Chapter 11 Where do they come from? Evaluation of unknown primary site of origin
INTRODUCTION
Accumulation of excess amounts of fluids in any body cavities is always pathologic. About 15% of effusions are due to direct involvement by a malignancy,1 and are a common occurrence in patients with neoplastic disease. It can be caused by both primary and secondary disease. The latter, which is more common, can be due to direct extension or distant metastasis. The development of malignant effusions or ascites usually indicates grave prognosis in patients with cancer; the mean survival time is usually measured in weeks or months. Therefore, the primary indication for cytologic examination of exfoliated cells in body cavity fluids is to rule out malignancy.
Once a diagnosis of malignancy is established, the next step is to determine the primary site of origin. Despite the grave prognosis, it is clinically important to identify the primary site of origin of the malignancy. Since subsequent management may depend on the tumor type, patients with malignant effusions and ascites caused by lymphomas, breast cancer, ovarian cancer, and small cell lung carcinoma may respond to systemic chemotherapy or hormonal therapy, whereas those with effusions and ascites secondary to therapy-resistant cancers, such as non-small-cell lung carcinoma, should be treated with palliative measures, such as pleurodesis or a pleuroperitoneal shunt.2,3 In addition, pathologists are often asked to confirm or rule out a malignant mesothelioma in patients with a history of asbestos exposure because of the potential medicolegal implications.
The cytology and differential diagnosis of malignant mesothelioma has been addressed in Chapter 8. In this chapter, we discuss the approach to determine the possible primary site of origin of a malignant effusion or ascites once a malignant mesothelioma is ruled out.
CLINICAL FINDINGS
The task is to ascertain that the cytologic morphology of the malignant cells in the current fluid specimens corresponds to that of the primary neoplasm. If available, review of the prior surgical and/or cytologic materials would greatly aid the process.However, when a clinical history of a prior malignancy is not available, determining the origin of the primary neoplasm can be a challenge. Furthermore, in a small proportion of patients, a malignant effusion or ascites is the initial presentation of the underlying malignant neoplasm.4 In a series of 154 malignant ascites and 174 malignant pleural effusions, Monte et al reported that ascites and pleural effusions were the presenting sign of cancer in 7% and 14% of patients, respectively.5 In the same series, none of the patients with malignant pericardial effusion was this finding the initial presentation of their cancer.
Patients’ gender and age, as well as the location of the effusion, can help to narrow the list of differential diagnoses. For example, papillary serous ovarian carcinoma should be at the top of the list of differential diagnoses in elderly female patients who present with malignant ascites as the first evidence of cancer.6 Serum CA 125 levels are usually elevated. When a malignant ascites is the initial presentation of cancer in male adult patients, a gastrointestinal origin should be suspected.7 For malignant pleural effusions, lung cancer is the most likely primary tumor to present as the first sign of cancer in both male and female adult patients. In female adult patients, one should also consider breast cancer as a possible primary source (see Table 9.2, Figure 9.3).
Table 11.2 Ultrastructual features and possible primary site of origin*
| Ultrastructural features | Differential diagnosis |
|---|---|
| Intracytoplasmic vacuoles | Adenocarcinoma, NOS |
| Tubular myelin figure | Lung adenocarcinoma |
| Uniform short microvillus with filamentous cores and core rootlets | Colon adenocarcinoma |
| Lipid droplets and glycogen | Renal cell adenocarcinoma |
| Premelanosomes | Melanoma |
| Electron-dense secretory granules | Neuroendocrine neoplasms |
| Z bands, thick and thin filaments | Rhabdomyosarcoma |
| Linear dense bodies, thin filaments | Leiomyosarcoma |
| Rhomboid crystals in cysternae of RER | Alveolar soft part sarcoma |
| Birbeck granules | Histiocytosis X |
* Most of these tumors have easy-to-evaluate corresponding immunomarkers (see Table 11.3 and Chapter 15). NOS, not otherwise specified; RER, rough endoplasmic reticulum.
Malignant effusions or ascites are uncommon in children. In a series of 103 pediatric specimens from various body cavities, 14% were classified as malignant.8 Most are caused by malignant lymphomas and leukemias followed by the so-called small blue cell tumors of childhood such as neuroblastoma, Wilms’ tumor, and rhabdomyosarcoma (see Chapter 10).8,9 Both germ cell tumors and osteosarcomas may also cause malignant effusions and ascites in children and young adults.
CYTOLOGY
Since the tumors originating in various primary sites often resemble each other, it is logical to consider the differential diagnosis based on the cytologic cellular patterns and individual cell appearance. Table 11.1 summarizes the differential diagnosis based on various cytologic features (see also Table 9.1).
Table 11.1 Cytologic features and the differential diagnosis (see also Table 9.1)
| Cytologic features | Most likely primary sites | Other possible sites |
|---|---|---|
| Architecture | ||
| Single cell pattern | Lymphomas and leukemias Melanoma | Carcinoma of breast, stomach, and kidney |
| Cannonball pattern | Carcinoma of breast (ductal) and ovary | Carcinoma of lung, stomach, and prostate |
| Papillary formation and/or psammoma bodies | Carcinoma of ovary | Carcinoma of thyroid, lung, and kidney Mesothelioma |
| Single-file pattern | Carcinoma of breast (lobular) | Carcinoma of breast (ductal) |
| Pseudomyxoma peritonei | Mucinous neoplasms of ovary and appendix | Carcinoma of pancreas, endocervix, and breast |
| Cellular features | ||
| Signet-ring cells | Carcinoma of stomach and breast (lobular) | Carcinoma of gall bladder, colon, pancreas, and ovary |
| Pigmented cells | Melanoma | Hepatocellular carcinoma |
| Small cells | Small cell carcinoma of lung Carcinoma of breast (lobular) Non-Hodgkin lymphoma (low grade) | |
| Squamous cells | Squamous cell carcinomas | |
| Spindle cells | Sarcomas | Spindle cell carcinoma Melanoma Mesothelioma |
ARCHITECTURE
Single-cell pattern
Malignant lymphomas, both Hodgkin and non-Hodgkin, as well as leukemias, typically present with a single-cell pattern without any tissue aggregates (Figure 11.1). The presence of tissue aggregates excludes a diagnosis of malignant lymphoma. Except for Hodgkin lymphomas, the specimens usually consist of a relatively monotonous population of lymphoid cells with or without reactive mesothelial cells. The diagnosis of Hodgkin lymphoma requires the identification of Reed–Sternberg cells and their variants against a background of mixed lymphocytes, eosinophils, and plasma cells. Because of the presence of effective chemotherapy, it is important to recognize hematologic malignancies among other secondary malignancies involving the body cavities. Generally, patients with lymphoma or leukemia seldom present with malignant effusions and ascites without a known history of malignancy.10 Only rarely, are body cavities the initial site of presentation of systemic disease or the primary lymphoma. The latter is more common in patients who are immunosuppressed and seropositive for human immunodeficiency virus (HIV).11–13 Marked chronic inflammation may be difficult to distinguish from malignant lymphoma. The presence of a mixed lymphoid population favors a reactive process. Immunophenotyping is helpful in differentiating a reactive process from a neoplastic one (see Chapter 12). In addition, it also helps to subclassify non-Hodgkin lymphomas and leukemias.
Epithelial malignancies can sometimes present with a single-cell population. This pattern is more frequently encountered in carcinomas of the breast, stomach, kidney, and prostate. Poorly differentiated non-keratinizing squamous cell carcinomas can also shed single cells into body cavity fluids and can resemble reactive mesothelial cells. The cells are mostly single in effusion fluid when secondarily involved by melanoma (see Figure 10.6c).14,15 When cytoplasmic melanin pigment is present, the diagnosis is often straightforward. Small, round to oval, non-cohesive cells are also characteristic of small blue round cell tumors, which include Ewing’s sarcoma, neuroblastoma, etc. (see Chapter 10).8,9
Solid cell ball pattern
Also known as cannonball pattern and proliferation spheres (see Chapter 3), the solid cell ball pattern is characterized by the presence of three-dimensional, cohesive, tightly packed balls of cells, with smooth community borders, and is usually quite obvious at low-power examination (Figure 11.2) The number of cells in the cell ball ranges from a few to several hundred. This pattern is typically seen in carcinomas of the breast and ovary, and therefore is commonly encountered in elderly women. In fact, very large cell balls are characteristic features of the ductal variant of infiltrating mammary carcinoma in fluids.16 Other malignancies that can present with a cannonball pattern include carcinomas of lung, stomach, and prostate. Malignant mesothelioma and, rarely, mesothelial hyperplasia, can also demonstrate a cannonball pattern in body cavity fluids (see Chapter 8). The cell balls of mesothelial origin typically demonstrate a scalloping border (see Figures 8.1 and 8.3).10,17
Papillary formation and psammoma bodies
Papillae are three-dimensional, cohesive structures that consist of fibrovascular cores or have one axis longer than the others (Figure 11.3). Individual cells are usually polarized; their nuclei are arranged perpendicular to the long axis or the fibrovascular cores. Papillae are often derived from papillary neoplasms arising in ovary, thyroid gland, kidney, and lung. Intranuclear cytoplasmic inclusions can be seen in papillary carcinoma of the thyroid and bronchioloalveolar carcinoma.
Psammoma bodies are often noted in association with papillary clusters. They are round to oval structures that consist of concentric layers of calcified material. They represent the cells in papillary formations that have undergone degeneration and calcification. The presence of psammoma bodies with or without papillary formations in ascitic fluid from an elderly female patient is highly suggestive of a metastatic ovarian carcinoma (Figure 11.4). Other malignancies that can be accompanied by psammoma bodies include primary peritoneal serous tumor, papillary carcinoma of the thyroid, bronchogenic carcinoma, malignant mesothelioma, and, less frequently, breast and gastric carcinomas.10,17 
One should be cautious not to over-interpret the presence of psammoma bodies and/or papillary formation in fluid specimens as unequivocal evidence of malignancy because patients with benign mesothelial hyperplasia may shed papillary groups of mesothelial cells and/or psamomma bodies.18–20
Single-file arrangement
Single- or Indian-file pattern refers to tumor cells aligning themselves in single rows. By electron microscopy, it is shown that intercellular connections are present between the members within the file. The presence of long chains of small, bland-appearing tumor cells is characteristic of infiltrating lobular mammary carcinoma.16 However, cells of infiltrating ductal carcinoma can occasionally arrange in single file, but the individual cells are larger and more pleomorphic. Small cell carcinoma of the lung can also present with a single-file arrangement along with prominent nuclear molding (Figure 9.4). This characteristic appearance has been variously described as ‘stacks of dishes,’ ‘piles of coins,’ or ‘vertebral column’21 (Figure 11.5). Individual cells have high N/C ratios and ‘salt and pepper’ chromatin.
Pseudomyxoma peritonei
Pseudomyxoma peritonei refers to the presence of a high content of mucin in the ascitic fluids.22 The mucin content appears as light blue to magenta amorphous material with modified Romanowsky stain. Epithelial cells, singly or in small clusters, are scattered within the mucin. Individual cells often appear bland, with or without cytoplasmic mucinous vacuoles. 
In female patients, ovarian mucinous cystadenoma and cystadenocarcinoma are the most likely primary neoplasms giving rise to pseudomyxoma peritonei. The appendix is the most common primary site in male patients and the second most common primary site in female patients.23 Other gastrointestinal neoplasms, pancreatic cancers, endocervical carcinomas, and mucinous carcinomas, such as those that occur in the breast, can also cause pseudomyxoma peritonei.10
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