Central Nervous System
Table 16.1 Antibodies Useful in Distinguishing among Lymphoma/Leukemia, Metastatic Carcinoma, Melanoma, and Primary Brain Tumors
GFAP=glial fibrillar/ acidic protein.
a specific diagnosis of melanoma can be made, even in the
absence of previous documentation of melanoma elsewhere in
the body.49 In the absence of pigment, it may be difficult to dis-
tinguish these cells from other large-cell malignancies, such as
large-cell undifferentiated carcinoma of the lung and large-cell
lymphoma. Here, positive reactivity with antimelanoma anti-
bodies, such as HMB-45 and reagents against S-100 protein with
absence of cytoplasmic cytokeratin, and lack of expression of
anticarcinoma antibodies and panleukocyte reagents are useful
in helping to establish the diagnosis.56-58
Although the majority of patients with meningeal carcino-
matosis have a known primary tumor at the time they develop
this CNS complication, occasional patients present first with
meningeal symptoms and an occult tumor. When cytologically
malignant cells are demonstrated in CSF from such a patient,
lymphoma, metastatic carcinoma, melanoma, and primary
brain tumors all should be considered. Although the morpho-
logic features of the cells may be sufficiently characteristic to
allow a specific diagnosis, we have found a panel of antibod-
ies to be helpful in making these distinctions (Table 16.1).59
Primary brain tumors express panneuroectodermal antigens
such as neural cell adhesion molecular (N-CAM) as detected
by monoclonal antibody, UJ13A, and synaptophysin.60,61 Malig-
nant gliomas express glial fibrillary acidic protein (GFAP) in
addition. Metastatic carcinomas, in contrast, are negative with
these reagents but generally express cytokeratins, and many
express carcinoma-associated antigens such as CEA or TAG-72
detected by antibody B72.3 as well. Melanomas are negative
for the reagents described but express S-100 protein and react
with melanoma-associated antibodies such as HMB-45. The use
of anti-S-100 protein antibodies alone, however, is insufficient
to distinguish melanoma from the other tumor types, because
these reagents react with many primary brain tumors and a sub-
set of carcinomas in addition to melanoma.58 Lymphomas are
negative for the reagents described but are detected by panleuko-
cyte reagents as well as antibodies against T- and B-cell antigens.
Because no single reagent reliably distinguishes metastases from
other tumor types, antibody panels when used in conjunction
with clinical history and cytologic features allow for an accurate
diagnosis in the majority of cases.
In many cases, one can establish that a meningeal tumor is
likely to be metastatic based on either the presence of an extra-
cranial mass or the pattern of an antigen expression in the tumor
cells. Here the problem may be to determine the site of the
primary tumor. With the exception of antimelanoma reagents
and a small number of organ-specific markers, such as prostate-
specific antigen in prostatic carcinoma, no reliable antibodies
exist to distinguish among metastases from various sites.
In this setting, it is useful to consider that the majority of cases of
meningeal carcinomatosis with occult primary tumors originate
in the lung. Breast carcinoma, in contrast, only rarely appears
first with subarachnoid dissemination before the discovery of
a breast mass.49,62,63 Carcinoma of the stomach should also be
considered in this situation, although the incidence with which
this tumor type spreads in the meninges is considerably lower
than that of carcinoma of the lung.
Primary Central Nervous System Tumors
As with metastatic tumors, the only primary CNS tumors detect-
able by examination of CSF are those that involve the ventricles
or SAS by direct extension and those that disseminate through
the spinal fluid pathways. Although any histologic type of
malignant adult glioma may produce this finding, advanced
glioblastoma multiforme is the tumor type that most frequently
spreads in this fashion. The morphology of the cells seen in CSF
in these cases is as varied as the histologic spectrum.2 Cells may
be anaplastic, ranging from small to large, or may retain their
resemblance to astrocytes. However, even the most poorly dif-
ferentiated tumors usually retain the expression of GFAP in at
least some cells, allowing for a specific diagnosis using antibod-
ies against GFAP.59 Another tumor type also exhibiting this type
of behavior is the malignant ependymoma, which also sheds
into CSF as morphologically undifferentiated cells. Low-grade
gliomas including astrocytomas, ependymomas, and oligoden-
drogliomas may also metastasize throughout the ventricular
system and SAS.64-68 These tumors are not always demonstrable
by cytologic examination of CSF, however, because they often
produce cohesive implants, which exfoliate poorly. In addition,
because these cells are cytologically benign, they can be difficult
to distinguish from macrophages and monocytes unless specific
antibodies are used.
The most common malignant primary brain tumor of
childhood, the medulloblastoma, commonly spreads through
the neuraxis by way of the spinal fluid pathway.69 This tumor
appears as cell clusters and isolated cells with high nucleocy-
toplasmic ratios, hyperchromatic nuclei, and scant cytoplasm
(Fig. 16.11). These cells express panneuroectodermal antigens
such as synaptophysin and N-CAM, are usually negative for
GFAP, and sometimes express neurofilament proteins.70 Glio-
mas represent another relatively large group of childhood brain
tumors. Although most of these neoplasms are low grade and
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