Secondary brain tumors, or CNS metastases, represent disseminations of a systemic tumor in the central and/or peripheral nervous system, usually at an advanced stage of the tumor (Posner, 1995; Schackert and Schlegel, 2003). Although the improved treatment options for systemic tumors have increased survival times, they also result in an increase in solid brain metastases and/or leptomeningeal spread because the blood–brain barrier patency to many cytostatic drugs is poor.
Types. The following types of secondary tumors are distinguished:
• Space-occupying lesions in the brain parenchyma; confirmation of the diagnosis by detection of tumor cells in the CSF is usually only successful when the lesion is close to a ventricle.
• Invasion of the meninges by diffuse and/or nodular leptomeningeal metastasis.
Of the two types, leptomeningeal spread plays by far the more important role in CSF analysis.
Meningeal carcinomatosis. The highest incidence of carcinomatous infiltration of the meninges is from breast cancer (40–50%), followed by lung cancer (20–25%) and malignant melanoma (10%). Meningeal dissemination from gastrointestinal and urogenital carcinoma is rare (about 5%). In terms of pathogenesis, leptomeningeal spread is caused by local meningeal infiltration from epidural, osseous, cranial, or vertebral structures, or by hematogenous dissemination into the subarachnoid space.
Diagnosis. Leptomeningeal infiltration is usually suspected because of clinical symptoms (headache, personality and mental changes, impaired alertness, focal and/or generalized convulsions, cranial nerve dysfunction, and/or radicular symptoms) and substantiated by contrast enhancement of the leptomeninges on MRI. The diagnosis is confirmed by detection of tumor cells in the CSF (Kaplan et al., 1990).
Detection of tumor cells in the CSF confirms the diagnosis of leptomeningeal spread.
Cell counts. After the cell count, several smears are prepared by cytocentrifugation (several CSF samples are pooled if cell numbers are low). This facilitates further investigation without the need to repeat lumbar puncture. May-Grünwald/Giemsa staining is commonly used.
The cell count ranges from one cell to several hundred cells per microliter; it is often high. In 30% of the samples examined, tumor cells are detected in the preparation even when the cell count is normal.
In 50–70% of cases, cytological detection of tumor cells in CSF is successful at the first puncture. If no tumor cells are detected and leptomeningeal spread continues to be suspected, lumbar puncture should definitely be repeated, because this will increase the chance of tumor cell detection to 80–90%.
A normal cell count does not rule out cytological detection of tumor cells.
Morphology. Tumor cells often appear in small groups or clusters. Cytomorphological criteria of malignancy include (Fig. 16.4):
• Cellular and nuclear polymorphism (due to regressive and proliferative processes).
• Prominent nucleoli.
• Polynuclear cells (due to amitotic cell division).
• A shift in the nucleocytoplasmic ratio.
• Basophilic cytoplasm.
Apart from tumor cells, the cytological analysis often reveals lymphocytic pleocytosis (activated monocytes, transformed lymphocytes, and plasma cells) due to a concomitant inflammatory reaction.
Leptomeningeal spread is often accompanied by an inflammatory reaction.
Tumor diagnosis. It is rare that leptomeningeal spread is diagnosed before the primary tumor. Diagnosis of the tumor by means of CSF cytology is only possible in special cases:
• Melanin granules in the cytoplasm of tumor cells suggest malignant melanoma.
Fig. 16.4 a–c Cytomorphological criteria of the malignancy of tumor cells.
• Cells with vacuolated cytoplasm and compressed nuclei located close to the cell membrane (signet-ring cells) indicate a mucus-producing tumor, such as adenocarcinoma of the stomach or the lung (Fig. 16.5).
Fig. 16.5 a, b Leptomeningeal metastasis from a lung adenocarcinoma.
In both leptomeningeal spread and intraparenchymatous CNS metastases, further indications as to the underlying tumor may be obtained by determining tumor markers. There are two types: humoral and cellular tumor markers. These are antigens which are either produced by the tumor cells themselves or induced by the tumor. Further characterization is possible by immunocytochemical procedures using antibodies against these tumor-associated antigens. Examples of tumor markers are:
• Oncofetal antigens (e. g., CEA).
• Carbohydrate epitopes (e. g., CA15–3).
• Differentiation or proliferation antigens (e.g., NSE, β2-microglobulin).
Tumor markers have low organ specificity. Their concentration in the serum depends on many factors, such as tumor mass, blood supply to the tumor, medication, and the time of serum separation from whole blood.
The main importance of tumor markers as diagnostic tools is in monitoring their concentration during the individual patient's course.
CSF analysis. In 75–80% of cases, a blood–CSF barrier dysfunction with a sometimes considerably increased total protein level indicates leptomeningeal spread of the tumor. An lactate concentration elevation above 3.5 mmol/L is another important indicator. In about 30% of cases, an increased IgG index and oligoclonal bands are detected as the result of concomitant inflammation.
Typical CSF findings in cases of leptomeningeal spread are:
Cell count: normal or increased.
Total protein: increased.
Lactate: increased (> 3.5 mmol/L).
Suspicious: elevated lactate levels without pleocytosis.
Tumor diagnosis. Detection of intrathecal production of tumor markers may help in the differential diagnosis of the underlying tumor type. Intrathecal synthesis of carcinoembryonic antigen (CEA) (Fig. 19.6) is highly specific of carcinoma, although not of the organ of origin. Detection of CA 15–3 suggests a probable diagnosis of breast cancer, CEA breast or colorectal cancer, NSE small-cell lung cancer, or CYFRA 21–1 large-cell lung cancer (Table 16.3).
In patients with CNS metastases and leptomeningeal spread, serum analysis is important to detect barrier dysfunction and to calculate the CSF/serum quotient, so that intrathecal synthesis of tumor markers can be identified. For example, intrathecally produced CEA is detected in about 80% of patients with metastases. However, the specificity of CEA is low.