Yonago Acta medica 1997;40:63–72

Massive Lung Metastasis from Cerebellar Medulloblastoma: a Report on
One Case and Review of Literature
Shinsuke Kato*, Hidenobu Aoki†, Kunihiko Tamura*, Hiroko Hayashi*, Hajime
Miyata*, Tomokatsu Hori‡ and Eisaku Ohama**Division of Neuropathology and ‡Division of Neurosurgery, Institute of Neurological Sciences,
Faculty of Medicine, Tottori University, Yonago 683 and †Department of Neurosurgery, Matsue
Municipal Hospital, Matsue 690, Japan
Cerebellar medulloblastoma with massive lung metastasis in a 10-year-old girl wasstudied histopathologically and immunohistochemically. She was treated twice by
operation and had bilateral lung metastases appearing 13 months after the second
operation. The autopsy revealed that the bilateral lungs were almost replaced by the
medulloblastoma, and that the residual tumor cells in the primary focus could only beseen at the level of light microscope. The primary and metastatic tumor cells did notshow any differentiation immunohistochemically. While researching the literature
between the years 1960 to 1996, 114 cases of all ages having medulloblastomas withextracranial metastases were found. The metastatic spread of the tumors occurs at therate of 3.9% (114/2,925). This is an invaluable report which clearly shows the massive
lung metastasis of medulloblastoma, based on the detailed review of literature.
Key words: extracranial metastasis; reviewing literature; lung metastasis; medulloblastoma;
immunohistochemistry

It is well known that extracranial metastasis ofprimary brain tumors is an unusual occurrence.
Some authors attribute the rarity of remotemetastases of primary brain tumors to an inability of tumor cells to proliferate in otherorgans during the short postoperative life spanof the patient (Winkelman et al., 1952; Perry,1957). In a series of 8,000 cases of central nervous system (CNS) tumors of neuroectodermal
origin, only 35 patients developed extracranial
metastases (Smith et al., 1969). Approximately
200 cases of extracranial metastases have beenreported in the literature in patients of all ages
with brain tumors (Smith et al., 1969; Liwnicz
and Rubinstein, 1979; Kleinman et al., 1981).

As for the incidence of extracranial metastases
in children with primary brain tumors, a clinicaland pathologic review of brain tumors (917cases in a 62-year period) identified only 21
cases (2.3%) with systemic metastases, and thisincluded 15 cases of medulloblastoma (1.6%)(Campbell et al., 1984). We report a child patient having medulloblastoma with massive
metastasis to the bilateral lungs appearing 13
months after the second resection of the cerebellar medulloblastoma, whose lungs arealmost replaced by the medulloblastoma. In
addition, we provide a detailed review of theliterature of the medulloblastomas with extracranial metastases.

Abbreviations: ABC, avidin-biotin-immunoperoxidase complex; BSA, bovine serum albumin; CNS, central
nervous system; CSF, cerebrospinal fluid; CT, computed tomography; GFAP, glial fibrillary acidic protein;
H&E, hematoxylin and eosin; NSE, neuron specific enolase; PBS, phosphate-buffered saline; pNFP,
phosphorylated neurofilament protein; PTAH, phosphotungstic acid-hematoxylin

63

S. Kato et al.

Fig. 1. Contrast enhanced computed tomographyscan of the brain shows a high density mass(arrows) with perifocal edema (arrowheads) in the
cerebellar vermis.
Fig. 2. Chest radiograph demonstrates multiple
radiopaque lesions in the bilateral lung fields andalmost complete opacity in the superior lobes on theright side.

Materials and Methods
On February 5, 1991, she suffered from unconsciousness again and was readmitted. A
second operation was performed on February 7,
1991, and the recurrent tumor in the cerebellar
vermis was subtotally removed. The chest
radiograph before the second operation showedno abnormality. The second postoperation
course was relatively smooth until she
complained of dyspnea 13 months after thesecond operation. X-Ray films of the chest
demonstrated multiple radiopaque lesions in thebilateral lung fields and almost complete
opacity in the superior lobe on the right side
(Fig. 2). Her dyspnea progressed and her
general condition deteriorated gradually, andshe died of respiratory insufficiency at the ageof 10, on April 23, 1992. A postmortem examination was performed 16 h after her death.

Patient
An 8-year-old female child was admitted to
Matsue Municipal Hospital with a 1-month
history of loss of consciousness on January 26,
1990. At the time of admission she was in good
general health and was afebrile. An contrast
enhanced computed tomography (CT) scan of
the brain demonstrated a high density mass withperifocal edema in the cerebellar vermis (Fig.
1). The chest radiograph showed no abnormalities. Suboccipital craniectomy was performedon February 1, 1990. The tumor in the cerebellar vermis was totally resected under direct
vision. Radiotherapy (total dose of 40 Gy) was
given on over a period of 4 weeks. The postoperative and postradiation state was uneventful. She became able to walk by herself and wasdischarged on April 3, 1990.
64

Medulloblastoma with lung metastasis

blocking reagent. Mouse monoclonal antibodies against GFAP (ready-to-use, BioGenex
Laboratories, San Ramon, CA), synaptophysin[1:100 in 1% bovine serum albumin (BSA)containing PBS, Boehringer-Mannhaim Biochemica, Germany], pNFP (1:5,000 in BSAPBS, Sternberger Monoclonals Inc., Baltimore,MD) and NSE (ready-to-use, BioGenex Laboratories) were used. Tissues sections wereincubated with the antibodies for 18 h at 4˚C.
PBS replaced the antibody in the controls. The
horse anti-mouse IgG Vectastain ABC kit (Vector
Laboratories, Burlingame, CA) was used todetect each bound antibody. 3,3'-Diaminobenzidine tetrahydrochloride was the final
chromogen. Hematoxylin was used to counterstain some sections while other sections werenot.

Histopathology and immunohistochemistry
After being fixed in 10% buffered formalin for 2
weeks, the specimens were embedded in paraffin,
and cut into 6 µm-thick sections. The brain, spinal
cord and lungs as well as lymph nodes were
stained by the following routine methods:
hematoxylin and eosin (H&E), Klüver-Barrera,
Holzer, Bodian, reticulin, phosphotungstic acidhematoxylin (PTAH) and Bielschowsky stains.
The sections of the visceral organs were stainedwith H&E. Representative paraffin sections
were used for immunohistochemical tests.
The avidin-biotin-immunoperoxidase complex (ABC) method (Hsu et al., 1981) was employed for glial fibrillary acidic protein(GFAP), synaptophysin, phosphorylated neurofilament protein (pNFP) and neuron specificenolase (NSE). Sections were deparaffinized,
endogenous peroxidase activity was quenchedby incubation for 30 min with 0.3% H2O2, followed by washing with phosphate-bufferedsaline (PBS). Normal horse serum served as a

Results

Autopsy findings
The brain weighed 1,080 g. At autopsy, the tumor infiltrating into the spinal cord lesions,especially the thoracic segments, were identified externally. However, the cerebellar vermis
showing the operative defect had no apparent
tumor tissue macroscopically (Fig. 3). The
tumors in the spinal cord were soft, rather
fragile and moderately demarcated from thenormal tissues. The tumor-cut surfaces weregreyish with small necrotic foci. The lungs on
the bilateral sides were almost replaced by thegreyish tumors. Sections of the lung tumors
were greyish in color, associated with hemorrhage and necrosis. The normal lung area not
involved by tumors was only one-tenth of thewhole lung, showing an advanced edema andcongestion (Fig. 4). The lymph nodes wereswelling in the hilus of the lung as well as in theareas adjacent to the esophagus, thoracic aorta
and trachea. Cross sections of these areas showed
an outline of fused nodes with tiny necrotic foci.
Other abnormalities of the visceral organs
included bilateral pleural effusion.

Fig. 3. Transverse section of the cerebellar vermis (primary focus), cerebellar hemisphere and pons. Although the cerebellar vermis shows an operative defect,
an apparent tumor mass is not seen macroscopically.

65

S. Kato et al.

Histopathology and immunohistochemistry
Although the cerebellar vermis showed no apparent tumor tissue macroscopically, tumor
cells were observed at the level of a light microscope. The tumors of the brain, spinal cord,lungs and lymph nodes had essentially the same
aspects. One feature of the tumors showed highcellularity. Every field was packed with small
cells in which the cytoplasms were scanty andpoorly defined, and the nuclei were round oroval, variable in size and highly hematoxyphilic

Fig. 5. Light micrographs of the cerebellar vermis(A, primary focus) and the lung tumor (B, metastatic
lesion). The tumors of the cerebellum and lung havethe same aspect: tumors are composed of small
undifferentiated cells in which the cytoplasms are
scanty, and the nuclei are oval and highly hematoxyphilic on account of their abundant coarse
chromatin. Mitotic figures are seen (arrowheads in
A and B). Hematoxylin and eosin (H&E). A, B: ×421.

on account of their abundant coarse chromatin(Fig. 5). Mitotic figures were abundant andnecrotic foci were occasionally seen. In many
fields there were no special architecturalarrangements of the cells: they simply formed
irregular masses and sometimes they were
supported by a tenuous stroma of blood vessels
and collagenous tissues. The formation ofrosettes of the Hormer Wright type was notobserved in the examined tumor areas. PTAHpositive fibers were not observed in the tumors.
Argyrophilic neurites in the tumors were also
not seen. The tumor of the thoracic segments
was characterized by a dense intercellular
network of reticulin and collagen fibers, andhad reticulin-free islands. This finding wascompatible with a so-called desmoplastic

Fig. 4. Section of the left lung. The lung is almost
replaced by the greyish tumor in association withhemorrhage and necrosis. The normal lung area not
involved by tumors is approximately only one-tenth ofwhole lung, showing an advanced edema and congestion (arrowheads).

66

Medulloblastoma with lung metastasischange. However, the other tumor areas did notshow a desmoplastic change. Immunohistochemistry revealed that the tumor cells in the
CNS, lungs and lymph nodes were not stainedby the antibody against GFAP (Fig. 6) and did
not have a glial differentiation. The tumor also
did not show a neuronal or neuroblastic
differentiation because the tumor cells did not
express the epitopes of synaptophysin, pNFP
and NSE, immunohistochemically. The final
diagnosis was undifferentiated medulloblastoma. Microscopic distribution of the
medulloblastoma in the CNS is illustrated inFig. 7.

thoracic segments demonstrated a desmoplasticchange as a result of its arachnoid involvement.
The patient was a 10-year-old female child.
Therefore, our case was one of typical medulloblastomas in terms of age, primary region andmorphology.
The present case showed a massive metastasis to the bilateral lungs and dissemination
along the cerebrospinal fluid (CSF). As for the
dissemination, in 1930 Bailley demonstrated

Discussion
The medulloblastoma is a neoplasm composedlargely of small undifferentiated cells and mostof them originate in the cerebellar vermis(Russell and Rubinstein, 1989; Burger et al.,1991). The incidence of the medulloblastoma ishighest during the first two decades of life,
declining sharply during adulthood (Hubbard etal., 1989). A slight male predominance appears
statistically valid (Caputy et al., 1987; Hughes
et al., 1988). Our medulloblastoma was also composed of small undifferentiated cells and its primary focus was the cerebellar vermis. Immunohistochemistry demonstrated that the present
medulloblastoma showed neither glial nor
neuronal differentiation. Tumor-disseminating

Fig. 6. A: Immunostaining with antibody against glial
fibrillary acidic protein (GFAP) in the tumor of primary
focus in the cerebellar vermis. This section is counterstained with hematoxylin. Tumor cells are not stainedwith the antibody to GFAP (arrowheads), while thereactive astrocytes around the tumor are intensely positive (arrows). B, C: Serial sections of a thoracic segment in the spinal cord involved by the tumor, stainedwith H&E (B) and the antibody against GFAP without
counterstain (C). The tumor infiltrating into the spinal
cord (arrows in B) is not stained by the antibody to
GFAP (arrows in C). However, a GFAP-positive reaction is seen in the normal spinal cord tissue compressedby the tumor (asterisks in C). There are small necroticfoci in the tumor (arrowheads in B). A: × 100, B, C:
× 6.

67

S. Kato et al.

"

Fig. 7. Microscopic distributionof the tumor cells in the central
nervous system. The shaded
areas show the microscopic presence of the tumor cells. A:
Transverse section of the cerebellar vermis (primary focus),
cerebellar hemisphere and pons.
As seen in Fig. 3, the cerebellar
vermis shows no apparent tumor
evidence macroscopically. As
indicated by Figs. 5A and 6A,
tumor cells are, however, observed at the level of a light microscope. B: Coronal section of thebasal ganglia in the cerebrum atthe level of mamillary body. C:
Midbrain. D: Medulla oblongata. E: Thoracic segment of
the spinal cord indicated by Figs.
6B and 6C.

$%#that medulloblastomas
tended to seed along CSF
pathways, and in the same
year Wohlvill (1930) was thefirst to draw attention to theoccurrence of systemic metastasis of medulloblastoma.
Since then, metastases
within the CNS have beenfound in one-third to onehalf of cases where a carefulsearch of the brain, spinal
cord and nerve roots was
carried out (Abbott and
Kernohan, 1943; Ingreham
et al., 1948; Strang, 1962).
Metastases outside the craniospinal axis, however, aremuch rarer. A review of thepediatric literature quoted 21
cases of extracranial metastases from 917 cases ofprimary intracranial tumors(Campbell et al., 1984). This
included 15 cases out of 152
medulloblastomas; 1 caseeach out of 555 gliomas, 100
ependymomas and ependy-&

Table 1. Frequency of medulloblastomas with extracranial
metastases
Authors

No. of casesof medulloblastomas

No. of casesof extracranial
metastases

Paterson(1961)
35
7
Friborsky´(1963)
6
1
Dexter and Howell(1967)
93
3
Bloom et al.
(1969)
82
2
Aron(1969)
24
1
McFarland et al.
(1969)
1,360
0
Chatty and Earle(1971)
201
4Smith et al.
(1973)
43
3
Hoffman et al.
(1976)
44
6
Brown et al.
(1977)
14
1
Das and Dalby(1977)
22
3
Schnitzler et al.
(1978)
28
4
Jackson and Graham(1978)
100
1
Raimondi and Tomita(1979)
51
0Naruse et al.
(1979)*
197
3
Paillas et al.
(1979)
17
3
Komatsu et al.
(1980)*
100
6
McComb et al.
(1981)
34
6
Campbell et al.
(1984)
152
15
Kasantikul and Shuangshoti (1986)
35
1
Nakamura et al.
(1987)*
243
32
Farwell and Flannery(1987)
44
12
Total
2,925
114 (3.9%)†*Literature in Japan.
†( ), percentage of medulloblastoma with extracranial metastasis.

68

Medulloblastoma with lung metastasis

Table 2. Location of medulloblastomas with extracranial metastases
AuthorsSex
No. of cases
Organ
Lung
Bone
Lymph node
Liver
PleuraDiaphragm
SpleenKidneyPancreas
AdrenalMesentery
UterusBladder
Retroperitoneum
Skin, muscle andsoft tissueM, male; F, female.

Rochkind et al.
(1991)M
F TotalNakamura et al.
(1986)M
F
Total

Komatsu et al. Wakamatsu et al.
(1980)(1972)
Total
Total

21

8

29

21

5

26

55

63

4
21
5
3
1
0
0
0
1
0
0
1
0
0
0

1
7
5
1
1
0
0
0
1
0
0
0
0
1
0

5
28
10
4
2
0
0
0
2
0
0
1
0
1
0

3
13
6
8
2
3
1
2
2
2
3
0
1
3
0

2
2
1
2
1
1
0
0
0
0
0
0
0
0
0

5
15
7
10
3
4
1
2
2
2
3
0
1
3
0

8
44
23
7
3
0
0
0
3
0
0
0
0
0
5

2
47
7
2
2
0
0
0
0
0
0
0
0
0
3

Even so, the great rarity of extracranial
metastasis of primary brain tumors is still not
clearly understood. The absence of cerebral
lymphatics (Elvidge et al., 1937; DuboisFerriere, 1940), early occlusion of venous channels by tumor compression (Smith et al., 1969),
immunoresponse to the tumor cells by otherorgans (Kato et al., 1995), and the significant
short postoperative life span in comparison withthe clinical detection of the metastatic foci(Alvord, 1976) have all been regarded as significant factors. Russell and Rubinstein (1989)
have documented in their textbook that resistance of the endothelium to invasion by glioma,
resistance of the lung to grow medulloblastomas, inability of glioma to induce stroma, andimmunological factors have also been considered to be important factors. By comparison, it isbelieved that surgical procedures play a majorrole in the entrance of tumor cells into extracranial blood vessels and lymphatics(Yokoyama et al., 1985). Direct lymphatic
spread is impossible because true lymphatics
are not present in the CNS. However, it is possible that the spread of tumors in continuity

moblastomas, and 43 pineal tumors; and an
additional 3 cases out of 67 other miscellaneous
types of brain tumors. In searching the literature from the years 1960 to 1996, 114 cases of
medulloblastomas with extracranial metastasesof all ages were found (Table 1). The metastatic
spread of the tumor occurs at the rate of 3.9%.
Although the present case was female, a marked
overall male predominance is evident from theliterature, with a 5:2 male/female ratio in
foreign countries (Rochkind et al., 1991 inTable 2) and a 4:1 male/female ratio in Japan(Nakamura et al., 1986 in Table 2). Although
remote metastases from intracranial tumors
could be found in almost all parts of the body,our case showed that the target organs of the
distant metastases from cerebellar medulloblastoma were lungs and lymph nodes. The
literature (Table 2) demonstrates that the bone
was the most frequent site for extracranial
metastases (58–97%). Lymph node metastases
were the second in frequency with an incidenceof 11–42%. Lung metastases (3–17%) wereslightly less frequent in comparison with liver
metastases (3–38%).

69

S. Kato et al.

along nerve roots may lead to the invasion oflymphatics (Das and Dalby, 1977), and indeed
Oberman and colleagues (1963) have reported
the presence of tumor cells in peripheral lymphatics. Russell and Rubinstein (1989)
conjectured that small veins might be the routesof extracranial dissemination because tumor
cells penetrating blood vessels, tumor invasionof dural veins, or direct extension to the cranium or to the operation site, were almost always encountered. By now, the hematogenous
route of spread is accepted by most authors(Rochkind et al., 1991). Therefore, our casewith massive lung metastasis is thought to be
the result of the hematogenous route because ofoperation maneuvers, and lymph-node metastasis might be a secondary lymphatic spreadfrom the tumors in the lung.
It is most conspicuous in the present casethat almost all areas of the bilateral lungs were
replaced by the medulloblastoma, appearing
only 13 months after operation. As Russell andRubinstein (1989) pointed out, the lungs have aresistance to the growth of medulloblastomas.
Table 2 demonstrates that the incidence of lungmetastases of medulloblastomas is rarer in comparison with those of the bone or lymph node.
One report (Komatsu et al., 1980) has documented that only a 2 cm tumor focus of medulloblastoma in the upper lobe of the right lungwas detected at autopsy, and that no clinicalmanifestation of the lung metastasis was observed. The responsibility for death in thepresent case was respiratory failure due tomassive medulloblastoma infiltration into thebilateral lungs. To our knowledge (Tables 1
and 2), there is no literature of the medulloblastoma with massive lung metastasis except
for the present case. Although the present
medulloblastoma was undifferentiated and wasthought to have a great growth potential, thereason why the medulloblastoma showed a rashproliferation in the lungs in comparison with
the CNS including the cerebellum, brain stemand spinal cord is still unknown.
After the Packers’ report on medulloblastoma treatment (1991), mainstream therapy supports irradiation plus adjuvant chemotherapy.
Therefore, if this patient could have been treat-

ed with additional chemotherapeutics after the
first operation, a short duration recurrence ofthe medulloblastoma in the cerebellum and/or a
massive lung metastasis might not have occurred.

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(Received December 20, 1996, Accepted January 9, 1997)72