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Diffuse bone marrow metastasis by glioblastoma Premortem diagnosis by peroxidase-antiperoxidase staining for glial fibrillary acidic protein.

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Diffuse Bone Marrow
Metastasis by Glioblastoma:
Premortem Diagnosis by
Staining for Glial Fibrillary
Acidic Protein
pathological diagnoses w e r e established using peroxidase-antiperoxidase (PAP) staining [1 S ] for glial
fibrillary acidic protein (GFAP).
Case Reports
Patient 1
From the ?Department of Neurology and Kotzias Laboratory of
Neuro-Oncology, Memorial Sloan-Ketrering Cancer Center, New
York, N Y 10021, and $Longwood Area Neurology Program, Harvard Medical School, and Division of Neurology, Brigham ancl
Women’s Hospital, Boston, MA 02 I 15.
A 57-year-old right-handed man was well until March 1079,
when he developed diplopia, headache, right visual field loss,
gait difficulty, and memory loss. Computed tomographic
(CT) scan of the head in May 1979 revealed a large left
temporo-occipital tumor that was subtotally resected and
proved to be a glioblastoma multiforme. Postoperatively the
patient was treated with whole brain irradiation (6,000 rads)
and chemotherapy (BCNU). His neurological symptoms improved and he remained essentially normal for 12 months.
C T scans showed gradual reduction in size of the residual
tumor. The patient subsequently was admitted to the hospital
when he developed progressive right hip and rib cage pain.
Neurological examination revealed no abnormalities except
for a limp from hip pain and muscle tenderness in both
thighs. Laboratory data included a white blood count of 6,100
per cubic millimeter, hemoglobin level of 9.8 g d l 0 0 ml,
platelet count of 23,000 per cubic millimeter, serum glutamic
oxaloacetic transaminase level of 5 10 U/L, alkaline phosphatase level of 1,143 UIL, and lactic dehydrogenase level of
1,161 U/L. Radiographs of the hip showed a poorly defined
lucent area in the proximal left femur. A liver-spleen scan
and roentgenograms of chest, ribs, left femur, and sacroiliac
joints were normal. A CT scan of the head showed enlargement of ventricles and a small area of contrast enhancement
in the temporoparietal region unchanged from the previous
scan. Because of persistent thrombocytopenia, a bone marrow biopsy was performed, which revealed replacement of
the marrow space by an undifferentiated small cell tumor.
Further systemic workup was normal except for an abnormal
bone scan, which showed increased uptake in multiple areas
including right sacroiliac joint, right ribs, left femur, and right
humerus. A second bone marrow biopsy again showed replacement of the marrow space by clusters of small spindleshaped cells. PAP staining for GFAP revealed patchy areas of
reactivity (Fig 1). The patient died of respiratory failure.
Postmortem examination revealed diffuse involvement of
all bone marrow space by metastatic glioblastoma. Gross examination of the brain showed no tumor mass. Microscopic
examination of the primary tumor site showed extensive
infiltration of the neighboring parenchyma by tumor cells
that consisted of heterogeneous populations of plump gemistocytic cells intermixed with smaller fibrillary cells (Fig 2).
Tumor extended to the meninges and meningeal vessels. Soft
tissue nodules on the fifth rib and on the visceral pleural
surfaces were composed of uniform clusters of spindleshaped cells similar to those seen in the bone marrow space
(see Fig 2). In these nodules many GFAP-producing cells
were demonstrated by PAP staining.
’Present address: Department of Neurology, University o f Texas
System Cancer Center, M D Anderson Hospital and Tumor Institure, Houston, T X 7’030.
Patient 2
A 24-year-old woman underwent subtotal resection of a right
W. K. A. Yung, MD,“I$ S. J. Tepper, MD,$
and D. F. Young, M D i
Extraneural metastases from malignant glioma and
glioblastoma are believed to b e rare. T h e most common
sites of metastases are lung, lymph nodes, bone, and
liver. We recently encountered two patients with glioblastoma multiforme w h o presented with pain and
thrombocytopenia caused by diffuse metastasis to bone
marrow. A premortem diagnosis was established in the
first patient with the aid of peroxidase-antiperoxidase
staining of the bone marrow biopsy specimen for glial
fibrillary acidic protein, a glial-specific marker. I n t h e
second patient glial fibrillary acidic protein staining
confirmed the glial nature of t h e primary brain tumor as
well as t h e metastatic tumor in bone marrow. T h e first
patient also had metastatic nodules o n t h e pleural surface and on the fifth rib. All three metastatic foci had
similar cellular morphology, suggesting selection of a
population of tumor cells with extraneural metastatic
Yung WKA, Tepper SJ, Young DF: Diffuse bone
marrow metastasis by glioblastoma: premortem
diagnosis by peroxidase-antiperoxidase staining for
glial fibrillary acidic protein. Ann Neurol
14:581-585, 1983
Extraneural metastases from malignant gliomas and
glioblastomas are rare and occur most frequently in
four sites: lung or pleura, lymph nodes, bone, and liver
[13]. We have encountered two unusual cases of
glioma metastasizing to b o n e marrow, presenting with
pain and thrombocytopenia. I n both cases premortem
Received June 20, 1981, and in revised form Jan 1’ and Mar 23,
1983. Accepted for publication Mar 2 5 , 1983.
Address reprint requests to Dr Dean F. Young, Department of Neurology, Memorial Hospital, 1275 York Avc, New York, N Y 10021.
frontal glioblastoma multiforme in May 1980. Postoperatively she was treated with 2,400 rads of whole brain irradiation followed by 600 rads focally to the tumor. She improved
neurologically and did well until January 1981, when she
Fig 1 . Peroxidase-antiperoxidasestaining for glial fibrillary
acidic protein IGFAP) on the bone marrw biop.iy specimen from
patient 1. Brown staining represents reactiz'eproducts of GFAP
outlining the cytoplasm of the tumor cells. Mawy tumor cells are
GFAP negative. ( x 400.)
Fig 2. (Patient I ) (A)Residual intracerebral glioblastoma, .thou'ing heterogeneous populations of large gemistocytii cells und small
fibrillary cells with an area of pseudopalisading (Bi Tumor
nodule on fifib rib, showing clusters of spindle-shaped tumor c e h
with nuclei slightly larger than those in the bone marrow cavitj~.
IC) Tumor nodule on pleural surface, shou'ing similar homogeneous clusters of spindle-shaped tumor cell.r. IH&E; x -300.~
582 Annals of Neurology
Vol 14 No 5
November 1083
developed abdominal cramps and low back pain. Physical
examination revealed diffuse guarding of the abdomen, mild
left-sided hyperreflexia, and an equivocal left Babinski's sign.
Laboratory data showed normal complete blood count,
platelet count, and electrolytes, but abnormal hepatic enzymes, a lactic dehydrogenase level of 1,095 UIL, serum
glutamic oxaloacetic transaminase level of 76 UIL, serum
glutamic pyruvic transaminase level of 81 UIL, and alkaline
phosphatase level of 157 UIL. A CT scan of the head showed
reduction in size of the residual primary tumor, which no
longer enhanced with contrast. Myelography excluded spinal
epidural or subdural tumor. A liver-spleen scan showed slight
liver enlargement without filling defects. Bone scan was normal. Hepatic enzyme values continued to rise simultaneously
with the development of anemia and a fall in the platelet
count from 200,000 per cubic millimeter on admission to
50,000. The peripheral blood smear revealed two myelocytes, one metamyelocyte, and nucleated red blood cells. A
bone marrow biopsy revealed a soupy necrotic marrow filled
with undifferentiated anaplastic tumor cells similar to those
seen in the original intracerebral glioblastoma multiforme.
PAP staining revealed scattered GFAP-positive cells. The
Brief Communication: Yung et al: Bone Marrow Metastasis by Glioblastoma
patient died late in March 1981. No p o s t m o r t e m examination was performed.
Since the first well-documented case of extraneural
metastasis from a glioma was reported in 1928 141,
many others have been described [ I , 9, 12, 191. Pasquier and colleagues (131 reviewed 72 cases of astrocytomas and glioblastomas with extraneural metastases
reported between 1928 and 1977; the four most common sites were lung and pleura, lymph nodes, bone,
and liver. Among the 22 cases of bony metastases, the
most common sites were vertebral bodies and ribs.
None of the 72 cases had bone marrow metastases, and
none developed thrombocytopenia.
Because nitrosoureas recently have been implicated
as a cause of secondary neoplasms in patients receiving
chemotherapy for brain tumors { 3 , 181, persistent
thrombocytopenia prompted a thorough search for a
second neoplasm in patient 1. The diagnosis of metastatic glioblastoma was established when PAP staining
for GFAP in the second bone marrow specimen
showed a positive reaction. In the second patient
metastatic glioblastoma was suspected on the basis of
routine histological findings but was confirmed by
GFAP staining.
GFAP was isolated by Eng and colleagues 171 from
multiple sclerosis plaques and later was localized by
immunofluorescence and immunoperoxidase techniques to fibrous astrocytes and their processes in the
white matter [2, 14). PAP staining for GFAP has
proved useful in establishing the glial origin of undifferentiated brain tumors 15, 61, even though the extent
of GFAP staining does not correlate directly with the
degree of malignancy in human astrocytomas [lo, 16,
17). Highly malignant glioblastoma multiforme often
contains little GFAP (as in patient 2) or none at all,
whereas lower-grade astrocytomas generally stain
prominently for GFAP. Thus the presence of GFAP in
a tumor specimen confirms the astrocytic nature of the
tumor, whereas the absence of GFAP does not necessarily mean the reverse. The patients presented here
demonstrate an important use of PAP staining for
GFAP in a difficult clinical situation, when one needs a
specific marker to define the astrocytic nature of an
extraneural metastasis.
The uniformity of cellular structure in the metastatic
foci in patient 1 suggests that a certain population of
tumor cells existing in the original tumor, in this case
the small fibrillary spindle-shaped cells, were capable of
penetrating the vascular wall and spreading to distant
sites via the circulation. Liwnicz and Rubinstein 1111
have established that the route of extraneural metastasis by glioblastoma cells is via the dural vessels, and
we found tumor cells in both meningeal veins and dural
veins near the tumor bed in patient 1. Although youn584
Annals of N e u r o l o g y
V o l 14
No 5
ger patients with malignant gliomas have a better prognosis than older ones [8}, they are more likely to develop complications, such as meningeal seeding [20),
spinal cord compression, and extraneural metastasis
Supported in part by Brain Tumor Study Group Contract N C - C M 07348 from the National Cancer Institute ( D r Young) and Fellow
ship Award CA-09207 from the National Cancer Institute (Dr
The authors thank D r Robert L. Ruff for providing the clinical materials for patient 2 (supported in part by Grant NS-00498 from the
National Institute of Neurological and Communicative Disorders
and Stroke), and Daisy Jiminez and Doris Flores for their technical
1. Abbot KH, Love JG: Metastasizing intracranial tumors. Ann
Surg 118:343-352, 1943
2. Bignami A, Eng LF, Dahl D, Uyeda CT: Localization of the g1i:d
fibrillary acid protein in astrocytes by immunofluorescence
Brain Res 43:429-435, 1972
3. Cohen JR, Wiernick P H , Walker MD: Acute nonlymphocytic
leukemia associated with nitrosourea chemotherapy: report of
two cases. Cancer Treat Rep 60:1257-1201, 1976
4. Davis L: Spongioblastorna multiforme of the brain. Ann Surg
5. Deck J H N , Eng LF, Bigbee J, Woodcock SM: The role ofglial
fibrillary acidic protein in the diagnosis of central nervous system
tumors. Acra Neuropathol (Bed) 42:183-190, 1978
6. Duffy PE, Graf L, Rapport MM: Identification of glial fibrillary
acidic protein by the immunoperoxidase method in human hrairi
tumors. J Neuropachol Exp Neurol 36:615-652, 1977
7 . Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B: An acidic
protein isolated from fibrous astrocytes. Brain Res 28:35 1-354,
8.Gehan E A , Walker MD: Prognostic factors for patients witli
brain tumors. Narl Cancer Inst Monogr 46:189-195, 19”
9. Glasamer FE, Yuan RHP: Intracranial tumors with extracranial
metastases: case report and review of the literature. J Neurosurg
20:474-493, 1963
1 0 -Jacque
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Bauman N GFA and S 100 protein levels as an index for malignancy in human gliomas and neurinomas. J Natl Cancer Inst
62:4?9-483, 1979
11. Liwnicz BH, Rubinstein LJ: The pathways of extraneural spread
in metastasizing gliomas. H u m Pathol 10:453-457, 197‘)
12. Pasquier B: Le metastases extranevraxiques des tumeurs du syst h e nerveux centre. Bull Cancer (Paris) 06.25-28, I970
13. Pasquier B, Pasquier D, N’Golet A, Panh MH, Conderc P:
Extraneural metastases of astrocytomas and glioblastomas. Cancer 45:112-125, 1980
14. Rueger DC, Huston JS, Dahl D, Bignami A: Formation of 100
A filaments from purified glial fibrillary acidic protein in vitro. J
Mol Biol 135:53-68, 1979
15. Sternberger LA, Hardy P H Jr, Cuculis JJ, Meyer HG: The unlabeled antibody enzyme method of immuno-hisrochemistry:
preparation and properties of soluble antigen-antibody complex
(horseradish peroxidase-antihorseradish peroxidase) and its use
in identification of spirochetes. J Histochem Cyrochem 18:315333, 1970
16. Van der Meulen JDM, Houthoff HJ, Ebels EJ: Glial fibrillary
acidic protein in human gliomas. Neuropathol Appl Neurohiol
4:177-190, 1978
N o v e m b e r 1983
17. Velasco ME, Dahl D, Roessniann V, Gambetti P: Immunohis-
tochemical localization of glial fibrillary acidic protein in human
glial neoplasms. Cancer 45:484-494, 1980
18. Vogl SE: Acute leukemia complicating treatment of glioblastoma muitiforme. Cancer 41:333-336, 1978
13 Wakamarsu T, Matsuo T, Kawano S, Teramoto S, Matsumma H:
Extracranial metastasis of intracranial tumor: review of literature
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20. Yung WKA, Horten BC, Shapiro WR: Meningeal gliomatosis: a
review of I 2 cases. Ann Neurol 8:605-608, 1980
Autosomal Dominant
Motor System
Degeneration in
a Black Family
plegias as well as lid retraction have been reported in all
three types of the disease ( I , 2, 8, 91. Most patients
described were members of four families with origins
in the Azorean Islands (I, 8, 91. Subsequently, a number of families in the Azores were found to have similar symptoms { 11. One non-Portuguese black family
has been described with clinical findings similar to
those in type I1 ADMSD { S ] . A Japanese family was
reported recently 1121. W e describe a second black
family with roots in the West Indies and a clinical picture similar t o that in type I ADMSD.
Case Report
Joanna A. Cooper, MD," Tsutomu Nakada, MD,"
Robert T. Knight, MD,* and Robert P. Friedland, MDV
Autosomal dominant motor system degeneration has
been described primarily i n Portuguese families from
the Azorean Islands. The symptoms include various
combinations of ataxia, pyramidal and extrapyramidal
signs, appendicular dystonias, tics, ophthalmoplegias,
and peripheral neuropathies with amyotrophy. O n e nonPortuguese, non-Azorean black family has been described previously; this report describes a second such
family affected by autosomal dominant motor system degeneration.
Cooper JA, Nakada T, Knight RT, Friedland RP
Autosomal dominant motor system degeneration in
a black family Ann Neurol 14 585-587, 1983
Autosomal dominant motor system degeneration
(ADMSD) affects primarily families of AzoreanPortuguese ancestry 11, 2, 7-9, 111. At present three
phenotypes of ADMSD have been described: type I
begins at a young age (second to third decades) with
primarily extrapyramidal and pyramidal manifestations;
type I1 is dominated by pyramidal and cerebellar
findings and starts later in life (fourth to sixth decades);
type I11 begins late (fifth to seventh decades) and the
patients primarily exhibit ataxia and peripheral neuropathy with prominent distal amyotrophy. OphthalmoFrom the *Departmen[ of Neurology, University of California,
Davis, Veterans Administration Medical Center, Martinez, CA
94553, and the tDonner Laboratory, University of California,
Berkeley, CA 94720.
Received Jan 31, 1983, and in revised form Mar 23, 1983. Accepted
for publication Mar 25, 1983.
Address reprint requests to D r Cooper, University of California,
Davis, Veterans Administration Medical Center, 150 Muir Rd, Martinez, CA 94553.
The propositus presented at the age of 3 1 years. H e was well
until the age of 23 years, when he developed gait difficulties,
dysarthria, and impaired mental function. Neurological examination revealed a reduction in memory functions,
difficulties with calculations and spelling, poor comprehension of complicated tasks or written text and concrete thinking. His eye movements were slow, with severe limitation in
spontaneous lateral movements and upgaze. The doll's eyes
maneuver improved his lateral movements and upgaze, indicating a supranuclear component. Lid retraction was present.
Gaze nystagmus was elicited bilaterally at 15 to 25 degrees,
and optokinetic nystagmus was present bilaterally. He had
mild difficulties in swallowing, a spastic dysarthria, and mild
facial and tongue weakness, and drooled on occasion. Facial
grimacing without tics was observed. There was bilateral
spasticity with a marked gait abnormality. The deep tendon
reflexes were symmetrically hyperactive, with clonus and extensor plantar responses bilaterally. Appendicular dystonia
with spooning of the hands was noted. Sensation was intact,
as was cerebellar function. Computed tomographic scan
showed a slight prominence of the primary fissure of the
cerebellar vermis but was otherwise normal. Visual, auditory,
and somatosensory evoked responses were normal, as were
an electroencephalogram, an electromyogram, and nerve
conduction velocity study. A chest roentgenogram, an electrocardiogram, complete blood count, electrolytes, muscle
and serum liver enzymes, serum creatinine and blood urea
nitrogen, serum amino acid electrophoresis, serum arylsulfatase A, serum copper, serum ceruloplasmin, serum phytanic
acid, and cerebrospinal fluid all were normal. Fibroblast cultures done from a skin biopsy specimen showed equivocal
protein pattern abnormalities.
The family pedigree IS snown in the Figure. The family
origins could be traced back to the West Indies. It is believed
that there is Irish ancestry in the proband's maternal grandfather's line. We could not elicit a history of Azorean, Portuguese, Angolan, or Mozambikian connection. Two of the
proband's siblings were affected by the disease. An older
brother had experienced onset of similar symptoms at age 28,
and a younger sister had become symptomatic at age 18. This
sibling also had facial tics. There were two unaffected siblings. The mother and both her sisters reportedly had been ill
with similar manifestations, with onset in their early twenties;
all three had died of cachexia in the fifth decade. The maternal grandmother and great grandfather reportedly had suffered similar symptoms and died in their early forties with
severe spasticity and dementia. No postmortem examinations
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diffuse, glia, metastasis, fibrillary, bones, premortem, marrow, protein, acidic, staining, glioblastoma, diagnosis, antiperoxidase, peroxidase
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