The Foturth Fredlerick H. Verlioeff Lecture*

VERHOEFF'S "TERATO-NEUROMA"A CRITICAL REAPPRAISAL IN LIGHT OF NEWOBSERVATIONS AND CURRENT CONCEPTS

OF EMBRYONIC TUMORSt

BY Loaenz, E. Zimmerman, MDT

IT WAS, OF COURSE, a most unanticipated honor for me to be invited todeliver this Fourth Verhoeff Memorial Lecture. Dr Verhoeff occupiedsuch a remarkable position, not onily in the history of American ophthal-mology, but especially in the development of ophthalmic pathology inthe United States, that I - as a pathologist - am most happy to be ableto pay this tribute to him. When he began his work in ophthalmic path-ology at the turn of the century, great contributions had been made bythe European masters, but on this side of the Atlantic there was only agreat void. Once Verhoeff rolled up his sleeves and began his work atthe NMassachusetts Charitable Eye and Ear Infirmary in Boston, that voidsoon began to disappear. Before long the Europeans knew they were infor some stiff competition. No one, of course, could have anticipated thenthat this remarkably energetic mani would continue his productive careerfor another 60-plus years!

I am so very pleased that Dr Verhoeff did remain active as long as hedid, for otherwise I would not have been able to see him in action. WhenI attended my first meeting of the Ophthalmic Pathology Club in 1954,Dr Verhocff was already 80 years old, but who would have thought soonce the meeting was under way! No matter what was beinig presented,

'Presented at the One Hundred and Seventh Annual Mleeting of The AmericanOphthalmlological Society, Hot Springs, V'irginia, 25 Nlav 1971.

fFrom the Registry of Ophthalmic Pathology, Armed Forces Institute of Pathol-ogy, WVashington, DC. Supported in part by Training Grant EY-00032 from theNational Eye Institute, Bethesda, Maryland.

tChief, Ophthalmic Pathology Branch, AFIB.

The opinions and assertions contained herein are the private views of the authorand are not to be construed as official or as reflecting the views of the Departmentof the Army or the Department of Defense. Photographs courtesy of Armed ForcesInstitute of Pathology.

TR. AM. OPHTH. Soc., vol. 69, 1971

Verhloeg's "Terato-Neurorn"

Dr Verhoeff would see things in the contributor's slides that had beenoverlooked, or he would recall a similar case that everyone else had for-gotten, or he would ask a question that no one else had considered.Dr Verhoeff had a very bad reputation for being a sort of "people-

eater," but, fortunately, he was very kind to me. I guess I was lucky thatI didn't enter the field of ocular pathology a decade or two earlier, forI've been told that Dr Verhoeff did mellow a bit after he became anoctogenarian.Everyone has his favorite stories about Dr Verhoeff, and Dr Cogan

even coined a new term to officially recognize them when he deliveredthe Third Verhoeff Lecture,1 so let me add my contribution to this"Verhoeffiana."

I am sure that many of you will recall that the ophthalmic pathologyclub used to meet in Washington just before the Wilmer Meeting inBaltimore and that Dr Verhoeff was always a prominent figure in thefront row at the Wilmer meeting, where he was usually called on toinitiate the discussion of almost every paper. The episode I will recounttook place at the 1956 Wilmer meeting, when Professor Alan Woods wasstill Chairman of the Department of Ophthalmology at Johns Hopkins.This was just a few years after Hellie Wilder had published her epochalpaper2 establishing toxoplasmosis as an important cause of chorioretinitisin adults and just two years after T. gondii was first recovered from theeye of an adult patient at the Walter Reed Army Hospital.3 ProfessorWoods had selected for his traditional opening lecture of the annualWilmer Meeting a review of the toxoplasmosis story in relation to hisclinical and laboratory investigations of uveitis patients studied at theWilmer Institute.4 Dr Verhoeff opened the discussion by immediatelyshocking the audience with his statemiient that Professor Woods andeveryone else interested in ocular toxoplasmosis had overlooked the factthat he himself had more than 25 years earlier presented an excellent,detailed description of the clinical and pathologic features of Toxo-plasma chorioretinitis. I still vividly recall how stunned I was by suchan impossible claim. I feared that Dr Verhoeff's age was getting the bestof him, but then - just as a ripple of skeptical snickering was beginningto go through his audience - Verhoeff explained, "the only trouble isthat I called it tuberculosis.That experience taught me several things about Dr Verhoeff. At age

82 he was still very sharp aind hald a great sense of humor. Hc was honest.In his original description of the case that he diagnlosed as one of local-ized tuberculous chorioretinitis,5 hel had adnmitted that he could notdemonstrate any acid-fast bacilli. Instead of leaving this mistake buried,

211

he was bringing it out in the open. He recalled his case vividly enoughto be able to make the correct diagnosis in retrospect, and I believe hisrevised diagnosis of toxoplasmosis was the correct one because his pub-lished photographs certainly are most consistent with such an inter-pretation.

Two-thirds of a century ago, at the 40th annual meeting of the Ameri-can Ophthalmological Society in Atlantic City, Verhoeff - then a guestof the Society - described in minute detail a rare tumor that arose fromthe pars ciliaris retinae.6 Although he considered it a "terato-neuroma,"his description is now generally accepted as the classic reference for theintraocular medullo-epithelioma (or "diktyoma," as many still prefer tocall this tumor). While justly proud of his original contribution and ofthe wide recognition it subsequently received, not only in ophthalmo-logic circles but also by such an eminent oncologist as Willis7 and bysuch authoritative neuropathologists as Russell and Rubinstein,8 he wasnevertheless miffed by the fact that his name for the tumor never becamevery popular. In discussing a paper entitled "Intraocular diktyoma andglioneuroma" by Fralick and Wilder9 at the 1949 meeting of this Society,Verhoeff10 typically and inimitably made the following remarks.

"In their very interesting paper the essayists indicate that I was the first topoint out the real nature of the type of tumor with which they are dealing. Idid this in a paper read by invitation before this Society 45 years ago, and Itherefore cannot deny the allegation. Scarcely a member is now alive whoremembers that famous day and year. I recall that I exceeded the time limitand the Society voted me an indefinite extension of time. I hope this carriesover to include my present discussion.The case I reported was all mine, clinically and pathologically. Conditions

were different in those days. I removed the eye, embedded it, repaired themicrotome, sharpened the microtome knife, cut all the sections, prepared allthe staining fluids, stained the sections by various methods, modified Mallory'smethod for neuroglia, made the drawings, supervised the making of the photo-micrographs, made the lantern slides, and typed the manuscript on a Blickens-dorfer typewriter. I did not sweep out the laboratory - a cross-eyed orderlydid this.

Fuchs never had one of these cases, but studied sections of such tumorsreported before 1908 by other observers. I sent him a full set of sections of mytumor, including some stained differentially. In his paper he accepted all myviews as to the nature of these tumors - in fact, he made them his own. Buthe rejected the name I suggested, terato-neuroma - meaning a monsterlikegrowth consisting primarily of nervous tissue - and brought forward the namediktyoma. This term had, five years previously, been devised by Emanuel forthe tumor now called retinoblastoma. In my opinion it is not a good name for

212 Zimmerman

Verhoeif's "Terato-Neuroma"

either tumor. That its meaning lacks precision is shown by the fact that it hasbeen used for two such different tumors. My tumor contained embryonicretina, abnormal neuroglia, and embryonic vitreous. It showed what appearedto be abortive attempts to form whole embryonic eyes. The tumor of theessayists contains embryonic retina, neuroglia, fibrous tissue and cartilage.Formation of embryonic vitreous if it occurs is not conspicuous. The tumoris said to contain ganglion cells, but it is not stated how these were identified.There is no evident reason why such a tumor should not contain ganglioncells, but atypical glial cells can closely resemble ganglion cells. I shouldlike to ask whether or not Nissl bodies were demonstrated. Obviously the termdiktyoma is inadequate for these tumors. The essayists realized that this wasso in their case, for they found it necessary to add the term 'glioneuroma.' Ifthey had used my term, terato-neuroma, this addition would have been need-less."

Verhoeff then concluded his discussion of the Fralick-Wilder paperby showing some of his original slides and in doing so stated, "It mightbe well to show these every 45 years." How I wish that he were heretoday so that he could give a spicy rebuttal to some of the criticisms Ishall be making of his pet name, for while I agree with him that terato-neuroma would have been an entirely appropriate designation for thetumor described and illustrated by Fralick and Wilder, I don't agreethat it was a suitable name for his original medulloepithelioma.For this Verhoeff lecture, then, I have chosen to review Verhoeffs

original description of his tumor and his concept of the nature of thattumor, which led him to propose the name "terato-neuroma." I shall dothis in the light of my own experience based on a recent re-examinationof over 100 tumors of the ciliary epithelium on file in the Registry ofOphthalmic Pathology."1 These rare tumors exhibit many histologicvariations from case to case, and it is therefore easy for the pathologistwho hasn't had the benefit of a large experience to become so impressedby certain features of a given case that he misses the "big picture."Fortunately, however, Verhoeff in his original description did describeand emphasize the most significant features that distinguish this tumorfrom others with which it might be confused. It is a tribute to his powersof observation and his facility for detailed description that his paperhas become a classic. Independently, when I first became interested inthese tumors several years ago, I made a number of the same observa-tions and arrived at some of the same interpretations12 as Verhoeff haddone many years earlier, and for a long while I believed them to be"original," as I had not then read Verhoeff's ancient paper. What asurprise when subsequently I found out that Verhoeff had "scooped" meby more than half a centuryl

213

Zimnern-an

FIGURE 1

The imedullo-epithelioma arises from the nonpigmented ciliary epithelium and pro-dluces intricate convolutions enclosing lumina of various shapes and sizes. The neo-plasmii is composed of structures resembling the medullary epithelium of the embryonicciliary epitheliuimii anid retinla. A. H&E. X 75. AFIP Neg. 70-9497; I3. II&E, X 52. AFIP

Neg. 70-9499.

Verhoeff's patient was a 232-year-old child whose affected eye hadbecome blind, cataractous, and enlarged from secondary glaucoma bythe time the parents brought her in for enucleation. Retinoblastoma("glioma retinae") was the preoperative diagnosis. Upon opening theeye, Verhoeff found a tumor that arose from the ciliary body in theupper nasal quadrant, filled the posterior chamber in that area, and dis-placed the cataractous lens, pushing it aside. It had many excrescencesover its surface, and there were in addition many tiny globular bodiesauttached to the pupillary margin of the iris. Microscopically' Verhoefffound the tumor to have had its origin in nonpigmented ciliary epi-thelium (pars ciliaris retinae) of the pars plicata (Figure 1). It producedintricate convolutions enclosing lumina of various shapes and sizes. Thestructures forming these convolutions were chiefly of two types. One,which Verhoeff considered the more primitive form, consisted of a single

'I hlad hoped to be able to show photoniicrographs from Verhoeff's original casebut was uinable to obtain any photogenic slides, so I will substitute photomicro-graphs from other cases in the Registry.

214

Verbloeff's "Terato-Neu roma"

layer of columnar epitheliumi wvith oval vesicular nuclei and stainingmore deeply than the normiial ciliary epithelium. The other conisisted ofthicker bands composed of multilaycred elongated cells. One border ofthese bands was typically sharply defined and resembled the outerlimiting membrane of the embryonic retina (Figure 2). Mitotic figureswere generally most conspicuous along this surface of the bands. Theopposite surface was less well defined but was almost always intimatelyunited with a "fibrillated connective tissue not to be distinguished fromvitreous humor." Verhoeff stressed that "this vitreous humor has notsimply been enclosed by the tumor, since the latter does not come incontact with the normal vitreous humor, but it is newly formed, and thestages in its formation can be easily traced." Verhoeff pointed out thatdepending upon how these bands were folded, one could see variouspatterns. Sometimes one could see lumina that were generally emlipty orperhaps filled only with cell debris or serum, bounded by the externallimiting membrane (Figure 2). In such instances the bands circum-scribing such structures were surrounded by the delicate connectivetissue resembling embryonic vitreous. In other instances the globoidbodies contained the embryonic vitreous and the outer surface of thebands was outlined by the external limiting membrane (Figure 3).

In my own studies of this curious structure of these tumors, I had theadvantage of some newer stains that were not available in Verhoeff'sday-stains that vividly reveal the acid mucopolysaccharide in thevitreous.'3 These stains provided dramatic confirmation of Verheoff'sobservations (Figures 3 and 4). The cellular bands that produce thecharacteristic diktyomatous pattern of these medullo-epitheliomas,whether they be those that resemble the embryonic ciliary epithelium orthose that resemble embryonic retina, are strikingly polarized, forming afenestrated membrane corresponding to the external limiting membranealong one surface while producing embryonic vitreous along the other.12

So much for our basic points of agreement about the structure of thesetumors. Wherein do we disagree? Verhoeff shared the classical views ofthe day concerning formation of the vitreous humor. This was regardedas a product of the mesoderm. He believed that blood vessels andassociated mesodermal structures derived from the stroma of the ciliarybody were carried into the lesion and were responsible for the formationof the vitreous humor that appeared to be such an integral part of thetumor. Verhoeff envisaged the neoplasm as making "abortive attemptsto form eyes," and since he regarded the formation of vitreous as afunction of the mesoderm, he thought the tumor was more closely alliedto the teratomata than to any other recognized class of tumors. More-

215

216 Zimmerman

A

J

m y.. ~~~~~~~~~~ ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~ .. ... ;

B

FIGURE 2

A. The multicellular bands are polarized, forming asharply defined structure analogous to the extemal limit-ing membrane of the retina along one surface (arrows);the less well-defined opposite surface is in contact withprimitive vitreous (v). H&E, X 75. AFIP Neg. 70-8363.B. The center of the field shown in A has been enlarged,revealing considerable mitotic activity along the outerlimiting membrane but hardly any along the vitreal sur-

face. H&E, X 198. AFIP Neg. 70-8362.

A

B

FIGURE 3A. In contrast with the structures shownin Figure 2, in which the luminal surfacesof the bands are formed by the externallimiting membrane and the lumina areempty, here the concavities are filled withvitreous (v) and the outer convex surfaces(arrows) are formed by the external limit-ing membrane. The vitreous is easier tovisualize here than in Figure 2 becausethe section was stained by alcian blue, x48. AFIP Neg. 70-8365. B. Adjacent sectionto that used for A, but before staining withalcian blue the section was treated withhyaluronidase. The vitreous is now un-stained by alcian blue, x 48. AFIP Neg.

70-8366.

Zimmerman

FIGURE 4In this preparation the embryonic vitreous (v) is deeplystained by alcian blue. Observe that this vitreous is neverpresent along both surfaces of the medullary epithelium,just as the embryonic vitreous is never formed alongboth surfaces of the embryonic retina and ciliary epithe-

lium. Alcian blue, X 198. AFIP Neg. 63-2182.

over, he felt the complexity of its structure, the degree of its differentia-tion, and the early period of life at which it occurs were all consistentwith this suggestion.

Already at the time of his paper, Verhoeff was aware of the fact thatsome investigators were challenging the traditional concept of the vit-reous as a product of the mesoderm. He cited the "recent views ofHaemers and others, who believe it to be derived from the neuroglia ofthe retina," but he rejected this suggestion because his own observationsmaking use of a variety of special staining methods led him to theconclusion that the fibrils in the vitreous did not take origin from theretina. Since then, however, embryologists and others have largely cometo agreement that the medullary epithelium does play a most importantrole in the formation of the embryonic vitreous.12'14-16That the mucoid material resembling primitive vitreous contained

within some of the vesicles cannot be ascribed to mesodermal elementscarried into the tumor from the stroma of the ciliary body is establishedby those cases in which free-floating vesicles in the anterior chamberhave been observed over a period of time during which they progres-sively enlarged.'7"8 In such cases there may be no connection of thesevesicles to the iris or ciliary body (Figure 5). As Treacher Collins19pointed out in his discussion of the remarkable case reported by Spicerand Greeves,17 it demonstrated how pathology can help to explain

218

Verhoeg's "Terato-Neuroma"2

FIGURE 5

Free-floating "cyst" in anterior chamber.Material indistinguishable from vitreous fillsthe lumen. Alcian blue, x 91. AFIP Neg.

71-5601.

embryologic processes. He stated, "It used to be generally thought thatthe vitreous humor was of mesoblastic origin; but of late embryologistshad regarded it as derived from the neural epiblast; and this specimenbore out that view very conclusively. Further, it showed not only thatthe vitreous humour was derived from the secondary optic vesicle, butthat it came from only the front part."

Thus, a major blow to Verhoeff's concept is the fact that he did notdemonstrate convincingly that his tumor had intrinsic elements repre-sentative of germ layers other than the neural ectoderm. Interestingly,however, earlier at the same meeting in 1904, Alling20 had presented thecase of a 4-year-old child whose enucleated eye had been found to con-tain a congenital tumor of the ciliary body containing cartilage as wellas epithelium. The tumor had been studied microscopically by ArnoldKnapp, who considered it an undifferentiated (embryonal) tumor. Fromthe description and from the remarkably good photomicrographs thatdocument the case report, I am convinced that Alling's case was, indeed,a medullo-epithelioma of the ciliary body containing cartilage. Verhoeffhad been sent sections of that tumor, and he commented on the caseafter it was presented at the meeting.21 Strangely, Verhoeff did notrecognize it as related to his own tumor, and, in fact, stated that hebelieved it was an endothelioma! Had he recognized Alling's tumor forwhat it was - a teratoid medullo-epithelioma - he would have been ableto make a much better case for his name, "terato-neuroma."There is, however, still another objection to that name, "terato-

219

neuroma." As Willis22 points out, ever since Virchow's time the term"neuroma" has been reserved for tumors that contain mature neurons.Verhoeff made no claim that his tumor contained such elements; to thecontrary, it consisted of immature derivatives of the primitive medullaryepithelium. It is difficult to understand, therefore, why the term"medullo-epithelioma" did not appeal to Verhoeff.

Verhoeff stated that he knew of no class of tumors other than theteratomata with which his tumor might be more appropriately grouped.There is, however, a group that Willis23 calls the "embryonic tumours,"which he defines as tumors that arise during embryonic, fetal, or earlypostnatal development from a particular organ, rudiment, or tissue whileit is still immature. He also points out that some embryonic tumors alsoshow divergent differentiation (heteroplasia), forming tissues of kindsthat do not normally occur in the part. A familiar example would be thepresence of rhabdomyoblasts in an embryonic tumor of the kidney(Wilms's tumor). I agree fully with Willis that the medullo-epitheliomasof the ciliary body logically belong in the group of embryonic tumors.The cases presented to this Society by Alling and by Fralick and

Wilder contained islands of hyaline cartilage; since then cartilage hasfrequently been found in the loose mesenchymal tissue associated withthese medullo-epitheliomas (Figure 6) .24 Differentiation into braintissue has also been observed in a number of them (Figure 7).

Before leaving the subject of names and classifications of tumors ofthe ciliary epithelium, I should point out that because I couldn't find agood classification of these tumors, I was forced to develop one of myown." Fuchs25 made an astute observation that is still generally correct.He noted that they could conveniently be placed in two main groups:(1) those occurring in children and resembling embryonic retina, whichhe called diktyomas, and (2) those of adults representing neoplastictransformation of hyperplastic epithelium, usually in eyes that had beeninflamed or traumatized. Fuch's name, "diktyoma," was selected to callattention to the network of medullary epithelial bands that are so con-spicuously present in some of these tumors of infancy. I have alreadycited Verhoeffs objections to the name "diktyoma." Russell and Rubin-stein8 summed up the situation very well: "Apart from brevity this termhas little to recommend it." Strangely, it continues to enjoy considerablepopularity. I must confess that unless I watch very carefully I find myselfusing "diktyoma" instead of "medullo-epithelioma"!GrinkerN apparently first introduced the term "medullo-epithelioma"

but based it, at least in part, on a misconception. He stated, "In theretina, medullary epithelium persists in almost undifferentiated form

200 Zimmerman

Verhoef'?s "Terato-Neuroma" 221

A

FIGURE 6

Benign teratoid medullo-epithelioma con-taining large islands of hyaline cartilageembedded in a loose mesenchymal stroma.A. H&E, X 10. AFIP Neg. 70-8749; B. H&E,

X 75. AFIP Neg. 70-7972.

Zimmnerman

A

FIGURE 7Teratoid medullo-epithelioma showing differen-tiation into brain tissue. Case reported by Fralickand Wilder.9 A. H&E, X 52. AFIP Neg. 70-8775;

B. H&E, X 198. AFIP Neg. 70-8774.

throughout adult life in the epithelium of the pars ciliaris retinae, and itis from this tissue that medullo-epitheliomas of the retina usually arise."Actually, the ciliary epithelium is not poorly differentiated tissue, andthe acquired tumors that arise from it do not resemble the medullo-epitheliomas that arise from the embryonic medullary epithelium. Nev-ertheless, certain authoritative writers such as Andersen,24 Duke-Elder

222

1V7ro1oiff's "Terlato-Net1'o 22la'

and Perkins,'7 and Reese28 have followed Griniker's suggestion and havelumped together both embryonic anid acquired tumors of the ciliarybody under the heading of medullo-epitheliomia. In Andersen's classifica-tion24 the former are called emiibryonal medullo-epitheliomas, the latter,adult medullo-epitheliomas. Both designations are objectionable. Tobetter understand why thcse are objectionable, let me again makereference to Willis's concept of medullo-epitheliomas. These are con-sidered embryonic tumors, neoplasms that arise from embryonic or fetaltissues. Following this concept, the term "embryoinal medullo-epi-thelioma" becomes redundant (medullo-epitheliomas are by definitionembryonic neoplasms, and "adult medullo-epithelioma" becomes con-tradictory. Duke-Elder and Perkins'27 tried to classify these tumors, buttheir classification is also objectionable oIn several grounds. They, too.place "adult epitheliomas" under the heading of medullo-epitheliomas,and all of these are grouped among the malignant neoplasms. Theyapparently do not recognize a benign form of medullo-epitheliomas.While I am criticizing the classification proposed by others, I should alsoadmit that the discussion of thesc tumors that Hogan and I9`) gave in ourbook, Ophitlhalmic Pathlology1, is very poor and our classification of themis totally inadequate. These deficiencies will be corrected in our nextedition!From a conceptual point of view I believe it is logical (and probably

correct) to assume that intraocular medullo-epitheliomas are congenitalneoplasms. At least the anlage from which the tumors arise are un-doubtedly present at birth even though the clinical manifestations ofthe tumor that lead to its recognition may not develop until long afterbirth. In striking contrast, the group that other authors have called"adult medullo-epitheliomas" arise, I believe, from fully differentiatedciliary epithelium that subsequently undergoes ni'oplastic change, notinfrequently after having passed through a stage of nonneoplastic re-active hyperplasia (pseudoadenomatous hyperplasia). Thus, I recentlysuggested" that Nwe divide these epithelial tumors of the ciliary bodyinto two main groups, the congenital and the acquired (Table 1).

Just a word about the glioneuroma: We have only two examples, theone recorded by Kuhlenbeck and Haymaker30 and a remarkably similarunpublished case presented to the Verhoeff Society by Dr WilliamSpencer of San Francisco. In both of these cases a large part of theanterior segment of the eye wvas replaced by a large mass of very mature,well-differentiated brain tissue containing neurons as well as glia. Noneof the usual embryonic retina, ciliary epithelium, and primitive vitreouscharacteristic of medullo-epitheliomas was present. Glioneuromas be.

223

ZimmermanTABLE 1. NEUROEPITHELIAL TUMORS OF

THE CILIARY BODY

I. CongenitalA. GlioneuromaB. Medullo-epithelioma1. benign2. malignantc. Teratoid medullo-epithelioma1. benign2. malignant

II. AcquiredA. Pseudo-adenomatous hyperplasiaB. Adenoma1. solid2. papillary3. pleomorphicc. Adenocarcinoma1. solid2. papillary3. pleomorphic

long in the class of choristomatous malformations, portions of the irisand ciliary body having failed to develop normally and having producedinstead large, well-differentiated masses of tissue resembling brain.1'With the exception of these rare glioneuromas, the congenital group

comprises the "pure" and the "teratoid" medullo-epitheliomas. The"pure" medullo-epitheliomas by definition contain elements that closelyresemble the medullary epithelium, but in addition they may also con-tain structures resembling those derived from the secondary optic vesicleor optic cup; of these, the most frequently observed are retinal pigmentepithelium, ciliary epithelium, vitreous, and neuroglia. In the malignantvarieties one also sees masses of tightly packed neuroblastic cells,sometimes showing marked mitotic activity, making these tumors in-distinguishable from poorly differentiated retinoblastomas. Structuresresembling poorly differentiated Flexner-Wintersteiner rosettes may alsobe observed (Figure 8).To qualify as a teratoid medullo-epithelioma there must be one or

more heteroplastic elements present in addition to the medullo-epithelio-matous components. From VerhoeffTs description and illustrations of histumor we would have to assume that there were no truly heteroplasticelements present. By far the most frequently observed heteroplasticelement in medullo-epitheliomas is hyaline cartilage (Figure 6); next istissue resembling brain (Figure 7). Recently we have become aware of

224

Verhoeffs "Terato-Neuroma"

FIGURE 8Structures resembling Flexner-Wintersteiner rosettes maybe observed in malignant medullo-epitheliomas. H&E,

X 247. AFIP Neg. 70-8781.

FIGURE 9Teratoid medullo-epithelioma. Many tubularand vesicular structures are contained in largeretrolental mass of mesenchymal tissue. SeeFigures 10-12 for details shown at greater mag-

nification. H&E, X 2.5. AFIP Neg. 70-9265.

the fact that skeletal muscle may also be present, usually resembling themoderately well-differentiated rhabdomyosarcomas.1131One of the most interesting teratoid medullo-epitheliomas that I have

seen (Figure 9) contained remarkably organoid formations consistingof a central tubular structure lined by medullary epithelium oriented asin the primary optic vesicle with a sharply outlined inner limiting mem-

225

brane along the luminal surface and mnuch less sharply outlined surfacein contact wvith the surrounding mesenchyme (Figure 10). The latter,however, appeared to be clearly oriented concentrically about themedullary epithelium. Within this mesenchyme one could sometimesfind bundles of larger, plumper spindle-shaped and straplike cells con-taining abundant cosinophilic cytoplasm (Figure 11). These bundleswere reminiscent of myotomes, and upon closer scrutiny, well-differ-entiated skeletal muscle cells containing typical cross-striations could beseCen among them (Figure 12).

In the first case of this sort that came to our attention, it was thepresence of large ganglioform cells that stimulated special interest.31 Wewere trying to prove to our own satisfaction that the cells were trulyganglion cells, but we were having no success. Finially, electron micros-copy was used, even though it was necessary to retrieve tissue from theparaffin block for examiniation of the cells in question. Instead of pro-viding support for the belief that the ganglioform cells were neurons,electron microscopy proved that they were, in fact, muscle cells with thetypical well-differentiated banding of mature rhabdomyoblasts.32 Evenbefore our electron microscopic study of that tumor was completed wereceived another that was even stranger in several respects. The entireretina was detached and incorporated in a large mass that involved theciliary body and iris (Figure 13). Microscopic examination revealed aremarkably haphazard mixture of neuroepithelial elements, myxoidmesenchymal tissue, and bands of long, plump, spindle-shaped cells(Figure 14) containing abundant eosinophilic cytoplasm in which onecould readily see, even without the aid of special stains, the typicalcross-striations of skeletal muscle cells (Figure 15). With appropriatestains one could see a greater number of cells containing such cross-striations (Figure 16), and even in the loose myxoid mesenchymal tissueone could establish that some of the stellate cells were actually rhab-domyoblasts, thus presenting a picture similar to what one sees in em-bryonal rhabdomyosarcoma.

In retrospect, the large ganglioform cells (a few of which were alsoobserved in our second case) should have been suspected of beingrhabdomyoblasts because we have frequently seen similar cells in rhab-domyosarcomas of the orbit and in other locations. They had the typicalconcentric cytoplasmic laminations produced by their highly organizedmyofibrils; they stained intensely with a deep brick-red color withMasson's tricbrome stain; and they were rich in glycogen (intensely PASpositive except after treatment with diastase). Nissl preparations andBodian stains had failed to provide support for the original notion that

226 Ziiiiiiierniaii

Verhoeffs "Terato-Neuroma"

FIGURE 10A field within the tumor shown in Figure 9 containingorganoid masses of mesenchymal tissue arranged con-centrically about tubular structures reminiscent of theprimitive vitreous (v). H&E, X 75. AFIP Neg. 70-8363.

FIGURE 1 1Another field from the tumor shown in Figure 9 in whichbundles of plump spindle-shaped cells (arrows) resem-bling a myotome are contained in the mesenchymal tis-sue surrounding the structure lined by medullary epithe-

lium. H&E, X 39. AFIP Neg. 70-8374.

227

228 Zimmerman

<b ..,. r < . .................... :

- Ai

FIGURE 12The plump spindle-shaped and straplike cells containedin the mesenchymal tissue of the tumor shown in Figures9-11 are well-differentiated rhabdomyoblasts exhibitingthe typical cross-striations of skeletal muscle cells. Phos-photungstic acid-hematoxylin stain, X 341. AFIP Neg.

70-9149.

FiGuRE 13Teratoid medullo-epithelioma.The entire retina and the ciliarybody are incorporated into alarge mass of neoplastic tissue.See Figures 14-16 for some ofthe histopathologic features ofthis unusual tumor. AFIp Neg.

69-8030-5.

Verhoeis "Terato-Neuroma"

LA

FIGURE 14Within the tumor shown in Figure 13 there are numer-ous neuroepithelial structures intimately associated withloose mesenchymal tissue and bundles of plump spindle-shaped and straplike cells. H&E, X 247. AFIP Neg.

69-9796.

FIGURE 15Rhabdomyblastic differentiation of many cells containedwithin the loose mesenchymal tissue of the tumor shownin Figures 13 and 14 is evident even without the aid of

special stains. H&E, X 247. AFIP Neg. 70-7862.

229

Zimmerman

FIGURE 16The typical cytoplasmic cross-striations of skeletal muscleare demonstrated much more vividly with the phospho-tungstic acid-hematoxylin stain, x 198. AFIP Neg.

69-9805.

these were ganglion cells; yet we didn't suspect that these ganglioformcells might be rhabdomyoblasts until we saw them by electron micros-copy. From this experience we should learn several lessons. The first isto be more objective. We failed to suspect that the ganglioform cellsmight be rhabdomyoblasts, not because they didn't have the character-istics of such cells but because their intraocular location and theirassociation with a neural neoplasm served to effectively eliminate sucha possibility from even being considered at our conscious level of differ-ential diagnosis. The second is to "beware of the obvious" and becomeimaginative. How much are we overlooking every day because ourstereotyped thinking doesn't permit us to imagine other possibilities?Finally, the experience again illustrates the potential diagnostic value ofelectron microscopy. Even when one hasn't had the opportunity to pre-pare the tissue properly for electron microscopy initially, it is stillpossible to obtain meaningful (sometimes, as in the present case, cru-cially diagnostic!) information by retrieving tissue from the paraffinblock and then reprocessing it for electron microscopy.Having had in quick succession these several medullo-epitheliomas

with a rhabdomyoblastic component, we naturally began to wonder howoften we had overlooked such a component in the past, and we alsowondered about the possibility that similar tumors might occur intra-cranially. With regard to the first consideration, I immediately recalled

230

Verhoeif's "Terato-Neuromd'

a case that I used for illustrations in a chapter I prepared for Ackerman'sSurgical Pathology.33 In that case, a huge intraocular medullo-epithelio-matous tumor that contained many large islands of hyaline cartilage,some of which suggested sarcomatous change, also had clusters of verylarge cells with abundant eosinophilic cytoplasm and large vesicularnuclei containing prominent nucleoli. These cells had always been sus-pected of being ganglion cells, but their identity had never really beenestablished. Unfortunately, we still don't know whether these cells arerhabdomyoblasts because the original tissue, processed in celloidin, wasused for study sets, and I have not been able to retrieve satisfactorytissue for further study by light or electron microscopy. In my recentreview of all our ciliary body tumors,11 I did come across several othercases in which strap cells, racquet cells, or ganglioform cells suggestiveof rhabdomyoblasts were present, but in those old cases I was never ableto establish conclusively the presence of a rhabdomyoblastic component.Among our more recently accessioned cases, however, we now have atotal of four specimens in which we have been able to demonstraterhabdomyoblasts with typical well-differentiated cross-striations. Inthree of the four tumors the cross-striations are demonstrable even insections stained by hematoxylin and eosin, but in one case they wereidentified only by electron microscopy.31With regard to the occurrence of a rhabdomyoblastic component in

other tumors of the central nervous system, a number of cases have beenreported.34-39 Most have been considered cerebellar medulloblastomasand have occurred in children. The term "medulloblastoma" has beencoined for them. Some authors have considered such tumors as beingteratomatous; others have suggested that they are immature leptomen-ingeal neoplasms (sarcomas) of the posterior fossa. According to Gold-man,38 the primary tumors of the central nervous system containingrhabdomyosarcomatous elements fall into three groups: a teratoidgroup, in which the sarcomatous elements are associated with medullo-blastoma; primary sarcomas that are probably of meningeal origin; andhis own "unique" case, in which the sarcoma appeared to be derivedfrom the mesodermal tissue associated with the vascular supply of aprimary glioma. Experimentally, medulloblastomas of the cerebellumhave been produced in mice, and in some of the resultant neoplasms,cells of a sarcomatous nature have been identified among the neuro-blastic elements, though no evidence of rhabdomyoblastic differentiationwas described.40The question also arises as to the histogenesis or embryogenesis of

the cartilage and skeletal muscle observed in association with these

231

medullo-epitheliomas. Several suggestions may be made, but we haveno absolute proof that any one is the correct answer. First, as Verhoeffpointed out, and as I have repeatedly observed in our cases, the tumorusually has some vascular stroma. Often there is a large vascularizedmesenchymal retrolental mass that resembles and probably is hyper-plastic primary vitreous. The vessels entering this mass in the posteriorchamber can often be shown to have had their origin from the stroma ofthe ciliary body, entering through a colobomatous defect in the con-tinuity of the pigmented and nonpigmented layers of ciliary epithelium.Thus, one must consider the possibility that heteroplasia took place inthe mesodermal tissue contained in the persistent hyperplastic primaryvitreous. As we have recently reported,41 one may see heteroplasticadipose tissue in persistent hyperplastic primary vitreous, but to datewe have not seen either skeletal muscle or cartilage in such cases, norhave we seen adipose tissue in our teratoid medullo-epitheliomas. Carti-lage, however, is a well-known constituent of the colobomatous defectsin the severely microphthalmic eyes of babies born with a 13-15trisomy,42 and it may rarely be seen in unilaterally malformed eyes notassociated with any systemic anomaly or chromosomal disorder.43 Thusa most likely possibility is that the cartilage and skeletal muscle observedin association with these medullo-epitheliomas are derived from meso-derm entering through a colobomatous defect in the medullary epithe-lium.

Another distinct possibility is the origin of these tissues from theneural ectoderm itself. At least one example of the origin of striatedmuscle fibers from the neural ectoderm is well established. In birds andreptiles the pupillary muscles have the typical cross-banding of skeletalmuscle fibers.44 Old embryologic studies indicated that these muscles arederived from the medullary epithelium,45 just as are the smooth iridicmuscles of man and most other species. Recently the embryologic devel-opment of these "skeletal" muscle cells from the medullary epitheliumat the rostral margin of the optic cup in the chick has been under in-vestigation by light and electron microscopy in our laboratory, and wecan confirm the fact that the neural ectoderm does have the potentialfor the production of rhabdomyoblasts.46 In some of our tumors theextremely intimate relationship of rhabdomyoblasts to neuroepithelialelements suggests the possibility that the two cell types may have arisenfrom a common precursor.

Still another possibility remains to be considered. According to someembryologists, the mesenchyme should be considered in a functionalsense rather than as a genetic entity. It can be derived from various epi-

232 Zimmerman

Verhoeis "Terato-Neuroma" 233

thelia regardless of their blastodermic layer of origin. In the region ofthe head, especially, much of the mesenchyme is derived from the neuralcrest. According to Starck,47 this neuroectodermal mesenchyme contrib-utes to the formation of cartilage, bone, and odontoblasts and may betermed the "mesectoderm." The cephalic neural crest is also believed togive rise to melanocytes, Schwann cells, neuroblasts, and ganglion cellsof the sympathetic nervous system and to leptomeningeal cells. In tissueculture, cells from the neural crest have been observed to differentiatealong several pathways, and when grown in the presence of entodermalcells from the pharyngeal area, they produce cartilage.48 Thus it seemspossible that the loose mesenchymal tissue contained in the stroma sup-porting the medullo-epitheliomatous elements may actually be mesecto-derm and that the islands of hyaline cartilage may be derived from suchneuroectodermal tissue. I have not, however, come across any referenceto the mesectoderm giving rise to skeletal muscle, though, as I havealready mentioned, it is well established that in birds and reptiles theneuroectoderm can give rise to striated muscle.

Finally, before closing let me say that the knowledge that a sarco-matous orbital tumor may have originated inside the eye can be usefulfor the surgical pathologist. Recently we were sent in consultation achondrosarcomatous neoplasm in the orbit of a 9-year-old boy whoseeye had been enucleated 3 years earlier - allegedly for retinoblastoma.When we were able to study the original ocular tumor, our'suspicionsproved to be correct. The intraocular tumor was not a retinoblastomabut, rather, a teratoid medullo-epithelioma containing a rhabdomyo-sarcomatous component. We were not able to demonstrate a cartilag-inous component in the two blocks of tissue obtained from the eye, butwe nevertheless have no doubts that the orbital chondrosarcoma repre-sents a recurrence of the original malignant teratoid medullo-epithe-lioma. In this connection the case of intraocular chondrosarcoma in acat reported by Barron and Saunders49 is of interest. I have studied thattumor very carefully and believe it, too, belongs in the category ofmalignant teratoid medullo-epitheliomas, but because the chondrosarco-matous component has so overgrown everything else inside the eye, it isdifficult to be certain of this interpretation.

SUMMARY

Although Verhoeff made an incredibly detailed and accurate histo-pathologic study of the tumor he described in 1904, the name he chosefor it ("terato-neuroma" ) seems inappropriate because the tumor was

neither truly teratoid nor neuronal. In retrospect and with the largeexperience we and others have had since Verhoeff's time, it is apparentthat his tumor was a sort of prototype of the pure medullo-epithelioma,an embryonic neoplasm containing structures resembling the medullaryepithelium of the optic vesicle and its derivatives. Other medullo-epitheliomas that have since been studied contain, in addition, hetero-plastic elements - tissues not normally observed in the eye - and maytherefore be called teratoid medullo-epitheliomas. Brain, cartilage, andrhabdomyoblasts are the most readily recognized heteroplastic elementsobserved in these teratoid medullo-epitheliomas.

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24. Andersen, S. R., Medulloepithelioma of the retina, in L. E. Zimmerman, ed.,Tumors of the Eye and Adnexa, Intemat. Ophth. Clin. vol. 2, pp. 483-506,Boston, Little, Brown and Co., 1962.

25. Fuchs, E., Wucherungen und Geschwulste des Ziliarepithels, v. Graefe's Arch.Ophth., 68:534, 1908.

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