Brain (1976), 99, 735-756

PRIMARY CEREBRAL NEUROBLASTOMA A CLINICOPATHOLOGICAL STUDY OF 35 CASES by BRUCE C. HORTEN and

LUCIEN J. RUBINSTEIN

(From the Department of Pathology (Neuropathology), Stanford University School of Medicine, Stanford, California, 94305, USA)

THE cerebral neuroblastoma is at this time a controversial tumour that is still incompletely described. Willis (1967) states that 'it is very doubtful whether neuroblastomas or ganglioneuromas ever occur in the central nervous system.' In his recent Atlas of the Histology of Brain Tumors Zulch (1971) does not list the cerebral neuroblastoma as a separate entity. Yet in the experience of one of us (L. J. R.) it has accounted in recent years for the largest single group of supratentorial neuro-epithelial neoplasms in children referred from outside sources because of diagnostic difficulty. There is therefore a need for a full description of this tumour and for its definition as a clinicopathological entity in the corpus of human neuro-oncology. Such a task could be undertaken only after a sufficient number of cases had been assembled since individual experience is uncommon and usually limited to single examples. The object of this paper is to present an account of 35 cases of cerebral neuroblastoma examined or reviewed by us, most of which were referred to this Department for consultation over the last twelve years. All tumours resembling the cerebral neuroblastoma but originating primarily below the tentorium have been excluded so as to avoid confusion with the medulloblastoma. From the cytogenetic point of view, the separation may be arbitrary, but it is justified in practice for two reasons. First, the medulloblastoma is a wellestablished and common entity with clear-cut clinical and pathological characteristics; the cerebral neuroblastoma, on the contrary, is extremely rare and still ill-defined clinically and pathologically. Secondly the origin of the medulloblastoma is by general agreement assigned to a site of neurocytogenesis in the neuraxis with unique developmental features, namely the cerebellar cortex, and evidence of divergent differentiation along either neuronal or neuroglial cell lines is sometimes demonstrable (Rubinstein, 1975); by contrast, the differentiating potential of the cerebral neuroblastoma is restricted to ganglion cells only. Excluded also from this study are olfactory neuroblastomas, which may sometimes present as primary intracranial neoplasms (Hamilton, Rubinstein and Poole, 1973); and the tumours originating from pineal parenchyma cells, for which there is mounting evidence of their neuronal nature (Russell and Rubinstein, 1977).

736

B. C. HORTEN AND L. J. RUBINSTEIN MATERIAL AND

METHODS

Thirty-one of the 35 cases were referred to us by other pathologists. Three (Cases 4, 12 and 35) were part of the primary surgical or autopsy material examined over the years by one of us (L. J. R.). Case 19 belongs to the London Hospital collection originally studied by one of us (L. J. R.) with Professor Dorothy S. Russell. In most cases, multiple paraffin blocks were available from different parts of the tumour and, in the case of post-mortem material, of the adjacent brain. In 10 cases, wet formalin-fixed tissue was also available for frozen preparations. Special stains on paraffin sections included Mallory's phosphotungstic acid haematoxylin (PTAH), Gordon-Sweets' silver method for reticulin, iron-hsmatoxylin and van Gieson, and the Nissl stain (toluidine blue or cresyl violet). Of special importance was a modification of Bielschowsky's silver method which has been successfully employed in this laboratory for the past twelve years for the demonstration of axonal and other neurofibrillary material on both paraffin-embedded and frozen sections. We are indebted to Dr. W. Jann Brown and Dr. J. Genis-Galvez, of the University of California, Los Angeles, for the development of this modification. This variant differs from other Bielschowsky silver impregnation methods in that it uses for sensitization, impregnation and reduction a single 20 per cent silver nitrate bath, to which the other agents are added at different stages. In brief, sections are sensitized in the above bath in the dark at 37° C for 15 min (paraffin sections) or 30 min (frozen sections). While they are washed in distilled water, the silver solution is titrated with ammonium hydroxide, the precipitate being just dissolved with no excess of ammonium remaining. The sections are then returned to this silver solution for a further 10 min (paraffin sections) or 15 min (frozen sections) at 37° C in the dark. While they are subsequently being rinsed again, 4-8 drops of developer (a 20 per cent solution of 10 per cent unbuffered formalin, to which one drop of concentrated nitric acid and 0-5 g of citric acid per 100 ml have been added) are added to the silver solution. Sections are then returned to the silver bath for a further 5 min (paraffin sections) or 10 min (frozen sections), the reaction being regularly checked under the microscope. Subsequent toning of the sections with 0-1 per cent gold chloride is optional. Fixing, rinsing, dehydration, clearing and mounting procedures are standard. For the demonstration, by the above method, of axons and neurofibrillary material originating from the tumour cells, frozen sections were almost always essential. With rare exceptions, sections from paraffin-embedded material demonstrated with clarity only pre-existing axons from the invaded or adjacent brain. In a few cases, frozen preparations impregnated with the Hortega double silver carbonate method for axons were also available for study.

RESULTS

The main clinical, biological and histological features of the 35 cases are shown in Table 1. Seven examples of special interest are described in greater detail below. Of the other 28 cases, one (Case 33) has previously been reported in detail, except for incomplete follow-up (Miller and Ramsden, 1966). Supplementary photomicrographs from the present case material have appeared in two other publications (Russell and Rubinstein, 1971, figs. 154 and 155 for Case 19; Rubinstein, 1972, figs. 167 and 168 for Case 29; fig. 169 for Case 19; fig. 170 for Case 27; and figs. 171 and 172 for Case 23). Two patients were lost to follow-up after operation, a Vietnamese child (Case 21) and a 60-year-old man (Case 12).

TABLE 1. CLINICAL, BIOLOGICAL AND HISTOLOGICAL FEATURES OF 35 CASES Histologicalfeatures

Case

Accession A'o.

Age

Sex

Site and gross features

1 C-1089 2J years F (Dr. J. Bebin, Jackson, Miss.; Dr. D. S. Horoupian, New York)

L. frontal, cystic (5 cm)

2 C-2168 4 years (Dr. P. A. Benson, Redwood City. Cal.)

L. frontal, large

F

3 C-705 4J years M (Dr. L. B. fCahn, Johannesburg) 16573

6 years

M

L. frontal, discrete

L. frontoparietal, soft discrete hxmorrhagic at autopsy (9 cm)

Recurrences (R) metastases (M) alive {A) or dead (D)

Survival after first operation 3 years

A

Homer Wright rosettes

Ganglionic differentialion

+

0

4J years

10 months

7$ years

Classical

R after 6 months D (autopsy: multiple ventricular and subarachnoid M)

Classical

R after 2 years A

Classical

6 C-685 29 years M (Dr. W. Winchell, Santa Cruz. Cal.)

R. lateral ventricle

6 years

7 C-327 2J years F (Prof. J. M. Bruchcr, Louvain)

R. temporal, massive soft invasive, resembling medulloblastoma

6 months

D (autopsy)

8 C-159 3j years (Drs. F. W. Wiglesworth and R. L. Denton, Montreal)

R. frontotemporal, discrete soft cystic ( 8 x 7 x 5 cm; 130 g)

2\ years

R (spinal M) after 18 months D (no autopsy)

L. frontoparietal, large cystic, with mural nodule

5$ years

R after 5 years D (autopsy: ventricular M)

4-

10 years

R after 7 and 8 years D (autopsy: multiple ventricular M)

-f

No op.

D (autopsy)

HH8450 5 years M SD 5935/58 (Prof. E. D. Williams. Cardiff)

10 C-1546 9 years F L. frontal (Dr. T. H. Gleason, Seattle, Wash.) 11 SD983/6I 45 years F Third ventricle, discrete (Prof. M. Wolman, Tcl-Hashomer) 12 NS4720 60 years M (Dr. Leo Davidoff, New Canaan, Conn; Dr. Asao Hirano, New York)

R. frontal

13 C-1053 4 years F C-1385 (Dr. J. E. Olvcra Rabiela. Mexico)

R. parieto-temporo-occipital, massive discrete

Subgroup Classical

R (local) after 18 months R (spinal M) after 4$ years D (no autopsy)

R. parieto-occipital, discrete (2-5 cm)

9

Desmoplastic features None

Classical

5 C-1806 9 years F (Dr. F. S. Vogel. Durham. N.C.; Dr. R. T. Fitzgerald, Lackland AFB. Texas; Drs. K. KaganHallctand K. M. lEurlc. Washington)

M

Argyrophilia of tumour cell processes

Classical

A

+

Classical

•

o m n m CD 70

Z m C jo

O CO r > H

Not known

No op.

Uni-, bi- and multipolar neuroblasts in silver carbonate

None

Classical

None

Classical

None

Classical

None

Classical

None

Classical

Moderate: in leptomeninges only

Early transitional

Lost to follow-up

D (autopsy: M in fourth ventricle)

(in meningeal extensions)

\continued overleaf

o 2

Histoiogicaifeatures

TABLE \~contd.

Case

Accession No.

Age

Sex

Site and gross features

Survival after first operation

14 C-1832 10 years (Dr. J. K. Borcich, Redwood City. Cal.)

F

L. parietal, cystic

1 year

A

15 C-545 2J months (Dr. H. Namiki, Honolulu; Dr. H. Matsuyama, Tokyo)

F

L. frontal horn and third ventricle, massive hjemorrhagic

No op.

M

L. frontal, presenting as haematoma, massive discrete lobulated cystic bifrontal at autopsy

16

C-754 2 years C-1023 (Dr. R. L. Davis, Los Angeles) 17 C-155 2j years (Dr. R. L. Davis. Los Angeles; Drs. K. Kagan-Hallet and K. M. Earle. Washington)

F

18 C-305 3 years M (Dr. C. S. Crusinbcrry, Santa Ana, Cal.; Dr. L. J. Mongcon, Fullerton. Cal.)

13 months

L. parietal, discrete soft lobular (4 cm)

No op.

L. temporal, large discrete cystic

Postop. death

M

R. frontal, firm lobular discrete cystic

6 months

20 C-1429 8 years (Drs. E. E.TuellerandJ. L. Graham, Burlingame, Cal.)

M

L. frontal, large cystic

2 years

21 C-485 8 years (Drs. K. Kagan-Hallet and K. M. Earle. Washington)

M

R. frontal, discrete lobulated cystic hxmorrhagic

22 C-1931 ' 4 years (Dr. H. H. Goebel. G6ttingen)

M

L. frontal, discrete (7 cm)

PM/451/47

Homer Wright rosettes

Ganglionic differentialion

-+-

0

Argyrophilia of tumour cell processes Numerous delicate neurofibrils

Desmoplastic features

Subgroup

Focal; intense in cyst walls

Early transitional

D (autopsy)

Slight; peri lobular and perivascular

Transitional

Rafter 1 year D (autopsy)

Focal; perilobular and meningeal

Transitional CO

3$ years

19

Recurrences (R) melastases (M) alive (A) or dead(D)

D (autopsy)

Slight; inter- and perilobular only

Transitional

Marked focally (inter- and perilobular; perivascular)

Transitional

Positive silver processes Marked focally (inter- and perilobular; perivascular)

Transitional

D (no autopsy)

D (autopsy)

4-

0

A

0

0

Focal; occasionally marked

Not known

R after 8 months, with 'dural' M. Lost to follow-up

-f

0

None in some areas; marked in others

2 years

Massive R after 15, 22 and 24 months D (autopsy: multiple cerebrospinal and extraneural M)

+

0

Positive silver processes Progressively increased in recurrences, with secondary sarcomatous change (mixed neurobtastoma and fibrosarcoma)

p X O

H m 2 Z D

Transitional

Transitional

JO

c 60

Transitional

rn

23 C-118 7 months F (Dr. J. F. Woodruff, New York)

L. frontoparietal, massive grey, partly firm

Op. death

D (autopsy)

+

+

Numerous delicate neurofibrils

Intense in more primitive areas Transitional only

24 C-1841 2 years (Dr. P. Lynch, Preston)

L. parietotemporal, partly cystic, partly firm rubbery invasive (6 x 6-5 x 5 cm)

Op. death

D (autopsy)

0

+

Uni-. bi- and multipolar neuroblasts

Highly variable; often perilobular and intercellular

25 C-1519 35 years M (Dr. H. W. Huntington, San Antonio, Texas; Dr. J. Gallucci, Portland, Ore.)

R. frontotemporal, discrete. superficial

IJ years

A

0

-+•

Positive silver processes None in some areas; marked in others

26 C-1859 2 years (Dr. J. D. Wilkcs, Las Vegas. Nev.)

R. frontoparietal, discrete cystic (4 cm)

I year

A

F

F

Intense, but stiil perilobular

Z -i

Transitional

Transitional

Desmoplastic

Desmoplastic

27 C-500 2j years (Dr. A. A. Miller. Preston)

R. parietal, discrete firm Iobulated(6x4x4cm; 27 g)

Op. death D (autopsy)

28 C-959 3 years (Dr. D. F. Uphoff. Hartford, Conn.)

L. frontal, discrete firm (8 cm)

3 months

D (no autopsy)

Dcsmoplastic

29 C-49 4 years F (Dr. R. L. Davis, Los Angeles; Drs. K. Kagan-Hallel and K. M. Earle, Washington: Dr. R. Hayner. Springfield, 111.)

R. parietal, discrete but invasive

Postop. death

D (no autopsy)

Desmoplustic

30 C-1843 6 years (Drs. R. J. Boubclik and R. Rcdulia, Stockton, Cal.)

R. frontotemporal. discrete cystic necrotic (6 cm)

I year

A

31 C-1771 II years (Dr. B. A. vun Ketel. Utrecht)

L. parieto-occipital, discrete. firm lobular cystic (15 cm)

11 years

A

32 C-1865 4 months (Drs. M. A. Hcrrcll and J. A. Robertson, Evansville, Ind.)

L. frontotemporal, discrete firm lobular, partly cystic ( 8 x 8 x 5 cm)

33 C-87 9 months M (Dr. A. A. Miller, Preston; Dr. A. M. Gregory and Mr. G. K. Tutton, Lancaster)

R. frontoparietal, discrete firm lobulated cystic ( 6 x 4 x 3 cm; 30 g)

34 C-2021 10 months M (Dr. S. Dachs, Great Kails, Mon.)

L. parietal, firm lobular cystic

5 months A

R posterior parietal, cyst ( 9 x 9 cm) with very firm superficial gritty mural nodule occupying cortex

Op. death

35

C-1286

II months

M

M

3 weeks D (autopsy) (inoperable; biopsy only) 13 years

+

0

Positive silver processes Intense

Intense, but still perilobular

0

0

0

0

0

Positive silver processes Intense

Desmoplastic

Desmoplastic

Intense (predominantly leptomeningeal growth)

Desmoplastic

0

Positive silver processes Intense (predominantly leptomeningeal growth)

Desmoplastic

0

0

Positive silver processes Intense (predominantly leptomeningeal growth)

Desmoplaslic

0

+

Numerous axonal processes

Desmoplastic

A

o m 7)

m

z

m C 70

D (autopsy)

Intense (predominantly leptomeningeal growth)

O CD

r >

H

o

740

B. C. HORTEN AND L. J. RUBINSTEIN

The following clinical and pathological features emerge from the data in the Table. Age. Thirty of the 35 patients (85 per cent) presented with symptoms of an intracranial tumour in the first decade of life, 23 (65 per cent) occurring in the first half. Six patients had the onset of symptoms under the age of 12 months. Sex. The sex ratio was 20 males to 15 females. Site. The frontal lobe was involved in 21 cases, the parietal in 16, the temporal in 8 and the occipital in 3. In 14 patients, the right hemisphere was involved, in 20 the left. In one case, the tumour was mid-line. Gross features. These were remarkably similar from case to case. The tumour was often very large (up to 15 cm in diameter), with an average diameter of 6-7 cm in 17 cases. It was discrete and well circumscribed in at least 20 cases (figs. 1 and 19), so that it often appeared to shell out from the surrounding brain at operation (fig. 15). It wasfirmon palpation in at least 10 cases, an observation that correlated well with some of the histological features described below. The cut surfaces were often homogeneous and grey-white. The tumour was cystic in 16 cases, the cysts being often responsible for its large size: in such cases, a large cavity was often uncovered at operation: it revealed one or more discrete firm mural nodules, or occasionally communicated with a ventricle. The tumour also was often lobular, with foci of haemorrhage and necrosis. Histological features. The tumours were always highly cellular, but both the histological pattern and the cytological features showed considerable variation both within the group as a whole and, frequently, in a particular case. A preliminary survey of the entire material led to its subdivision into three main groups, which were, however, not clear cut and were often bridged by transitional examples and by transitional fields. The main criterion for distinction was the degree and extent of the fibrous connective tissue stroma, which was a notable feature, either FIG. 1. (Case 13.) Massive tumour with well-circumscribed margins in the right parieto-temporo-occipital region of a 4-year-old girl. FIG. 2. (Case 13.) Conspicuous Homer Wright rosettes in the meningeal extensions of an 'early transitional' variant of neuroblastoma. Hsmatoxylin and eosin. x 225. FIG. 3. (Case 13.) Proliferation of fibrous connective tissue restricted to that portion of tumour which invades the leptomeninges. Hsmatoxylin and eosin. x225. FIG. 4. (Case 14.) Fibrous connective tissue confined to blood vessel walls in an 'early transitional' variant of neuroblastoma. Gordon-Sweets' silver method for reticulin. x225. FIG. 5. (Case 14.) Abundant fibrous connective tissue in the cyst wall of an 'early transitional' variant of neuroblastoma. Gordon-Sweets' silver method for reticulin. x225. FIG. 6. (Case 14.) Numerous delicate randomly orientated neurofibrils in an 'early transitional' variant of neuroblastoma. Paraffin adaptation of Bielschowsky's silver impregnation, x 225.

CEREBRAL NEUROBLASTOMA

FIG.

FIG.

1

741

Fie;. 4

FIG.

2

5

*9*JjZ*

• •

*^&V FIG.

3

FIG.

6

•

B. C. HORTEN AND L. J. RUBINSTEIN

hlC. 8

FIG.

FIG. 9

FIG.

12

CEREBRAL NEUROBLASTOMA

743

throughout or in places, in 23 tumours (approximately two-thirds of the material). By analogy with the previous study by one of us on the fibrous tissue component of cerebellar medulloblastomas (Rubinstein and Northfield, 1964), these cases were divided into 'classical,' 'transitional' and 'desmoplastic' The 'classical' subgroup, which was characterized by the presence of an only scant connective tissue stroma limited to the blood vessel walls, had the closest affinity with the well-known equivalent tumours in the peripheral nervous system, namely the peripheral neuroblastomas, or sympathicoblastomas. Approximately one-third of our material (12 cases) belonged to this variant. In this group, the tumour cells were characteristically small, round or slightly oval, and had darkly staining nuclei. Homer Wright rosettes (fig. 7) were frequently demonstrable (in 11 out of 12 cases). Although not encapsulated, this variant often showed a relatively abrupt transition into the adjacent brain. In some areas, however, more diffuse microscopical invasion was demonstrable. Half the cases showed focal differentiation to more mature ganglion cells (fig. 13). The latter were never a major component of the neoplasm. The 'transitional' subgroup accounted for approximately another third of the material (13 cases). In most examples, the tumour showed variable degrees of lobulation, which, in the most extreme cases, blended with the desmoplastic subgroup to be described below (figs. 20 and 21). These cases were characterized by variable amounts of fibrous connective tissue, which was often restricted either to the locally invaded leptomeninges (fig. 3), or to focal increases that divided the tumour into a lobular pattern and often appeared to extend from the blood vessel walls (figs. 4 and 5). While all degrees of transition were seen to lead to the intensely desmoplastic variant, the fibrous tissue on the whole remained restricted to an inter- and perilobular pattern. In 2 cases (Cases 21 and 25), the same tumour showed the juxtaposition of both the classical and the desmoplastic variants of neuroblastoma. In one case (Case 23), the fibrous connective tissue was associated only with the areas composed of neuroblasts and became progressively less intense FIG. 7. (Case 5.) Small uniform round to oval cells arranged in Homer Wright rosettes in a 'classical' variant of neuroblastoma. Hsmatoxylin and eosin. x 225. FIG. 8. (Case 35.) Small undifferentiated neuroblasts arranged in clusters in a 'desmoplastic' variant of neuroblastoma. Hasmatoxylin and eosin. x 225. FIG. 9. (Case 35.) Nests of mature ganglion cells in a 'desmoplastic' variant of neuroblastoma. Bielschowsky's silver impregnation, x 225. FIG. 10. (Case 35.) Irregularly orientated leashes of axonal processes streaming from the cytoplasm of tumour cells. Bielschowsky's silver impregnation, x 225. FIG. 11. (Case 35.) Dense fibrous network within a 'desmoplastic' variant of neuroblastoma. Gordon-Sweets' silver method for reticulin. x 120. FIG. 12. (Case 35.) Islands of reactive neuroglia along the margin of a 'desmoplastic' variant of neuroblastoma. Hsmatoxylin and eosin. x 90.

744

B. C. HORTEN AND L. J. RUBINSTEIN

in the areas of ganglionic maturation. In one example (Case 22), desmoplasia became conspicuous in the recurrences only (fig. 22), resulting in a secondary sarcomatous change, with the development of a mixed neuroblastoma and fibrosarcoma (fig. 23). In this group, the tumour cells were often larger than in the classical variant, and demonstrated vesicular nuclei, conspicuous central nucleoli and polar cytoplasmic extensions. The latter were, in some cases, directed towards the blood vessels, or towards other cells with the formation of Homer Wright rosettes. Such rosettes were conspicuous in the meningeal extensions in one case (fig. 2); however, their incidence as a whole was not as constant as in the classical variant. Differentiation towards mature ganglion cells was also less frequent. The third, or 'desmoplastic,' variant (10 cases) was characterized by the presence of an intensely compact fibrous connective tissue network throughout most or all of the tumour. This microscopical picture almost invariably corresponded to the very firm lobular growths identified grossly. In some examples, the perilobular distribution of the connective tissue could still be made out, but in most it had become so abundant as almost to surround individual tumour cells. Occasionally, a parallel streaming arrangement of fibres was found (fig. 17). In addition, the connective tissue was especially intense when the tumour occupied the leptomeninges, being in such cases equal only to that found in some examples of desmoplastic medulloblastoma. Among this stroma, the tumour cells were frequently arranged in clusters (fig. 8), streams (fig. 16), solid cords or short trabeculae. They otherwise resembled those in the transitional group in that they were larger than in the classical variant, with a pale vesiculated nucleoplasm, delicate nuclear membranes and often small conspicuous nucleoli. Their cytoplasm was usually very indistinct. They did not demonstrate any PTAH-positive fibrils. Homer Wright rosettes were less often demonstrable than in the transitional and especially the classical variants, and only one example showed differentiation to mature ganglion cells (fig. 9). In several cases in this group, the surrounding brain showed a marked hypertrophic astrocytic gliosis, and in some examples the edges of the highly fibrous tumour encompassed distinct islands of hypertrophic astrocytes (fig. 12). Of particular interest in this variant was a small subgroup of 4 cases (Cases 32-35) in which the intense desmoplasia was associated with a direction in the growth of the tumour which was predominantly within the leptomeninges (fig. 11). Thus most of the neoplasm was actually extracerebral, although more diffuse focal invasion of the brain was demonstrable histologically. All these 4 cases originated in patients under the age of 12 months. Specific silver impregnations. In addition to the 10 cases in the entire material with foci of clear-cut ganglionic differentiation, the neuroblastic nature of the tumour cells in the non-differentiating examples was established by specific silver impregnation for axons and neurofibrils in seven tumours, which included three

CEREBRAL NEUROBLASTOMA

745

transitional (fig. 6) and four desmoplastic examples (figs. 10 and 18). In all but 2 cases, this could be established solely in frozen sections, which were available in only a relatively small number of examples; however, positive argyrophilia was established in all those in which such preparations were obtained. The intensely positive affinity of axons and neurofibrils usually made their distinction quite easy from the reticulin fibre network, which stained various shades of brown in these preparations. Metastases. Metastatic spread in the cerebrospinal pathways, manifested either as leptomeningeal or ventricular implants, or both, developed in 8 (38 per cent) of the 21 deceased patients. The incidence is probably an underestimate, since 8 of the latter had no autopsy. One patient had had no operation, thus demonstrating the ability of the tumour to disseminate spontaneously through the cerebrospinal axis. Among the other 7 cases, one (Case 22) developed, in addition, extraneural metastases. Biochemical data. Serum catecholamine levels were investigated in one patient (Case 1): they were not raised in this instance. No data are available on the catecholamine concentrations in any of the tumours themselves. Survival. Of the 33 patients available to follow-up, 5 had either no operation or at most a diagnostic biopsy or a ventricular shunting procedure: they all died during or shortly after admission to hospital. Of the other 28 patients in whom the tumour was either partly or totally excised, 16 (57 per cent) died, either during or shortly after operation (6 cases), or from three months to ten years afterwards (10 cases). There is a wide scatter in the post-operative survival range. Twelve patients (43 per cent) are alive at this time, from five months to thirteen years after operation, but of these, only 4 so far have been followed up for three years or more. In view of the high incidence of recurrence {see below) even after several years, their prognosis remains uncertain. Noteworthy, however, is Case 33, who had a tumour removed at the age of 9 months and who is known to be alive and well thirteen years later. Recurrence. Nine (40 per cent) of the 22 patients who survived initial operation had a recurrence of tumour over a period spanning from six months to seven years after excision; of these 9 patients, only one is known to be still alive. Two patients developed a recurrence after five years or longer, pointing to the need for caution in the interpretation of surgical cures. Treatment. Radiation directed to the whole brain, to the specific tumour site, and/or the entire neuraxis was given post-operatively in at least 12 cases. The follow-up figures are too small at this time to evaluate the results of radiation. We have a record of cancer chemotherapy in only one patient (Case 16).

746

B. C. HORTEN AND L. J. RUBINSTEIN CASE

REPORTS

Case 5. A 9-year-old girl had one generalized seizure. At craniotomy, a small discrete right parietooccipital mass, 2-5 cm in diameter, was totally excised. No post-operative radiation was given. She remained well for two years, when she developed headache, vomiting and bilateral papillcedema. Brain scan and arteriography showed recurrence of the tumour. At operation, a large, grey-white, globoid, well-circumscribed right parieto-occipital mass measuring 4 x 3 x 3 cm was found, extending medially to the falx and inferiorly to the tentorium. Following apparent total removal, she was left with a visual field defect. 4 040 rads of CO 60 were delivered to the tumour site. She has remained well over the past five years without clinical evidence of tumour recurrence. Microscopically, the tumour was composed of small uniform round or oval cells often arranged in Homer Wright rosettes (fig. 7). Mitotic figures were frequent. The tumour was well defined in places; elsewhere, the adjacent cortical parenchyma showed discrete invasion. Connective tissue was confined to the blood vessel walls.

This case is representative of the classical variant of cerebral neuroblastoma without ganglionic differentiation. The long post-operative survival, despite the recurrence, is noteworthy. Case 9. A 5-year-old boy with headaches and vomiting was found at operation to have a large left frontoparietal cyst containing a highly vascular mural nodule. The nodule was excised, but the cyst was left intact. Three years later, vision began to deteriorate in the left eye. Five years after the operation, he once more developed headaches. At re-exploration, a large tumour was found along the roof of the third ventricle, surrounded by ten cysts containing more than 80 ml of yellow fluid which clotted on exposure to air. He died one month later. At autopsy, a cavity, 11 cm in diameter, communicating directly with the left lateral ventricle, replaced the left frontoparietal lobe. The walls of the cavity and the lateral ventricles were studded by small grey tumour nodules, each approximately 0-5 cm in diameter. More tumour replaced the hypothalamus. Microscopically, the material from the two surgical resections and from the autopsy specimen were similar. The cells were small, uniform and spherical, arranged in broad lobules in an abundant delicate neuropil, and included clusters of mature ganglion cells (fig. 13). A silver carbonate impregnation on frozen material showed many uni-, bi- and occasional multipolar neuroblasts with long neuritic extensions (fig. 14). Focal calcification was present in the tumour margins. Connective tissue was confined to the blood vessel walls.

FIG. 13. (Case 9.) Mature ganglion cells and immature neuroblasts in a 'classical' differentiating variant of neuroblastoma. Hxmatoxylin and eosin. x225. FIG. 14. (Case 9.) Uni-, bi-, and multipolar neuroblasts with long neuritic extensions in a 'classical' differentiating variant of neuroblastoma. Silver carbonate impregnation, x 225. FIG. 15. (Case 31.) Cut surfaces of two firm, discrete, lobular tumour masses, each 5 cm in diameter, resected from the left parieto-occipital region of an 11-year-old boy. FIG. 16. (Case 31.) Spindle cells with vesicular nuclei and occasional mitotic figures. Iron-hsmatoxylin-van Gieson stain. x360. FIG. 17. (Case 31.) Tumour cells arranged in palisades with intervening bands of fibrous connective tissue. Gordon-Sweets' silver method for reticulin. x 120. FIG. 18. (Case 31.) Delicate leashes of axonal processes emerging from the cytoplasm of tumour cells. Bielschowsky's silver impregnation, x 480.

747

CEREBRAL NEUROBLASTOMA

o

•

^.»«

a •-. >

16

lie, 13

FIG.

Kio. 14

Fie; 17

FIG.

15 FIG.

18

B. C. HORTEN AND L. J. RUBINSTEIN

748

FIG.

19 FIG.

22

20

FIG.

23

FIG. 21

FIG.

24

FIG.

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This case illustrates the classical variant of cerebral neuroblastoma with ganglionic differentiation. It also demonstrates late tumour recurrence, with the ultimate development of multiple ventricular metastases. Case 10. A 9-year-old girl developed sudden nausea and vomiting. A large left frontal tumour was excised, and she was given post-operative radiation. She remained well for seven years, after which time tumour recurrence required two further craniotomies. Nine years after the first operation, a fourth craniotomy uncovered a chronic streptococcal meningitis. She died one and a half years later, that is, ten years after the initial onset of symptoms. At autopsy, a left frontal lobe cyst, measuring 4 x 4 x 3 cm, was found to communicate with the left anterior horn. Numerous grey tumour implants, 0-5-1-5 cm in diameter, studded the walls of the lateral, third and fourth ventricles. Microscopically, the features were those of the classical variant of cerebral neuroblastoma with ganglionic differentiation, closely similar with those of the preceding case.

This case again illustrates an interval of many years between the initial surgical resection and tumour recurrence, as well as the protracted duration of the over-all clinical course. Case 16. A 2-year-old male with seizures and a dilated left pupil was found by angiography to have a large left frontal avascular mass. A large intracerebral haematoma was evacuated. Three weeks later, the child presented with mild right hemiparesis and re-exploration revealed a large necrotic, haemorrhagic, cystic tumour of the left frontal lobe. Post-operative radiation therapy included 4000 rads to the entire brain and 2 000 rads to the frontal areas. The child was then given cyclophosphamide (75 mg/ day). Thirteen months later additional tumour was resected from the previous operation site. The child died one month thereafter. Autopsy revealed a massive, well-circumscribed bifrontal recurrence of growth (fig. 19). Microscopically the histological features ranged from a predominant classical pattern to foci of spindle cells with desmoplasia, primarily in a perilobular and leptomeningeal distribution (fig. 20). On occasion the lobules delineated by the reactive stroma were further subdivided into small cell clusters by an intense desmoplastic response (fig. 21).

This case illustrates the transitional variant of cerebral neuroblastoma. Case 22. A 4-year-old boy presented with listlessness, vomiting, slurred speech, a mild right facial palsy, hypotonia of the right leg and bilateral papilloedema. A large, sharply demarcated left frontal

FIG. 19. (Case 16.) Massive, well-circumscribed bifrontal tumour in a 2-year-old boy. FIG. 20. (Case 16.) Diverse histological patterns of 'transitional' variant of neuroblastoma. Broad sheets of tumour (in upper half) alternate with tumour lobules (in lower half). Hsematoxylin and eosin. x90. FIG. 21. (Case 16.) Same field as fig. 20. Variable distribution of fibrous connective tissue. Gordon-Sweets' silver method for reticulin. x 90. FIG. 22. (Case 22.) Dense reticulin fibre network in the first recurrence of a 'transitional' variant of neuroblastoma. Gordon-Sweets' method for reticulin. x 300. FIG. 23. (Case 22.) Nests of ovoid tumour cells separated by a broad cellular band of thin streaming fibroblasts in the second recurrence of a 'transitional' variant of neuroblastoma. Haematoxylin and eosin. x225. FIG. 24. (Case 22.) Homer Wright rosettes in the subarachnoid tumour deposits of a 'transitional' variant of neuroblastoma. Hjematoxylin and eosin. x225.

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tumour extending from the falx to the lateral ventricle was resected, followed by 5 000 rads directed to the operative site. Fifteen months later, craniotomy revealed a sharply demarcated, spherical, left frontal periventricular tumour recurrence, measuring 5 x 6 cm in diameter and weighing 75 g. Seven months later, a second left frontal recurrence invading the falx and the dura of the convexity, measuring 7 x 5 x 4 cm and weighing 60 g, was again excised. The child continued to deteriorate after operation and died two months later. At autopsy, tumour replaced the left frontal lobe and extended medially and posteriorly to involve the right frontal lobe, the basal ganglia and both temporal and occipital lobes. Many subarachnoid tumour nodules were scattered over the cerebral convexities and spinal cord. Tumour also invaded the superior sagittal sinus and occupied the vertebral bodies. One metastatic deposit was found in the liver. Microscopically, the histological features varied considerably throughout the two-year evolution of this case. The tumour originally resected showed the picture of the classical variant of cerebral neuroblastoma. Rosettes were frequent, and connective tissue was confined to the blood vessel walls. The tumour at the first recurrence was composed mostly of spindle cells in a dense reticulin fibre network, now recalling the desmoplastic variety (fig. 22). This was recapitulated in the second recurrence, in which much of the tumour was formed by broad sheets of hyalinized fibrous tissue. In addition, spheroidal to plump ovoid tumour cells devoid of reticulin were grouped in small clear-cut nests separated by broad cellular bands of thin streaming fibroblasts (fig. 23) which contained many mitotic figures. Proliferating blood vessels were intimately related to the latter cells, which appeared to extend outwards from the vascular walls. At autopsy, the residual frontal lobe tumour was largely necrotic. The subarachnoid deposits were a mixture of the classical and desmoplastic variants, with sheets of simple spheroidal cells rich in Homer Wright rosettes (fig. 24) alternating with spindle cells enmeshed in dense reticulin networks. The tumour within the superior sagittal sinus and the liver metastasis both showed a mixture of neuroblastoma and fibrosarcoma cells.

This case illustrates the development, in the classical variant of cerebral neuroblastoma, of a sarcomatous transformation occurring at the time of recurrence in the mesenchymal stromatous component of the tumour, presumably originating from the hyperplastic blood vessel walls. It also illustrates the development of distant metastases, both in the cerebrospinal pathways and outside the central neuraxis. Case 31. An 11-year-old boy with a six-month history of headache and vomiting had a right hyperreflexia and bilateral papilloedema. At craniotomy, three firm, well-demarcated but interconnected tumour masses, each 5 cm in diameter, were resected from the left parieto-occipital lobe: each mass was very firm, lobular and focally cystic, with gross necrosis (fig. 15). Apart from a mild residual hemiparesis and dysphasia, the child is alive and well eighteen months later, without clinical evidence of tumour recurrence. Microscopically, much of the tumour consisted of hyalinized, poorly cellular fibrous connective tissue. Adjacent areas were highly cellular and coarsely lobular, composed of spindle cells with vesicular nuclei and arranged in streams or palisades (fig. 16) separated by dense bands of fibrous connective tissue (fig. 17). Large numbers of delicate randomly orientated axonal processes, often traceable to the tumour cell bodies, were demonstrated with the Bielschowsky silver impregnation (fig. 18). These processes were easily distinguishable from the abundant reticulin fibre network. •

This case illustrates the desmoplastic variant of cerebral neuroblastoma without ganglionic differentiation. Case 35. An 11-month-old male infant presented with a suspected right subdural haematoma. Craniotomy revealed a massive cystic tumour, but the child died during operation. Autopsy disclosed

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a right posterior parietal cyst, 9 cm in diameter, with a firm white-grey superficial mural nodule apparently replacing the cortex and measuring 2x1-5 cm. Microscopically, the tumour showed cell clusters (fig. 8) ranging from small undifferentiated, round and spindle-shaped cells to mature ganglion cells (fig. 9), all of which were surrounded by a dense fibrous network (fig. 11). Bielschowsky silver impregnations revealed leashes of axonal processes (fig. 10) sometimes streaming from the cytoplasm of the less differentiated cells. Mature ganglion cells demonstrated two to four broad silver-positive cytoplasmic processes. The tumour cyst wall was formed by a thin band of spherical and spindle tumour cells intermixed with abundant connective tissue. The margin of the tumour, which seemed to occupy mostly the leptomeninges (fig. 11), was usually well demarcated, but in a few places tumour cells invaded the cortical parenchyma. In some areas, the tumour encompassed conspicuous islands of reactive neuroglia (fig. 12).

This case illustrates the desmoplastic variant of cerebral neuroblastoma with ganglionic differentiation and with a direction of growth which is largely leptomeningeal. The case previously reported by Miller and Ramsden (1966) (Case 33) also belongs to this subgroup.

DISCUSSION

The primary cerebral neuroblastoma is a very rare tumour which, on a general estimate, might be encountered no more than once in ten years in the average clinical or pathological practice. Although it may on occasion be found in older age groups, it is predominantly a tumour of early childhood, more than half the cases arising within the first five years of life. Histological Criteria The criteria which define this tumour as a specific entity derive from a survey of the present series and from the few similar cases individually reported in the past. These criteria fall into two broad categories. First are those that are concerned with the identification of the individual tumour cells themselves. Because the cerebral neuroblastoma is densely cellular and composed of primitive cells arranged in variable histological patterns, it is not surprising that precise recognition of the tumour cells by means of standard histological techniques is often difficult. None the less, three criteria have proved useful in the present survey. (1) Distinctive Homer Wright rosettes, present in 24 cases, served to align the cerebral tumours with the peripheral neuroblastoma, in which these rosettes were first described. (2) Maturation to ganglion cells, although generally uncommon (10 cases), was evident in 50 per cent of the cases in the classical variant, but much less frequent in the transitional and desmoplastic forms. (3) With silver impregnation techniques neuroblastic cell forms were demonstrable in poorly differentiated areas in 7 cases. In frozen sections, neuroblasts are, in our experience, always demonstrable; paraffin adaptations are less successful. Access to wet tissue for frozen sections is therefore a limiting factor in the unequivocal diagnosis of the more primitive tumours. The demonstration of argyrophilic cell processes in

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some of the transitional and desmoplastic cases in the present survey considerably reinforces the inclusion of these otherwise puzzling examples among the cerebral neuroblastomas. Secondly, there are three additional general histological features that collectively separate the cerebral neuroblastomas from the other central neuro-epithelial tumours of childhood: (1) the growths are characteristically circumscribed; (2) they often evoke an intense stromal response; and (3) particularly along the margins of the desmoplastic variants, a conspicuous hypertrophic astrocytic glial reaction is often present. Stromal Response The striking connective tissue reaction has some features in common with that seen in the desmoplastic cerebellar medulloblastoma, in that (1) an intense fibrous tissue proliferation is elicited when the meninges are infiltrated, and (2) the tumour may sometimes be largely extracerebral, its origin being restricted to a small area only of the parenchyma, as in the last 4 cases of this series. The distribution and the intensity of the stromal response cannot, however, be ascribed solely to leptomeningeal infiltration. In some cases it is secondary to necrosis, in others it is confined to the walls of cysts. In both these instances the proliferation of blood vessels probably underlies the fibrous response. Most frequently, however, the fibrous tissue proliferation in cerebral neuroblastoma seems to be associated with the partitioning of the tumour cells into small discrete lobules. As the desmoplastic stroma increases, the lobules are further subdivided into still smaller clusters. On occasion, the connective tissue may be arranged in streams closely adjacent to undifferentiated cells, suggesting that highly primitive neuronal cells may have an unusual capacity for stroma-induction. Review of the Literature Using the above cellular and general histological criteria, we would accept the following 12 cases from the literature as authentic examples of primary cerebral neuroblastoma. Those without ganglionic differentiation include Bailey's case (1927) in a 37-year-old male with a right cerebral hemispheric mass (originally reported as a cerebral medulloblastoma), Vuia's (1967) example in a 48-year-old male with a right temporal mass, and Case 7 of Feigin and Budzilovich (1974) in a 12-year-old male with a right frontotemporal tumour. The differentiating cerebral neuroblastomas include a 16-year-old female with a left temporoparietal mass (Kernohan, Learmonth and Doyle, 1932, Case 1), a 13-year-old female with a mass in the floor of the third ventricle (Doyle and Kernohan, 1931; Kernohan et al, 1932, Case 4), a 31-year-old male with a right parietal mass (Liss, 1960), a 2-year-old female with a right parietal, largely meningeal, tumour (Jellinger, Minauf and Brenner, 1970), a 7-year-old male with a spontaneously metastasizing left frontoparietal neoplasm (Henriquez, Robertson and Marshall, 1973), a

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4-year-old female with a left parieto-occipital mass (Feigin and Budzilovich, 1974), a 25-year-old female with a right frontal tumour (Pearson, Milstoc, Harris, Budzilovich and Feigin, 1976, Case 2), a 60-year-old male with a left frontal mass (Pearson et al, 1976, Case 4) and a 12-year-old female with a right temporal mass (Pearson et al, 1976, Case 5). Of particular interest are the examples of Kernohan et al. (1932, Case 1) and of Liss (1960), in each of which ganglionic maturation of. the tumour cells occurred after a prolonged clinical course. Differential Diagnoses

The cerebral neuroblastoma often appears to be confused with other tumours. The classical variety is sometimes mistaken, in our experience, for an oligodendroglioma or an ependymoma. It is our impression that many supratentorial tumours in children interpreted as cerebral ependymomas may in fact be neuroblastomas. The distinction between Homer Wright and ependymal rosettes may create additional confusion, as for example in a recent report of 3 ostensible cerebral neuroblastomas, 2 of which are illustrated as containing ependymal rosettes (Escalona-Zapata, 1972). In general, however, the classical form of cerebral neuroblastoma resembles the well-known peripheral tumours sufficiently closely to give rise to only minimal diagnostic difficulty. The transitional and desmoplastic variants, on the other hand, can easily be interpreted as forms of sarcoma, especially of the polymorphic type. A reticulin preparation, however, will display in sarcomas a uniform network of reticulin throughout the tumour, whereas in neuroblastomas small islands of cells free of reticulin will be evident. Failing this, a careful examination of the tumour for small foci of ganglionic differentiation may help in the diagnosis. Optimally, a positive Bielschowsky silver impregnation on frozen material is essential to establish it. Biological Behaviour

As our survey of the present material indicates, these tumours, by virtue of their high recurrence rate and their frequent tendency to metastasize, behave as highly malignant neuro-epithelial neoplasms. Our Case 22 exemplifies the development of both intra- and extraneural metastases, as previously described by others in another case (Henriquez et al, 1973), in which it occurred in the absence of previous operation. In addition, the evolution of Case 22, in which a sarcomatous change developed in the reactive stroma of a desmoplastic neuroblastoma, is analogous to the mixed gliomas and sarcomas described by Feigin and Gross (1955) and by Rubinstein (1956), and presumably occurred through a similar mechanism of secondary neoplastic induction. The extraneural extension of this neuroblastoma-sarcoma via the superior sagittal sinus, follows a pathway that has previously been recorded in a spontaneously metastasizing malignant astrocytoma (Rubinstein, 1967).

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Treatment and Prognosis

The present series is too small and the data too recent to provide definitive information on prognosis or the effects of treatment. Caution is especially needed in view of the demonstration of late recurrences in 2 of our cases. Histological criteria, such as the presence or absence of ganglionic differentiation, or a classical or desmoplastic stromal pattern, do not offer reliable indicators of future tumour growth. Long-term follow-up studies of more cases are needed to clarify further the biological evolution of these rare tumours. However, in some aspects of their clinical and pathological behaviour, including the occasional long survival recorded in the desmoplastic variant, they recall the picture of the cerebellar medulloblastoma before the days of total craniospinal radiation therapy. By analogy with the medulloblastoma, it is suggested that vigorous radiation of the entire neuraxis should be considered for these tumours. SUMMARY

A series of 35 primary cerebral neuroblastomas is reported. These rare tumours occur most often in children in thefirsthalf of thefirstdecade. Grossly the tumours are often massive, discrete, lobular, firm and cystic. Histologically three variants, largely determined by the extent and distribution of the fibrous connective tissue stroma, are recognized: (1) a classical variant, which most resembles the peripheral neuroblastoma and is characterized by a high frequency of Homer Wright rosettes and a relatively high frequency of ganglionic differentiation; (2) a desmoplastic variant, which is characterized by an intense connective tissue stroma; and (3) a transitional variant, in which both the classical, and the desmoplastic features may be present within the same case, either concurrently or consecutively. Both the desmoplastic and the transitional forms are less likely to exhibit differentiation to mature ganglion cells, but the importance of identifying the primitive cell elements as neuroblasts is emphasized. With rare exceptions, this can be established only by specific silver impregnations on frozen material. Occasionally the direction of growth may be largely leptomeningeal. Seven illustrative clinical histories with pathological correlations are described. The over-all clinical behaviour of these tumours is that of malignant neuroepithelial neoplasms, characterized by a high recurrence rate. Recurrence may, however, be a late development, in some cases occurring five or seven years after apparently successful surgical removal. The tumour shows a high incidence of metastatic spread, almost 40 per cent of the cases examined at autopsy having disseminated in the cerebrospinal pathways. Exceptionally, extraneural metastases may also develop. However, long post-operative survival occasionally occurs, and the subsequent clinical course is not always predictable in the individual case. The differential diagnosis is briefly discussed. The cellular nature of the tumour and its biological behaviour recall those of the cerebellar medulloblastoma. Postoperative radiation to the entire neuraxis should be considered for these neoplasms.

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ACKNOWLEDGEMENTS This work was supported in part by Graduate Neuropathology Training Grant 5 T01 NS05500-10 from the National Institute of Neurological and Communicative Diseases and Stroke, US Public Health Service. We thank physicians named in Table 1 for kindly referring consultative material to us or providing us with clinical information, and for allowing us to publish their cases. The late Miss Carol Ineson performed the silver impregnations.

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Fortschritte auf dem Gebiet der Neurochirurgie. Edited by K.-A. Bushe. Stuttgart: Hippokrates Verlag, pp. 276-282. KERNOHAN, J. W., LEARMONTH, J. R., and DOYLE, J. B. (1932) Neuroblastomas and gangliocytomas of

the central nervous system. Brain, 55, 287-310. Liss, L. (1960) Neuroblastoma (malignant gangliocytoma) of the parietal lobe. Journal of Neurosurgery, 17, 529-536. MILLER, A. A., and RAMSDEN, F. (1966) A cerebral neuroblastoma with unusual fibrous tissue reaction. Journal of Neuropathology and Experimental Neurology, 25, 328-340. PEARSON, J., MILSTOC, M., HARRIS, J., BUDZILOVICH, G., and FEIGIN, I. (1976) Anaplastic neuronal

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RUBINSTEIN, L. J. (1975) The cerebellar medulloblastoma: its origin, differentiation, morphological variants, and biological behavior. In: Handbook of Clinical Neurology. XVIII. Tumours of the Brain and Skull. Part HI. Edited by P. J. Vinken and G. W. Bruyn. Amsterdam: NorthHolland, pp. 167-193. and NORTHFIELD, D. W. C. (1964) The medulloblastoma and the so-called 'arachnoidal cerebellar sarcoma.' A critical re-examination of a nosological problem. Brain, 87, 379-412. RUSSELL, D. S., and RUBINSTEIN, L. J. (1971) Pathology of Tumours of the Nervous System. Third Edition. London: Edward Arnold, p. 191. (1977) Pathology of Tumours of the Nervous System. Fourth edition. London: Edward Arnold. In press. VUIA, O. (1967) Neuroblastoma de emisfera cerebrala la adult. Studii si Cercetari de Neurologie, 12, 303-310. WILLIS, R. A. (1967) Pathology of Tumours. Fourth Edition. London: Butterworths, p. 857. ZULCH, K. J. (1971) Atlas of the Histology of Brain Tumors. Berlin: Springer-Verlag.

(Received May 4, 1976)