VERHOEFF: Tumorfrom Pars Ciliaris Retina. As already stated, I have used the method as an ...

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VERHOEFF: Tumorfrom Pars Ciliaris Retina. 35I
As already stated, I have used the method as an accessory
measure of suggestion without hypnosis in case of chalazion
and other minor surgical operations, and it was attended by satis-
factory results. It is not improbable that with a certain class of
patients this method of fixation may for this reason do much to
insure quiet submission for the short period necessary, if the
mental attitude of the patient and operator and the surroundings
will to make it so.
Dr) St. John's favorable report with this method of fixation
confirms my own experience. In deep-set eyes with overhanging
orbital margin it should not be practiced. Convinced by my own
experience of the usefulness and advantage of this modification
of fixation I have had but one desire, and this to bring it to a more
general notice of the society and have it put to the test in suitable
cases.
A RARE TUMOR ARISING FROM THE PARS CILIARIS
RETINIE (TERATO-NEUROMA), OF A NATURE
HITHERTO UNRECOGNIZED, AND ITS RELATION
TO THE SO-CALLED GLIOMA RETINA,.*
By F. H. VERHOEFF, A.M., M.D.
(From the PathologicalLaboratory ofthe Massachusetts Charitable Eye and Ear
Infirmary.)
Badal (i) and Lagrange, in I892, gave a description of a
tumor arising from the pars ciliaris retinae, which they regarded
as an adenocarcinoma. Four years ago Emanuel (2) reported
from Leber's clinic a case similar in almost every respect, but he
took the view that in both cases the growths were gliomata. The
writer has recently met with a third case of the kind, which pre-
sents a number of important features that either did not occur in
the other two, or, as seems more likely, were overlooked. The
findings in this case seem to be absolutely unique, and not only to
demonstrate beyond question the real character of these three
tumors, btit to indicate the nature of the whole class of tumors
ordinarily referred to as gliomata retinae. The case is as fol-
lows:
Annie C., white, aged 2V/2 years, admitted to the Carney Hospital March
I4, I904. Family history negative in regard to tumors. Mother noticed
for the first time 3'/2 months ago that the child's right eye was more
*Read by invitation of the society.
352 VERHOEFF: Yumorfrom Pars Ciliaris Reliiw.
prominent than the left, that the pupil-was enlarged, and the eye inflamed.
The child cried often at this time and frequently vomited. The inflamma-
tioni soon disappeared, but the eye gradually became more and more promi-
nent and the child "acted as if she did niot see with it." About two
months ago the child was seen at the Massachusetts Charitable Eye and
Ear Infirmary, where the diagnosis of glioma retinae was made and
ehucleation advised. It was noted there that the lens showed cataractous
changes in the cortex.
On admission to the Carney Hospital, the right eye was muclh more
prominenit than the left and showed two bluish staphylomata in tht ciliary
region, each about the size of a bean; one situated on the nasal and the
other on the temporal side above. There was no sign of inflammation and
no pain. The cornea was perfectly clear, the pupil dilated, irregular, and
unreacting. Tension +I. The lens was completely cataractous, brilliant
white in color, and was dislocated downward and outward, the inner edge
being tilted slightly backward. A red reflex could be obtained with the
ophthalnioscope past the nasal side of the lens. No new growth could be
made out in the ciliary region, but the child was so refractory that only
a hasty examination was possible. The right eye appeared normal. The
child was well nourished, and aside from the ocular condition, apparently
healthy. On the day after admission the eye was enucleated. No signs
of a new growth could be found in the orbit.
Pathological condition. Immediately after enucleation the globe was
sectioned in a vertical plane passing 'just anterior to the ora serrata.
Diameters of globe, ant. post. 27mm., vertical 23.5mmn., horiz. 24mm.
The cornea is 11.5mm. in diameter, and at the center is only .5mm. thick.
The two staphylomata are seen to be of the intercalary type, due to a thin-
ning of the sclera between the ciliary body and cornea. Each is about
4mm. in diameter and 2mm. high, the walls being .25mm. in thickness.
The anterior chamber is I.5mm. deep, and is free from coagulum after
fixation. The pupil is 6mm. in average diameter. Hanging from the
pupillary margin above there are five small white globular bodies attached
by short delicate pedicles. The largest is .35mm. in diameter. On closer
inspection a larger number of bodies apparently of the same kind, but
much more minute, can be made out along the margin of the pupil. The
iris is adherent to the cornea for a distance of imm. from the limbus all
around. Beneath the staphlyomata it is not recognizable, probably having
undergone atrophy. At one point there is a small anterior synechia.
Arising from the ciliary body in the upper inner quadrant, there is a
white irregular growth showing numerous rounded excrescences of
various sizes, which fills the space between the ciliary body and lens,
pushing the latter aside. Many of the excrescences are similar to the
globular bodies attached to the margin of the pupil. Posteriorly the
growth nowhere extenids as far backward as the ora serrata. Anteriorly
the main body of the growth extends only a short distance beyond the
anterior margin of the ciliary body, but as a thinner layer, showing, how-
ever, here and there globutlar bodies,' it can be seen extending beneath
VERHOEFF: Tumorfrom Pars Ciliaris Retinal. 353
the staphyloma on the nasal side, and growing over the posterior surface
of the iris (Fig. I). On the temporal side the ciliary body appears to be
unaffected and there is apparently no growth beneath the staphyloma on
this side.
The lens, g7nm. x 6.5mm., is completely opaque, swollen unequally, the
nasal side being most enlarged, and is pushed over in contact with the
ciliary body at the lower outer quadrant. The vitreous body, at first per-
fectly clear, is after fixation coagulated in the form of an opaque granu-
lar mass. The sclera is not appreciably thinned except at the sites of the
staphylomata. The retina and choroid are in.situ, the optic disc is not
cupped, and the nerve is apparently normal:
I-listological examination. Fixation in Zenker's fluid. Embedding in
celloidin and paraffin. Sections were made at different levels throughout
the growth so that nothing important could escape notice. Staining in
hematoxylin and eosin, Van Giesen's stain, Weigert's elastic tissue stain,
Haidenhain's iron hematoxylin, and Mallory's connective tissue stain3.
In addition the following modifications of Mallory's method3 for staining
neuroglia were emploved:
METHOD A.
(i) Mallory's. phospho-molybdic acid hematoxylin. I5 min.-2 hrs.
(2) Wash in water.
(3) Mallory's phosphotungstic acid hematoxylin (or hematein), I h. or
longer.
(4) Wash in water.
(5) io% aqueous sol. phosphotungstic acid, II/2 hrs. or longer.
(6) Wash in water; examine on slide under microscope, and, if desired,
differentiate further according to (5) below.
(7) Acid fuchsin I2% solution, 5 min. or longer.
(8) Wash quickly in water.
(g) Alcohol 95%. Mount on-slide.
(io) Blot, and apply xylol quickly.
(ii) Blot, xylol, blot, xylol-balsam, cover glass.
METHOD B.
(I) Mallory's phospho-molybdic acid hematoxylin, 24-48 hrs.
(2) Wash in water.
(3) Mallory's phosphotungstic,acid hematoxylin (or hematein), i hr.
(4) Wash in water.
(5). Differentiate by placing sections for 5 seconds in aqueous solution of
potassium permanganate, I:2000, then in oxalic acid solution,
I: iooo, then in distilled water. Examine on slide under micro-
scope and repeat process as often as necessary. The further steps
are as in Method A, beginning with (7).
The advantage of Method A is that it not only. gives a strong stain,
but also sharp differentiation. It can be greatly shortened, and good
354 VERHOEFF: Tumorfrom Pars Ciliaris Retinae.
results still obtained, by omitting step (3). Method B is to be used chiefly
for staining cell processes. Both methods are especially successful after
fixation in Zenker's fluid.
On microscopic examination, the cornea shows nothing of importance.
The iris is considerably atrophied and below shows marked ectropion
uveac. Near its root, where it is adherent to the cornea and sclera,
it is reduced to scarcely more than a line of pigment, and beneath the
staphylomata only a trace of it remains. At one point it is adherent to the
cornea and in retracting has formed an anterior synechia. Descemet's
membrane, however, is intact at this point. The ciliary body and ciliary
processes elsewhere than in the region of the tumor show simple atrophic
changes. At the sites of the staphylomata the ciliary processes are car-
ried forward, pressed together, and incorporated in the walls of the
staphylomata. The lens presents the appearance of a traumatic cataract.
Its fibers are widely separated, especially in the cortex, and the spaces
filled with hyaline balls and granular material. "Bladder cells" are
also to be seen. There is no proliferation of the capsular epithelium, but
the latter shows degenerative changes. The choroid, retina, and optic
nerve are normal.
The main body of the new growth is attached to the surface of the
ciliary body, being supported by the greatly elongated ciliary processes and
by a certain amount of connective tissue arising from them. In the
sections it appears in the form of intricate convolutions enclosing lumina
of various shapes and sizes (Figs. 3 and 4). The structures forming
the convolutions are chiefly of two types, one type being derived by more
or less gradual transition front the other. That which is evidently the
primitive form consists of a single layer of columnar epithelium with oval
vesicular nuclei, and differs from the normal unpigmented epithelium of
the ciliary body only in staining more deeply. The convolutions of this
kind are perhaps most numerous over the posterior surface of the ciliary
body, and both here and over the ciliary processes they can often be traced
into direct continuity with the normal unpigmented epithelium. In some
places the latter simply changes its character without altering its position,
so that the pigment epithelium is lined directly by the epithelium of the
tumor (Fig. 2). In other places the new epithelium grows over the normal
unpigmented layer. The other type of convolution is several cells in thick-
ness, but strictly speaking is not stratified epithelium, since the cells are
not arranged in parallel rows. The cell outlines are generally seen with
difficulty, the appearance presented being that of a band the central two-
thirds or more of which is closely packed with elongated nuclei, having
their axes all perpendicular to the surface. One border of the band is
sharply defined and beneath it there is a clearer zone in which no nuclei
occur unless they are undergoing karyokinesis. In this zone the outlines
of the cells are easily recognizable, giving it a striated appearance. The
other border of the band is not sharply outlined, and next to it there is an
ill-defined zone having a reticulated structure, in which the nuclei are
fewer in number, smaller and more rounded in shape. The picture pre-
....
6
5
VERHOEFF: Tumorfrom Pars Ciliaris Retina,. 355
sented by this type of convolution, even in hematoxylin and eosin speci-
mens, recalls at once that of an embryonic retina in an early stage of
development. This type never arises directly from the normal epithelium,
but always by transition from the simple columnar type.
That this band type of convolution really does represent different stages
in the development of an embryonic retina is demonstrated beyond any
manner of doubt by staining after Method B given above. After this
method, if the differentiation is not carried too far, the individual cells are
plainly brought out and are seen to correspond in every way to those of
an embryonic retina. Fig. 5 shows the growth in this form over the pos-
terior surface of the iris, where the bands attain their highest development,
and Fig. 6 shows its detailed structure as brought out by special staining.
The embryonic rods and cones, their nuclei and fibrils, are clearly shown.
The cell processes which run toward the sharp margin of the band are
always more deeply stained than those running in the opposite direction.
The cells nearest the iris probably represent early forms of Muller's fibers.
As already noted, only one margin of the band type of convolution is
sharply defined. This is true also of the simple columnar epithelium. In
sections stained by Method A it is easily seen that the sharp margin is
due to a definite fenestrated membrane (Fig. 7), similar to the mem-
brana limnitan-s externa and to the membrane in the pigment layer of the
retina recently described by the writer.' When the membrane lies in the
plane of the section, the openings in it are clearly made out. They are
small, much smaller in the band convolutions than in the columnar epi-
thelium, and hexagonal in shape. Into these openings the ends of the cells
exactly fit without projecting through, in the case of the columnar epithe-
lium, but in the case of the band convolutions, protruding beyond the mem-
brane in the form of knob-like processes, the embryonic rods and cones.
Besides these projections, the cells here and there end in large bulbous
expansions, which are plainly granular, but which can be seen distinctly
only when a small diaphragm is used in the microscope. These expan-
sions evidently do not correspond to rods and cones. Similar appearances
are to be seen in the ependyma of an embryo pig, and they are probably
connected in some way with the process of cell division.
Near the center of each opening in the membrane and usually exactly
on a level with it, there are always two dots, and occasionally four
dots, to be seen (Fig. 7). The dots stain intensely in the neuroglia stain,
and are extremely minute, so much so that it is impossible to make out
their exact shape, but they do not appear to be quite round. They always
occur close together in pairs, but occasionally one of the pair is not seen
distinctly owing to its being obscured by the other. Sometimes the dots
are so close together as to appear as short rods. Frequently the dots seem
to be situated in an indistinct round body; possibly this is an optical effect.
Very rarely, instead of the one or two pairs of dots there occur as many
as fourteen pairs of very much larger dots. Sections stained in a simple
aqueous solution (.5%) of acid fuchsin often show the dots and the mem-
brane fairly well.
356 VERHOEFF: Tumorfrom Pars Ciliaris Retina.
The margin of the epithelium which shows the membrane is never in
contact with connective tissue, and in fact is usually perfectly free, lining
a space or lumen. The lumina of this kind may contain apparently noth-
ing, or they may be filled with coagulated serum, or more rarely, with
tumor cells. It is only in those places where the epithelium of the pars
ciliaris retinae first becomes changed into tumor cells, or where the con-
volutions are massed together, that the membrane is in contact with other
surfaces. On the other hand the opposite margin of the epithelium is
almost always closely united with connective tissue, and it is this margin
which faces the surface over which the tumor grows. It is, however,
never in direct contact with the underlying surface, but is separated from
the latter by a greater or less amount of loose connective tissue..
The lumina, too, formed when the diffuse margin is internal, are
entirely different from those just described. In this case they are filled
with fibrillated connective tissue not to be distinguished from vitreous
humor. This has not simply been enclosed by the tumor, since the latter
does not come in contact with the normal vitreous humor, but it is newly
formed, and the stages in its formation can be easily traced. It is best
brought out in sections stained by Mallory's connective tissue stain; Van
Giesen's stain is far less satisfactory. In the small lumina, hyaline con-
nective tissue can be seen entering their openings and filling the cavities.
Soon after entering, the connective tissue changes its character, forming
a loosely fibrillated tissue containing a few vacuolated connective tissue
cells and leucocytes of different kinds. It is only occasionally that a
blood vessel is met with in this tissue, and when one is found its walls are
very thin, like those in the vitreous body of the embryo. In the larger
lumina the tissue is still more fibrillated, and what is particularly striking,
at the periphery it is condensed into a more homogenous layer, identical
in appearance and staining reactions with the hyaloid membrane of the
normal vitreous body. This hyaloid membrane is usually most fully
developed in the larger globular bodies formed by a single layer of epi-
thelium (Fig. 8). However, it is also present as a thinner layer in the
lumnina enclosed by the band-like convolutions.
As already noted, the lumina vary greatly in size and shape, but they
always show a decided tendency to become round. The smallest ones,
which are quite numerous, correspond in size to the rosettes of the so-
called glioma retinae, and are seldom formed by the simple columnar
epithelium. The walls of the larger lumina, on the other hand, may con-
sist of either type of convolution. Both the small and the large lumina
are undoubtedly formed by a continuous growth of the convolutions, and
there are probably no strictly isolated spherical bodies in the tumor like
the rosettes of "glioma retinxe." The rosette-like pictures here in most
cases represent small globular buds from the walls of the larger lumina,
in which the fenestrated membrane is internal.
At some levels the growth is in contact with and has spread over the
surface of the lens, eroding the capsule in places, but not infiltrating the
lens substance. Near by and often upon the surface of the lens, the
VERHOEFF: Tumorfrom Pars Ciliaris Retina,. 357
growth undergoes a remarkable change in character, becoming converted
into a meshwork of fnbrils containing large cells. The cells are irregular
in shape but have rounded outlines, present a homogeneous appearance,
and often are continued into one or more long processes. Their nuclei
are oval or round, and, as a rule, relatively small compafed to the size of
the cells. The fibrils are sometimes very fine, sometimes very thick, do not
branch, and are free from nodosities. Even in hematoxylin and eosin
specimens this tissue is easily recognized as neuroglia, but its nature is
fully demonstrated by the neuroglia stain, Method A, which differentiates
the fibrils in a most beautiful manner (Figs. 9, lo). In addition to this,
they fail to stain by Weigert's elastic tissue stain, are colored red by Mal-
lory's connective tissue stain, and yellow by Van Geisen's stain. It is note-
worthy that the transition into neuroglia always takes place from the
columnar oI- cuboidal epithelium, never directly from the thicker convolu-
tions, and occurs where the growth extends far from its blood supply. In
places, ouitgrowths of connective tissue are found coated with neuroglia
in the same way as the lens capsule.
In addition to the form of neuroglia proliferation just described, there
is another variety which consists simply of an aggregation of spindle and
somewhat stellate cells among which there are few neurofglia fibrils.
These cells are somewhat similar to the cells in the optic disc which were
described, the writer believes incorrectly, by Nikolai as muscle fibres. It
is not possible to demonstrate by staining methods that these are glia cells,
since the neuroglia stains are only differential for the fibrils, but they can
scarcely be looked upon in any other light. JIn some situations their grad-
ual transition into the cells of the distinct neuroglia formations is per-
fectly plain.
The epithelium forming the walls of some of the globular bodies,
especially the larger ones in which the hyaloid membrane is well devel-
oped, differs somewhat from the columnar epithelium already described.
The cells are lower, often somewhat globular, and stain more intensely in
eosin. This change in character of the epithelium is no doubt the result
of a lack of nourishment, since the walls of the globular bodies are entirely
dependent for their blood supply upon the few vessels in the enclosed
vitreous humor. A similar but more marked change is seen in other parts
of the tumor, particularly near its surface where the columnar epithelium
grows far from its base. Here the cells may even become elongated
horizontally. Such an appearance is seen in places also beneath the
staphylomata, and the epithelium usually takes on this character just before
it passes into neuroglia tissue. Not infrequently this modified epithelium
is found within a mass of connective tissue, or in the vitreous humor which
fills some of the lumina, where the cells may take on the appearance of
neuroglia cells.
Leaving the ciliary body, the growth anteriorly follows along the pos-
terior surface of the iris, passing around the pupillary margin and growing
for a short distance on the anterior surface. The whole upper half of the
iris is lined in this way by the tumor, and on the temporal side the latter
OPH.-24
358 VERHOEFF: Tumorfrom Pars Ciliaris Retince.
extends for some distance beneath the staphyloma. Between the ciliary
body and cornea, especially beneath the nasal staphyloma as already noted,
the iris has almost disappeared and so that here the tumor is really brow-
ing upon the sclera. In places it grows as a uniform layer, sometimes in
the simple columinar type, and sometimes in the band type. More often
than not-ir fact, always in the case of the band type-there is a cer-
tain amount of new-formed connective tissue between the growth and the
underlying structures. In places the growth is heaped up in the form of
nodules showing on a smaller scale the convoluted structure in the main
body of the tumor. These nodules are particularly apt to contain the
rosettes already described. In other places, after assuming the simple col-
umnar type, the growth is transformed into comparatively large papillary
projections composed almost entirely of neuroglia (Fig. ii). In'one situa-
tion a very interesting formation is observed. This is a cyst-like struc-
ture formed by columnar epithelium and containing coagulated serum into
the lumen of which a bud of neuroglia projects (Fig. I2). Another
peculiar formation is produced by a layer of columnar epithelium growing
over the layer of the band type and at intervals undergoing transformation
into neuroglia. But perhaps- the most interesting as well as the most
instructive appearance of all is that illustrated in Fig. 5. Here the growth
comes down in the band form over the posterior surface of the iris, passes
around the pupillary margin and buds out as a perfectly globular body
filled with vitreous humor. The hyaloid membrane is present in this
structure but can be made out well only by an oil immersion lens. On
the temporal side of the iris, where the growth is farthest from the parent
tumor, it assumes the modified columnar type, but here, too, globular
bodies are formed at the pupilary margin filled with vitreous humor show-
ing a well-marked hyaloid membrane.
At certain places along the sclera the tumor shows a decided tendency
to invade the underlying tissue. In no place, however, does the invasion
extend very far, nor do the cells accumulate in such numbers as to form
definite nodules. As a rule they are seen simply as lines, or double rows,
of cells filling the tissue spaces. In every case the invasion is by direct
continuity of growth, and there is no evidence of local metastasis by the
lymphatics. In a number of sections the growth is seen in the iris stroma
at the angle made by the junction of iris and cornea. Here it takes the
columnar type and sometimes forms rosettes. Occasionally the growth is
found growing not upon but within one of the ciliary processes, and in a
few sections it is found invading the ciliary body itself.
The tumor is dependent for its blood supply upon the few vessels
which accompany the connective tissue stroma. The latter, as already
indicated, is derived chiefly froni the ciliary processes and is not very
abundant. The tumor cells in general grow upon the surface of this
stroma, and not in it, just as they do upon the surfaces of the ciliary
processes. It is from this stroma that the vitreous humor is derived which
fills some of the globular bodies. No vessels are ever found in the convo-
lutions themselves, as they are in the adult retina. Notwithstanding the
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