination with well-recognized diagnostic pitfalls in this field (see Chapter 4), may lead to a lack of reproducibility and even serious misinterpretation.

The approach to processing and evaluating effusion cytology for interpretation of metastatic carcinoma is comparable to that of other specimens. However, it is crucial not to ignore the need for incidental modifications with reference to the limitations associated with effusion cytology (see Chapter 3; Figures 3.1 and 3.2). A brief discussion about this, with reference to metastatic carcinoma, follows (see also Chapters 3, 4, 5, 15).

CLINICAL HISTORY

Clinical details may be important for cytologic interpretation of effusions. However, depending on the clinical scenario and cytologic picture, the clinical history may be misleading, especially with beginners. In addition, some effusions may develop without any history of cancer and may present a diagnostic challenge.^5–7 In a series of 248 patients with malignant effusions, 10% of cases (25 effusion fluids—18 pleural and 7 peritoneal) presented with effusion as the initial manifestation of cancer.⁸

The clinical history can play a critical role in ensuring proper triaging and processing of effusion specimens; therefore, to facilitate appropriate processing of effusions, the clinical history should be provided in all the requisitions. This could avoid suboptimal cytopathologic interpretations. In our laboratory, cell blocks are prepared in all cases with a history of malignancy and also in cases with suspected malignant effusions. If the history is not available, the decision to make a cell block is based on cytologic findings. If indicated, the cell blocks are prepared from the remaining effusion fluid stored in the refrigerator. However, this approach will increase the turnaround time by usually 1 day.

CYTOPATHOLOGY

Reactive mesothelial cells may have significant morphologic overlap with cancer cells (see Chapter 2). Such reactive mesothelial cells may be a major or a minor component of the malignant effusion. Some of these factors are significant diagnostic pitfalls, which may lead to false-positive interpretations (see Table 3.2). This is particularly applicable to cases with a previous history of carcinoma. Although a false-positive diagnosis may be difficult to disprove, it may subject the patient to improper management decisions and emotional distress.

On the other hand, adenocarcinoma cells may resemble reactive mesothelial cells, leading to false-negative interpretations. Some well-differentiated and low-grade adenocarcinomas show features such as intercellular spaces resembling ‘mesothelial windows’ (see Figures 1.15, 1.16, 9.2c, 9.14),⁹ hyperchromasia, high nucleocytoplasmic ratios, anisokaryosis, etc., overlapping with reactive mesothelial cells (see Tables 2.2, 2.3).

Changes secondary to irradiation usually show bizarre cells in effusions. The reported findings include:

cytomegaly with normal nucleocytoplasmic ratio

degenerative hyperchromasia with smudgy chromatin

cytoplasmic vacuoles deforming the nucleus

degenerative cytoplasmic changes with two-tone staining [shades of cyanophilia (blue-green) and eosinophilia (pink)].

Mitotic figures may be present.¹⁰ These features may be present collectively in association with irradiation, but they are not specific. There are no consistent cytologic changes in effusions that can confirm the irradiation therapy in effusion cytology. The important concern is that these changes should not be misinterpreted as neoplastic, representing recurrence of initial disease for which the radiation therapy was administered.

Scanty, degenerated, poorly preserved cells and improperly processed specimens by inadequate protocols hinder proper interpretation. If the initial findings are equivocal for cancer cells, it is prudent to be extra cautious by recommending repeat cytologic evaluation on a new specimen. If the initial effusion is caused by cancer, it usually reaccumulates rapidly and may contain unequivocal cancer cells with improved morphology (see Figure 3.2 (29b)).

The cytologic examination of effusions not only allows a definite diagnosis of metastatic carcinoma but may also help to locate the site of origin of some carcinomas (Table 9.1, Figures 3.2). Once malignant cells are confirmed in effusion fluid, the clinical history and radiologic findings may also assist in identifying the site of origin of the carcinoma (see Figure 3.2 (4)). Depending on the clinical scenario, the exercise of attempting to identify the primary site may be just an exercise of intellectual curiosity, especially if it does not change the clinical management.

Table 9.1 Different cytomorphological patterns of carcinoma cells in effusions and possible primary sites (see also Table 11.1)

Compiled from references 2,11–14.

This chapter describes cytomorphologic and salient clinical features of different types of metastatic carcinoma in serous effusions. Various features are summarized in Table 9.1 and discussed in brief below. Although many cytomorphologic features are characteristic,^11,12 there is a significant overlap of some features amongst different neoplasms, which may lead to repetition of some features in the description. Features such as intercellular windows, papillary configurations, Indian file pattern, etc., are generally identified with specific primary sites; however, they may also be observed unexpectedly with other metastatic carcinomas (Figures 9.2, 9.10, 9.14).^13,14

Figure 9.2 Metastatic poorly differentiated adenocarcinoma of lung, pleural fluid. The DQ-stained preparation (a) demonstrates reactive mesothelial cells (arrowhead 1 in a) mixed with a ‘second population’ of cohesive groups of cells (arrow 2 in a) with eccentric nuclei that touch the periphery of the carcinoma cells (arrowheads in b,c,f). Some cells are less cohesive with scattered small groups or solitary carcinoma cells (arrows in d–f). Occasional intercellular spaces, resembling mesothelial windows, are present (arrowhead w in c). The patient had poorly differentiated adenocarcinoma of the lung. [a–c, DQ-stained Cytospin smear; d–f, PAP-stained SurePath smear (a, 10×; b,c, 100×; d, 10×; e,f, 100×).]

Figure 9.10 Metastatic pancreatic adenocarcinoma, peritoneal fluid. The neoplastic cells (NC) are seen as loosely cohesive groups (a) or as solitary cells (b,e) with eccentric nuclei. PAP-stained preparations facilitate evaluation of cellular details in cohesive groups (c,d). A few cell groups show gland-like structures (arrow in d). ‘A second population’ (arrows in f–h) of neoplastic cells is highlighted distinctly in immunostained cell block sections f–h (the neoplastic cells are immunoreactive for BerEP4 in f, non-immunoreactive for vimentin in g, and calretinin in h). As inbuilt corresponding positive controls, inflammatory and reactive mesothelial cells (arrowhead in g) are immunoreactive for vimentin and reactive mesothelial cells (arrowhead RM in h) are immunoreactive for calretinin. The patient had pancreatic adenocarcinoma. NC, neoplastic cell; RM, reactive mesothelial cell. [a,b, DQ-stained Cytospin smear; c–e, PAP-stained SurePath smear; f–h, immunostained cell block sections (a–e, 100×; f–h, 40×).]

Figure 9.14 Metastatic ovarian adenocarcinoma, peritoneal fluid. The neoplastic cells show an Indian-file pattern. This arrangement is not specific for this particular carcinoma;¹⁴ in addition to metastatic mammary carcinoma and small cell carcinoma of lung (see Figure 9.4a,b,g), this pattern may be seen in other non-small-cell carcinomas, as in this case with metastatic ovarian adenocarcinoma. [a, PAP-stained SurePath smear; b, DQ-stained Cytospin smear (a,b, 100×).]

LUNG CARCINOMAS^15–25

Lung cancer is the most common cause of malignant pleural effusions in men and the second most common cause of malignant pleural effusions in women (Table 9.2, Figure 9.3). About 50% of patients with disseminated lung cancer develop pleural effusions, which may be due to neoplastic obstruction of hilar lymph nodes, blockage of the pleural lymphatics by carcinoma cells, by direct extension of neoplasm to the pleural surfaces, or a combination of these.

Table 9.2 Common primary sites of neoplasms causing malignant effusions (see also Figure 9.3).

Figure 9.3 Common sources of primary neoplasms causing malignant effusions (compiled from refs 8, 89 and 90).

Adenocarcinoma is the most common primary lung cancer leading to pleural effusion, followed by undifferentiated small cell carcinoma. This appears to be due to frequent peripheral location of pulmonary adenocarcinomas, which facilitates their early spread to the pleura.

Other subtypes of lung cancer encountered in pleural effusions include bronchioloalveolar cell carcinoma and large cell carcinoma. In contrast, although squamous cell carcinoma is a common subtype, it is found with far less frequency in serous effusions, especially the keratinizing subtype. Although giant cell carcinoma of the lung is rare, it is a fast-growing neoplasm with a rapid course, commonly involving the pleura, with pleural effusion at the time of initial presentation. The diagnostic cytologic features of these subtypes are described below.

ADENOCARCINOMA (see Figure 9.2)

Well-differentiated variant

The cells in smears of effusions show a second population of loosely cohesive clusters of medium- to large-sized cells, which usually have round to oval hyperchromatic nuclei with fine to coarsely granular chromatin and variably conspicuous nucleoli. They have a moderate amount of cytoplasm, which is usually vacuolated (see Figure 9.2). Even when accompanied by a well-differentiated component, some of the neoplastic cells are easy to interpret unequivocally as malignant. As an adjunct, the periodic acid–Schiff (PAS) stain after diastase digestion or mucicarmine stain may demonstrate mucin in the cytoplasm of the neoplastic cells (see Figure 1.14).

Non-cohesive variant

This variant predominantly shows poorly cohesive, isolated, medium to large cells with eccentrically located, round to oval, hyperchromatic nuclei with fine to coarsely granular chromatin, variably conspicuous nucleoli, and a variable amount of cytoplasm which may be vacuolated (see Figure 3.8). This variant may be difficult to distinguish from the epithelioid type of mesothelioma and high-grade, poorly differentiated large cell lymphoma in effusions. The PAS stain (with diastase) and mucicarmine stain may help to confirm the presence of intracytoplasmic mucin in some of the cells. Immunophenotyping with immunocytochemistry may be extremely valuable in arriving at a correct diagnosis [see Figure 3.2 (4)].

Figure 9.8 Metastatic adenocarcinoma of colon, peritoneal fluid. Cohesive groups of cells (a) show high nucleocytoplasmic ratios and eccentric nuclei touching the periphery of the cell (arrow in b). Some adenocarcinoma cells show cytoplasmic vacuoles containing mucin (arrowhead in the inset of b). The cell groups in papillary configurations are difficult to study at lower magnification (c). Peripheral palisading is better observed under higher magnification (d). The patient had colonic adenocarcinoma. [a,b, DQ-stained Cytospin smear; c,d, PAP-stained SurePath smear (a, 40×; b, 100×; c, 40×; d, 100×).]

Poorly differentiated variant

The cytomorphology of this variant is easy to interpret as malignant (see Figure 3.11). The smears show poorly cohesive groups of large carcinoma cells with variable amounts of cytoplasm which may show vacuoles and pleomorphic, round to oval to irregularly shaped, hyperchromatic nuclei with coarsely granular chromatin. The nucleoli are usually prominent in the most cells (Figure 3.11d).

Figure 9.11 Metastatic ovarian serous papillary cystadenocarcinoma, peritoneal fluid. Psammoma bodies (red arrows PSM in a,b,c,e,f,i) are present, isolated, and in association with papillary clusters (d,f) of adenocarcinoma cells without stromal cores (g,h). Some carcinoma cells show degenerative vacuoles (blue arrows VAC in h), which should not be misinterpreted as mucinous. Some apoptotic neoplastic cells (blue arrow AP in i) are present. AP, apoptotic cancer cell; NC, neoplastic cell; PSM, psammoma body; VAC, vacuole. [a–I, PAP-stained SurePath smear (a, 20×; b, 40×; c–e, 100×, f–i, 100× zoomed).]

POORLY DIFFERENTIATED SMALL CELL CARCINOMA (Figure 9.4)

In effusions the neoplastic cells of this variant are usually present as loose groups or as isolated cells. These fragile cells are usually small with high nucleocytoplasmic ratios.A most significant and reliable diagnostic feature of small cell carcinoma is insignificant nucleoli, which, in smears, are usually unrecognizable. However, as compared to cytology of small cell carcinomas in other specimens, effusion cytology may exhibit small, insignificant nucleoli in some nuclei. The chromatin is of ‘salt and pepper’ type with a mixture of fine and coarse chromatin dots in hyperchromatic nuclei (Figure 9.4). Most cells may appear as stripped nuclei without visible cytoplasm or with a scant amount of poorly discernible cytoplasm in Papanicolaou (PAP)-stained smears. However, this scant rim of cytoplasm is highlighted better in Diff-Quik (DQ)-stained smears. Because the nuclei are delicate and cytoplasm is scanty, the nuclei often mold with each other. This nuclear molding feature may help in distinguishing them from other poorly differentiated carcinomas, but not from high-grade lymphoma cells which may also show nuclear molding. The cell groups have a tendency to undergo focal single cell necrosis with scattered apoptotic bodies, concurrently admixed with some mitotic figures. Long-standing and recurrent effusions may contain small proliferation spheres of carcinoma cells which appear to wrap around one another to impart an onionskin appearance.

Figure 9.4 Metastatic small cell carcinoma, pleural fluid. Cancer cells are present as solitary cells (c,d), small groups (g–i), and large groups (j). The cells are small with high nucleocytoplasmic ratios (c,d,g–i). The nuclei are hyperchromatic with salt and pepper chromatin (c,d,i). Solitary cancer cells (NC in c,d) resemble lymphocytes (blue arrow Ly in f) and may be misinterpreted as lymphoma, especially in PAP-stained preparations. However, the presence of cohesive groups (g–j) with various patterns, including Indian-file pattern (g), favor carcinoma. The nuclear molding (arrows nm in g,i) distinguishes them from other poorly differentiated carcinomas. Mitotic figures (arrowhead in e) and apoptotic cancer cells (arrowheads in d,f,h) are also present. Rare reactive mesothelial cells (blue arrows RM in a,b,e) are present with a few chronic inflammatory cells (blue arrow Ly in f) in the background. Immunostained cell block sections showed immunoreactivity for neuroendocrine immunomarkers (chromogranin, synaptophysin, and CD56). The patient had poorly differentiated small cell carcinoma of lung. NC, neoplastic cell; RM, reactive mesothelial cell, nm, nuclear molding, Ly, lymphocyte.[a–j, PAP-stained SurePath smear (a,b, 100×; c–j, 100× zoomed).]

BRONCHIOLOALVEOLAR CELL CARCINOMA

Non-secretory variant (Figure 9.5)

This variant of bronchioloalveolar cell carcinoma usually shows monolayered sheets and three-dimensional groups of carcinoma cells. The individual cells have features of well-differentiated adenocarcinoma (Figure 9.5). The carcinoma cells may also form proliferation spheres. Medium to large cells have a small to moderate amount of cytoplasm and relatively uniform, round to oval nuclei with fine chromatin. Although usually not conspicuous, some of the carcinoma cells may have prominent nucleoli, and some nuclei may have intranuclear pseudoinclusions. Psammoma bodies are occasionally seen in the clusters of carcinoma cells.

Figure 9.5 Metastatic bronchioloalveolar cell carcinoma of lung, pleural fluid. Cellular specimen (a) shows three-dimensional groups of carcinoma cells (arrowheads in a–f) mixed with reactive mesothelial cells (blue arrow RM in f,g). The two populations are demonstrated more distinctly with the DQ stain (f,g) than with the PAP stain (a–e). However, the morphologic details of individual neoplastic cells are more distinct in the PAP stain (a–e), especially under higher magnification (c–e). The individual cells show features of well-differentiated adenocarcinoma (red arrows NC in d,e,g). Although usually not conspicuous, some of the carcinoma cells have prominent nucleoli (d,e). The neoplastic cells demonstrate nuclear immunoreactivity for TTF-1 (arrowheads in h) consistent with a lung primary. The patient had bronchioloalveolar cell carcinoma of lung. NC, neoplastic cell; RM, reactive mesothelial cell; TTF-1, thyroid transcription factor-1. [a–e, PAP-stained SurePath smear; f–g, DQ-stained Cytospin smear; h, immunostained cell block section (a, 10×; b, 40×; c, 100×; d–e, 100× zoomed; f, 40×; g, 100×; h, 40×).]

Secretory variant

The cytomorphologic features of this variant overlap those of the non-secretory variant, except that the cells have large amounts of clear to vacuolated cytoplasm. The appearance of cytoplasm in all bronchioloalveolar cell carcinoma cells forming a particular group is identical. In contrast, other adenocarcinomas typically show variation in cytoplasmic appearances from one cell to another in the same group.

SQUAMOUS CELL CARCINOMA

Keratinizing type

Although frequently observed in sputum, the cells of keratinizing squamous cell carcinoma are uncommon in serous effusions. If detected in effusions, the cells of keratinizing squamous cell carcinoma are seen as rare solitary cells or in small loose groups. Keratinizing carcinoma cells with pyknotic nuclei are not proliferating; therefore, they do not form proliferation spheres. These carcinoma cells show moderate amounts of relatively dense, orangeophilic cytoplasm with medium to large-sized nuclei without recognizable nucleoli.

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