NEUROBLASTOMATA: WITH A STUDY OF A CASE ILLUS-

TRATING TIIE THREE TYPES THAT ARISE FROM THE

SYMPATHETIC SYSTEM.*

H. R. WAHL, M.D.

(From the Pathological Laboratories of Western Reserve University andLakeside Hospital, Cleveland, Ohio.)

SYNOPSIS.I. INTRODUCTION.

II. REVIEW OF THE LYrERATURE:(a) Ganglioneuromata; (b) embryology of the sympathetic system;

(c) malignant neuroblastomata; (d) chromaffine tumors; (e)discussion of the tables of the cases:

I. Table I., ganglioneuromata.2. Table II., malignant neuroblastomata.3. Table III., chromaffine tumors.

III. REPORT OF A CASE:(a) Clinical history; (a) post-mortem examination; (c) the tumor

tissue:i. Macroscopical description.2. Microscopical description.

A - Differentiated nerve tissues (ganglioneuroma).B -Undifferentiated nerve tissues (malignant neuroblas-

toma).C- Chromaffine tissues (paraganglioma).

(d) Summary; (e) anatomical diagnosis.IV. DIscusSION:

(a) Relation of the tumor to the sympathetic system; (b) differentiatednerve tissue elements (ganglioneuroma); (c) cystoid forma-tions; (d) myeloid tissue; (e) undifferentiated nerve tissueelements (malignant neuroblastoma); (f) vascular changes;(g) nature of the tumor tissue as a whole and its relation tonerve tumors in general; (h) nomenclature; (i) diagnosis.

V. SUMMARY AND CONCLUSION.

INTRODUCTION.- It is becoming recognized, especially inthe last four or five years, that the most highly differentiatedtissue of the body- the nerve tissue- may and does fre-quently undergo blastomatous change. True nerve tumors,i.e., growths consisting of specific nerve tissue elements, may

* Received for publication Feb. 25, I914.(205)

WAHL.

occur in any part of the nervous structure, but by far thegreater number of them have their origin in the sympatheticsystem. These tumors may be either benign or malignant,and though they often differ widely in their structure,behavior, and occurrence, yet they are closely related onto-genetically. Both the benign and malignant forms are mostfrequent and best illustrated in the sympathetic system.The former includes the ganglioneuromata and the chro-maffine tumors, in both of which the cells are more or lesshighly differentiated -depending on the rapidity of theirgrowth and their location. The latter is represented in thecentral nervous system by the gliomata. Outside of therentral nervous system, this form was not generally recog-nized until the last four or five years. It originates in ablastomatous change of undifferentiated and embryonic nervecells. In the peripheral ganglia it forms what Marchandhas termed the neurocytoma. In the sympathetic system,where almost all of the reported cases, especially the moremalignant ones, have been found, often associated with theadrenal gland, it is composed of the embryonic formativecells (" Bildungszellen") of the sympathetic system. Thedevelopment of the present knowledge concerning these truenerve tumors is outlined in a very brief review of theliterature.

REVIEW OF THE LITERATURE: (a) Ganglioneuromata.- The term neuroma was first used by Odier, in I803, todesignate " deep-seated tumors which are characterized bypainful swellings of the nerve involved." Later, it wasemployed more loosely, being applied to any tumor in rela-tion to a nerve, and indicated an overgrowth of the connec-tive tissue sheaths of the nerve. Then it became entirely aclinical term regardless of whether the tumor to which it wasapplied was an inflammatory swelling, a metastatic growth,or a new formation of nerve tissue, and it was not until I863that the pathology of neuromata was placed on a histologi-cal rather than a clinical basis. In this year Virchow clearedup the confused status of the neuromata and made a sharp

206

NEUROBLASTOMATA.

distinction between the true and the false forms. Accord-ingly, the true neuromata arise in the nerve tissue, andare composed essentially of nerve elements. The falseneuromata have their origin in the interstitial connectivetissue of the nerves. Virchow sub-divided the true neuromatainto: (i) the neuroma gangliocellulare, containing newlyformed ganglion cells; (2) the neuroma fibrillare amyelini-cum, consisting chiefly of non-medullated nerve fibers; and(3) the neuroma fibrillare myelinicum, composed mainly ofmedullated fibers. He also pointed out that undoubtedlythe nervous nature of many neuromata had been overlooked,because the non-myelinated fibers were mistaken for connec-tive tissue fibers, and many of the ganglion cells and nervefibers had disappeared through pressure atrophy anddegeneration, and had been replaced by fibrous tissue.While Virchow admitted the possibility, he did not believethat a true neuroma containing proliferating ganglion cellshad been carefully described and proved to be such withoutquestion. Gunzberg in I847 reported such a case, butVirchow did not consider his description sufficiently com-plete or convincing to warrant his diagnosis.The first well authenticated case of a ganglioneuroma was

that reported by Loretz in I870. This was followed by AxelKey's case in i879 and Weichselbaum's ganglioneuroma inadrenal gland in I88I. No cases were reported for the nexteighteen years until I 897, when Busse and Borst eachdescribed a typical ganglioneuroma. From this time onsimilar tumors were reported with gradually increasingfrequency. The following year Chiari and Knauss eachreported a case. The latter gave the first careful descrip-tion of multiple neuromata situated in the subcutaneoustissues all over the body. Knauss believed that all of thetumors of his case bore a direct relation to the blood vessels,and that they were derived from the sympathetic cellsembedded in the sympathetic plexus about these vessels.He maintained that most, if not all, true neuromata hadtheir origin in the sympathetic system, a view also held by

207

WAHL.

Czerny, and suggested that many multiple neuromata con-taining only newly-formed nerve fibers probably had gan-glion cells that either were overlooked or had gone to piecesin some stage of their development.

In I9OI Beneke reported two cases of considerable inter-est. The tumor in his first case was a retroperitoneal pelvicgrowth, containing nerve fibers and ganglion cells that variedin size from that of small lymphocytes to fully developedlarge ganglion cells. Beneke believed that all of the nerveelements - sheath cells, ganglion cells, and nerve fibers-were actively proliferating. He also pointed out that theganglion cells had no specific functional activity, because thefibers had no end organs. Furthermore, he maintained thatin pathological new growths of nerve tissue a true newformation of fibers can arise only in relation to the ganglioncells. Beneke's second tumor is interesting in that it illus-trates the malignant transformation of a ganglioneuromawith metastases into the surrounding lymph glands. Thetumor enclosed the aorta and metastasized into the surround-ing lymph glands. Many of the ganglion cells were scarcelyrecognizable, being large, irregular and more or less packedwith nuclei, giving the appearance of multinucleated giantcells. Typical and atypical ganglion cells were present inthe metastases. Beneke pointed out that in the metastasesthe cells have acquired an epithelioid tendency to line thealveolar framework, and that the ganglioneuromata wereassociated only with the sympathetic system, and were dueto an embryonic fault, i.e., displaced cell rest.The first true neuroma of the central nervous system was

probably that described by Worcestor in I9OI. The authorbelieved that the ganglion cells in his tumor arose from smallround cells with very little cytoplasm and a nucleus so richin chromatin that no structure could be made out. Heregarded these small cells as having an indifferent character,and as being capable of developing into nerve cells or glialcells.

In I907, Oberndorfer, in describing a case of a ganglioneu-roma involving the adrenal gland, emphasized the intimate

208

!EROBLASTOMATA.

association of the ganglioneuromata with the sympatheticsystem, maintaining that with a true new formation of nervefibers there must also be newly formed ganglion cells andthat every true neuroma must of necessity be a ganglioneu-roma.

In the same year Falk from a brief review of the liter-ature concluded that in all cases there was a growth of nervefibers and ganglion cells as well as glial cells and sheathcells; that most cases occurred in individuals under thirtyyears of age; and that the size of the tumor bore an inverseratio to the age of the host. He also pointed out that withbut two exceptions (Haenel and Axel Key) all the tumorsarise in the sympathetic system. He did not believe thatthere was a ganglion cell for each nerve fiber, explaining thegreat preponderance of nerve fibers over the ganglion cellsin three ways:

(a) The nerve fibers represent the product of all genera-tions of ganglion cells that had existed and gone to piecessince the growth began; (b) a new growth of nerve fiberslong after the ganglion cells have degenerated, and lastly (c)the development of nerve fibers from the sheath cells. Heis thus the first of many workers on nerve tumors to supportthe cell chain theory of the origin of peripheral nerve fibers.He described many nerve fibers as arising from the cells ofthe sheath of Schwann through the continuous growth anddifferentiation of the protoplasm of the latter.

In I908 Verocay described the case of a man with anendothelioma of the dura, many subcutaneous neurofibro-mata, several true neuromata involving spinal nerves, gliomatain the brain stem and a true neuroma arising in the trunk ofthe sympathetic system. He pointed out that multiplenerve tumors (the so-called neurofibromata) are not madeup of connective tissue, but of true neurogenous tissueformed by nerve fiber cells (sheath cells) or by correspond-ing cells so altered that they are unable to produce the nor-mal elements of nerve tissue. He explained the presence ofsheath cells, ganglion cells, and nerve fibers as being due toa varying differentiation of a misplaced mother cell - the

209

WAHL.

neurocyte - and looked upon all of the cases of multiplenerve tumors as manifestations of a "Systemerkrankung"of the entire nervous system. To these growths, derivedfrom nerve fiber cells (neurocytes) and composed of apeculiar tissue that is distinguished from connective tissueby its staining reaction, by the formation of peculiar nucle-ated bands, and by the pale fibrilla arranged in bundlesresembling nervous and glial tissue, but identical with neithertypical nerve fibers nor typical glial tissue, he gave the nameof neurinomata, meaning, literally, fibrous tumors of a nervetissue nature.

Verocay's case suggests some relation between multipleneurofibromata (at least of one type) and true ganglioneu-romata, and gives some basis for his conception that mostso-called false neuromata begin as true neuromata, that theganglion cells and other specific elements sooner or laterdisappear through degeneration or other processes, and thatthe only difference between a single true neuroma and multi-ple neuromata is that in the former the blastomatous changeis merely local, whereas in the latter it is pleuricentric.Contrary to previous authors, Verocay did not limit thesetumors to the sympathetic system.

Schminke's case (I9IO) established the fact that trueneuromata occur in the central nervous system. He notedthe presence of nests of young cells having the morphologyof neurocytes grouped about vessels. These nests he called" Bildungsnester " and " Proliferationszentren." He describedall transitions from sheath cells to nerve fibers, thus support-ing the theory of the peripheral origin of nerve fibers evenin the central nervous system, and noted the presence ofyoung nerve forming tissue in the form of syncytial neuro-blastic masses and their differentiation into non-medullatednerve fibers, an unusual condition for the central nervoussystem. He believed that the tumor was a further develop-ment of a part of the brain that was separated from the restof the cerebrum in an early period of fetal life, and that thenerve tracts in the brain are developed normally in muchthe same way.

210

NEUROBLASTOMATA.

In the following year, Friederich reported a ganglioneu-roma in which he maintained that the nerve fibers were adirect continuation of the sheath nuclei, i.e., that the sheathcells were capable of further differentiation into nerve fibersand their adnexa. His conception of the multicellular originof nerve fibers in tumors is supported by the work of Falk,Schminke, Weichselbaum, Duirck, and recently by Obern-dorfer.

In the same year Pick and Bielschowski reported a gan-glioneuroma of the central nervous system, and introduced anew and accurate classification of true neuromata. Accord-ing to these authors all true neuromata have their origin inembryonal malformations and displacements of cells in theform of multipotential embryonal neurocytes, according tothe degree of differentiation of which a " reifende" ori "unreifende " type of a neuroma is obtained. The formeris the ganglioneuroma and occurs most frequently in thesympathetic system. On account of the multipotentialpower of the cells from which the tumor has arisen, glialtissue may be formed in all three groups. These tumors arealmost always benign. On the other hand, the growths ofthe " unreifende " type are almost always more or less malig-nant and include (i) the pure cellular neurocytoma of thecerebro-spinal system first described by Marchand in 1907;(2) ganglioma embryonale sympathoma (Wright's neurocy-toma, Schilder's malignant glioma); (3) "Hirnschlerose; "and (4) the neurinomata of Verocay, for the peculiar neuro-genous fibrillar tissue of these tumors is identified in no waywith glial tissue nor with amyelinic nerve tissue and maycontain newly-formed ganglion cells. They did not agreewith Friederich's conception that the sheath cells may formnerve fibers.The following year McNaughton-Jones described a tumor

composed of areas containing differentiated nerve elements(" reifende"), alternating with patches of undifferentiatedcells. Peters in I913 described a highly differentiated retro-peritoneal nerve tumor containing tissue with few cells andmany nerve fibers, alternating with areas very rich in small

2I11

WAHL.

undifferentiated nerve cells. Peters noted, for the first time,nodules of lymphoid-like cells with larger faintly stainingcells in the center, resembling lymphoid nodules with germi-nal centers. He believed that the cells in these lymphoidnests represented different developmental stages of the sameindifferent nerve cells, showing a continuous cycle of lym-phoid-like cells, differentiating into fully developed ganglioncells, and that the lymphoid-like cells are really " sympatho-gonien" (Poll). He pointed out that foci of lymphoid-likecells were characteristic of ganglioneuromata, and that oflate years they have been generally interpreted as being notlymphocytes, but embryonic nerve forming cells. Hedenied any genetic relation between the sheath cells and the-nerve fibers.About the same time Martius reported a case with two.

distinct tumor masses, both, however, taking their origin inthe cervical part of the sympathetic trunk, one of which was.benign and composed of well differentiated elements, andthe other malignant and made up of undifferentiated nervecells. The former was a typical ganglioneuroma, the lattera malignant neuroblastoma. This case illustrates the close-relationship between the ganglioneuroma and the malignantneuroblastoma, a fact that Kohn, Wiesel, Poll, and Held hadtanticipated in their embryological researches, and whichPick and Bielchowski suggested but which hitherto had not:been described. As this relation is still more strikingly illus-trated in my case, a very brief account of the embryologicalresearches that throw considerable light on this case andiother related nerve tumors will be given preliminary to abrief survey on the literature on these recently recognizedlembryonic nerve growths.

In his paper on the development of the sympatheticsystem, Kohn (1905) pointed out that the embryonicsympathetic cells (" Bildungszellen") are not migrating-preformed ganglion cells, but are simple neurocytes formediin situ that have, locally, a different power of differentiation:from elsewhere, in that they become differentiated, on theone hand, to ganglion cells, capsule cells, nerve fibers, and

212

NEUROBLASTOMATA.

sheath cells and even glial cells, and on the other hand, tochromaffine cells. He pointed out that peripheral ganglioncells are seen in many organs, e.g., the tongue, and aredescribed in clusters in the brachial plexus, and maintainedthat such cells do not arise from preformed ganglion cells,but from the indifferent cells (neurocytes) of embryonalnerves that have lain dormant in these locations and latertaken on growth and differentiated into ganglion cells, andsuggested the same mode of origin for the pathological newformation of ganglion cells.

Kohn's paper on the paraganiglion is of special interest,especially in connection with my case. In this article hedescribed a new intrinsic tissue, hitherto unrecognized, whichhe called the " Paraganglion" (chromaffine bodies) whichgenetically and anatomically is a derivative of the sympa-thetic nervous system, and which attains its greatest develop-ment during fetal life with more or less marked retrogressionshortly before cessation of this period. This paraganglionis characterized: ( i ) by its peculiar origin, arising from theformative cells of the embryonic sympathetic ganglia; (2)the affinity that its matured cells have for the chrome salts;and (3) its inherent relation to the sympathetic system inall stages, and in all vertebrates. The medulla of the fetaladrenal contains mostly undifferentiated formative cells,which at first cannot be distinguished from young sympa-thetic nerve cells. Later some of these cells differentiate intochromaffine cells. Kohn maintained that chromaffine cellsmay be found all over the body wherever there is a part ofthe sympathetic system; and that they may give rise topathological new growths, especially in the retroperitonealregion. This work of Kohn was confirmed by Wiesel in hispaper on the development of the adrenal glands.

Poll gave a very exhaustive account of the developmentand comparative embryology of the adrenal glands and thechromaffine system. He showed that throughout the entirevertebrate series the chromaffine cells arise from the sym-pathetic system, and has named the small embryonicundifferentiated sympathetic cell the " sympathogonion."

213

These cells he held become differentiated either into theelements of the sympathetic system-ganglion cells, nervefibers, sheath or glial cells, or into chromaffine cells, but, indoing so, always pass through an intermediate stage, whichhe called the sympathoblast or phaochromatoblast, as thecase may be. The genetic relation of the different nerveelements may be expressed in the following scheme (modifiedfrom Poll and Landau):

Neuroectoderm of the medullary tube.

Sympathogonien (Poll).Neurocytes (Kohn) of the sympathetic system."Bildungszellen" of the sympathetic system

(Wiesel).

Sv,nnathetic system. V Chromaffine system.

I

Sympathoblasten (Poll).(Transition cells.)

VGanglion cells

andSheath cells.

I

Peripheral glial cells(Held).

I

Phaochromoblasten(Poll).

Phaochromocytes(Poll).

(Chromaffine cells.)

Malignant neuroblastomata. - Marchand ( I 89 I ) reportedthe first neuroblastoma of the undifferentiated type. Hedescribed a small tumor of the adrenal medulla composed ofsmall, round, deeply-stained, lymphoid-like cells, containingvery little protoplasm and embedded in a finely fibrillarground substance, making the whole tissue resemble a softcellular glioma. In fact, he noted that Virchow regarded asgliomata, tumors occupying the same region. He believedthat, because the cells in his case so closely resembled thosein the medulla of the fetal adrenal, they represented the cellsof the medulla in an indifferent stage of development, andthat these may later give rise to definite ganglion cells. Healso pointed out that the growth of these cells may be so

21I4 WAHL.

-. -- r-X- - - /-J __

NEUROBLASTOMATA.

excessive that the entire picture may resemble that of a small,round cell sarcoma.

In I902 Kretz suggested that many of the combined round-celled sarcomata or lympho-sarcomata of the adrenal glandand the liver, frequently reported in very young children, arereally derived from formative sympathetic cells normallypresent on the under surface of the fetus.

In 1905 Kuster reported two peculiar medullary adrenaltumors, which he concluded were gliomata. Both were char-acterized by being made up of a very large number of smallround chromatin rich nuclei, surrounded by little or no pro-toplasm, embedded in a fine mesh of delicate fibrillk andshowing a marked tendency to polarize in two or three rowsabout a round mass of this fibrillar ground substance, forminga characteristic structure that he called a "rosette." Hebelieved that the growths were derived from a misplacedtissue that had the potential power of forming glial tissue.At the same time Wiesel reviewed these cases and came tovery different conclusions, maintaining that since these tumorsare located in the sympathetic part of the adrenal glands, andsince the sympathetic formative cells have the same mor-phology and the same tendency to form " rosettes," Kuster'scases are really growths of the "' Bildungszellen " of thesympathetic system, i.e., malignant neuroblastomata.

Marchand (1907) reported another tumor, which hedescribed as a neurocytoma of the Gasserian ganglion. Thiswas a small tumor composed of neurocytes having an epithe-lial character, without any fibrillar differentiation in theground substance. It represented probably the earliest andpurest type of cellular neuroblastomata.

In i910 Wright collected twelve of these tumors (four ofhis own) and described them as a distinct tumor entity, con-firming and elaborating the views of Wiesel and Marchand.He pointed out that the cells composing the growths wereindifferent nerve cells or neurocytes because (i) they aremore or. less associated with delicate fibrils that do not stainlike neuroglia, collagenous or fibroglia fibers by Mallory'smethod, and are, therefore, like the fibrillae that occur in the

2I5

WAHL.

anlage of the sympathetic system; and (2) the tumor cellsand the fibrillae have the same morphology and arrangementas the formative cells and fibrille of the sympathetic systemand of the medulla of the adrenal glands in an early stage oftheir development. He noted the presence of two verycharacteristic aggregations of cells and fibrille, and was thefirst to emphasize the similarity of these structures to themasses of neurocytes in the anlage of the sympathetic system.One is the tendency of the fibrillae to run in parallel bundles,associated with masses of cells, clustered especially about theends of these bundles and the other is the ball-like structurecomposed of two or three concentric rows of nuclei, sur-rounding a central mesh of delicate fibrillae (Kuster's rosettes).Wright postulated that owing to the occurrence of indifferentnerve cells which have migrated out from the central nervoussystem in any part of the body, these neurocytomata, as hecalled these tumors, may also occur in any part of the body.The fact that he had recognized four of these tumors in oneyear led him to believe that this type of growth is rare, notin its occurrence, but in its recognition, and he suggestedthat possibly the so-called adrenal sarcomata collected byPepper and Hutchinson belong properly to this group.

Pick and Bielchowski (1912) pointed out that the malig-nant neuroblastoma is the " unreifende" counterpart of the" reifende" true neuroma (ganglioneuroma), and that, inits substance, there are scattered throughout, structures thatrepresent physiological stages in the development of theadrenal gland or of the sympathetic ganglia; and that thecells in these structures are but variations from the physio-logical course of development in that they have not produceda fully differentiated nerve tissue. They adhere closely toHeld's idea that, for the anatomical basis of all neuro-blastomata, one must go back to the embryonal malforma-tion and cell division in the differentiating qualities ofmultipotential neurocytes. They call these indifferent nervetumors arising in the sympathetic system the "gangliomaembryonale sympathicum," homologous with a similar

2 I6

NEUROBLASTOMATA.

growth of the Gasserian ganglion (Marchand's neuro-cytoma), which they termed " ganglioma embryonale nervo-rum or cranialum." A ganglioneuroma of the sympathetictrunk they would term a " ganglioma adultum sympathicum."Furthermore, they pointed out that all small round celledmedullary sarcomata or alveolar sarcomatoid or carcinoma-toid tumors, occurring in early childhood, have a specialsignificance as being possible embryonic nerve tumors.They also believed that these tumors may contain any com-bination of differentiated or undifferentiated nerve elements.

Landau (I913) described three interesting cases in whichhe showed that fibril formation is not necessarily presentsince it represents only the degree of differentiation of thecells, for he pointed out that the fewer the fibrilla the youngerand less differentiated is the tissue, and the more nearly doesit approach the appearance of a sarcoma. He consideredthe fibrillm as a primitive differentiation of the plasma ofneuroectodermal cells; that is, as embryonic nerve fibers.He pointed out that ganglion cells may occur in chromaffinetumors and vice versa, and sympathetic formative cells inboth, while in the embryonic nerve tumors various transi-tional types of cells may occur. In conclusion, Landau gavethe following three main characteristics of these tumors, viz.:(a) congenital anlage; (b) appearance of malignancy in earlychildhood; (c) genetic relation to the neuroectoderm; andlaid stress on the direct relation of the tissue differentiationof the tumors, the character of the growth, and the age ofthe host, with each other, such that differentiation increaseswith age, while malignity decreases and the growth assumesmore the appearance of a malformation.

1artius (1913) reported a unique case, composed of twodistinct parts, one a fully differentiated ganglioneuroma andthe other a partially differentiated malignant neuroblastoma.The two suggestive features of the latter were the highdegree of differentiation of the fibrillae and the presence ofmany cells that correspond to Poll's sympathoblasts, whichrepresent an intermediate stage between the undifferentiated

2I7

WAHL.

formative cell and the ganglion cells. Since these cellsformed the predominating cell in the tumor, Martius calledthis tumor a sympathoblastoma, and looked upon it asaffording the missing link between the ganglioneuroma andthe malignant neuroblastoma.

Chromaffine tumors. -The third type of growth derivedfrom the sympathetic system is the chromaffine tumor, orparaganglioma, as it is often called, because of its originfrom the paraganglia. But very few of these tumors havebeen reported, and these only in the last five years. Hed-inger (I909) reported the first case, calling it a "strumamedullaris cystica suprarenalis." Ganglion cells, sympatheticformative cells, non-medullated nerve fibers and fat tissuewere noted in addition to chromaffine cells. An extract ofthis tumor gave a " typical reaction for adrenalin." Hedingerpointed out that this tumor could well be called a paragan-glioma derived from the adrenal medulla.The following year Zuzuke collected from the literature

six cases which were otherwise classified, but which hebelieved should be called chromaffine tumors. In additionhe reported three cases of his own, all of which he lookedupon as paragangliomata. Kawashima (I9Ii) reported acase of a small tumor of the medulla of the adrenal gland,associated with multiple cutaneous fibromata and patchypigmentation of the skin, and believed that the cutaneouslesions bore a direct relation to the chromaffine tumor in theadrenal gland, that this case represents a disease of thesympathetic system and the adrenal gland, and that thechromaffine tumor is not an accidental complication, but apart of von Recklinghausen's disease. Wegelin (Ii 2)nioted many "sympathognien" in his tumor with varioustransitions to chromaffine cells.

218

TABLE II.11falignant Neiiroblastomata.

I I~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Age, Sex.Author, Date.

-~~~~~~~~~~

Dalton, I885.........

Marchand, I 89I ......

*Haberfeld, I909.....

Amberg, I904.........

*Bruck, 1904 ........

Richard, I905 ........

Kuster, 1905 (Case I.)

Case II..........

Lapointe and Lecene,I907 ..............

Alezais and Peyron,1907...............

Schildler, il909........

Hecbt, igog .........

Tileston and WVolbach,I190 ..............

Wright, I9Io (Case II.)

Case II..........

Case III.........

Case IV.........

Pick and Bielschowsky,lI912..............

Marchand, I907 ......

Landau, 19 I 3 (Case I.)

Case II..........

Case III.........

SymnPrs, TAT-3 ....

Martius, 9I913 ........

Anitschkow, I1g9I3 ....

I

I

I

I Metastasis. Secotidary Changes. I

MIucoidl (legenera- IL,Nmphtion. Ilemorrha-ges.

Henioriliages. NSeuroc

-IGliosar

Hemorrhages. iMSalignacdren

cell s-

.;Small r(coma.

_Glioma,

~~~~~~~ss

Structure. 'l tiior Cells.

Alveolar design. Sinall roundI cells.Rosettes? Fibrillar stroma.

Resembles glio-ma. Rtoundl cells withFinely fibrillar lrnatrix. scanty cytoplasm.

Alveolar design. Simall roundl cells,Rosettes r e s e m b I e 6; cytoplasm a n d1months' fetus. nuclei.

? 81ll~Siiall roundI cells.

.1 ssi i

Size. Location. Source. Diagnosis. Remarks.

ht sarcom)a. Fib)rous stroma 1livides the growth into alveoli.

cvtom-a? Resenmbles fetal brain or sympathetic gang-lion of a fetus.

rcoma. Reported in the discussion of Hecht's caseand wvas very similar to it.

iant tumor of Noted resemblance of cells to those of thenial medulla. m-edulla of a six iiionths' fetus.

rrhagic round Cells resembled lymphocytes.'arcoiiia.

'oun(l celled sar- Very vascular.

l. ~~~Afewr cells are present that resemble ganglioncells.

Has muiltinucleated cells, also some large cellsw ith vesicular nuclei and protoplasml thattended to give off processes.

Had infiltrated the diapbragm. Later theauthors called this a parasympathoma.

mpathoma. Seemedl to be associated with the coccygealIgland.

iant glioma. Contains ganglion and chromaffine cells, butno newly formed ones. lnfiltrates the adja-cent tissues.

io- or g I i o - In discussing this case Haberfeldt believedma. that it arose from the "1 Bildungszellen " of

the sympathetic system.

ioma ? Cells resemble the immature cells of the bloodseries. hIlitotic and amitotic figures present.

,vtoma.

6 weeks.MN.

g months.F.

7 weeks.M.

2 montbs.F.

14montbs.F.

2 weeks.M.

I4 weekss.

34 years.hi.

I9 mIontbsF.

6 years.M.

7 days.F.

g years.F.

I6 nIonlthsM.

I day.M.

Adult.M.

i6 montbs.F.

23 years.F.

56 years.M.

8 montbs.i'.

2.5 years.F.

X day.F.

M.

2.5 years.WI.

4 months.F.

Circumference19.5 in.

"Cherry."

2 5-I1*3-2-5 cm.

"Apple."

| 2-1! 5 cm-

| "Watch."

"Two fists."

r " Nut."

113-7-5 mm.n

|Large.

|13-8-8 cm-

Large.

7-7-3.5 cm-

" Fist."

Large.

Smal.

Walnut( Weight, I 7 gins. ) .

Very large.

|Left adrenal.

|Right adrenal.

Left kidney.

|Rigbt adrenal.

|Left adrenal.

|Right adrenal.

Left adrenal.

Bewel

and rectum.

Attacbed to 2d leftvertebra.

Iney and liver.

Both adrenals.

Retroperitoneal.Skull.

Iligament.

|Gasserian ganglion.

|Retroperitoneal.

|Right adrenal.

|Left adrenal.IRight adrenal ?

Right side.

Lumbar region.

| Retroperitohticnervou

| Cerebellum.tem

Sympathetic n e r v o u ssystem.

(Sympathetic ne rv ou ssystem.)

Medulla.(Sympathetic nervoussystem.)

Medulla.(Sympathetic nervoussystem.)

Medulla.(Sympathetic nervoussystem.)l

AMedulla.|(Sympathetic nervoussystem.)l

NN edulla.|(Sympathetic nervoussystem.)

(Sympathetic ne rv ou ssystem.)

Sympathetic n e r v o u sIsystem.I

|Sympathetic n e r v o u sI system.l

|Sympathetic n e r v o u s

Isystem.

|Sympathetic n e r v o u s|I system.l

|Sympathetic n e r v o u s|Isystem. l

Sympathetic n e r v o u ssystem.?

|Sympathetic n e r v o u s|system.

Crna gagia

Sympatheticnerv ussystem. l

|Sympathetic n e r v o u s LIsystem. l

1~~~~E|Sympathetic ne rv o us |L

system. L

ISpinal nerves. N

Sympathetic n e r v o u s |I]system.

Sympathetic nervousIsystem.

ILiver.

;.

None.

Liver.Right adrenal ?

Liver. Pancreas.Skull.Lymph gland.

Liver.Lymph gland.

Liver.Left adrenal.

None.

Lymph gland.Mediastinum.

None.

Adrenal ? Liver.Lymph gland.Duodenum.

Bones an(l lymphglan(l .

Liver.

None ?

Nlediastinum.Liver. Pelvis ?

Liver.Lymph gland.

Infiltration i n t osurrounding tis-sues. None.

Liver.

Liver.

Kidlney. Bones.

L,iver.ILymph gland.

qone.|

v e iy

scantv(I ark

|Vascular sarcoma.jRosettes?

|Resembles glioma.Rosettes. Fibrillar stroma.

|Alveolar design.IAs in Case I.

Resembles glioma.1Rosettes.

Rosettes. Fibrillar stroma.

IRosettes. Glial stroma.

Resembles sarccoma an d|glioma.|Fibrillar stroniaa.

Rosettes.Reticular and fi b r i I I a rIstromna.

|Rosettes.iFibrillae often in bundlles1with clusters of cells.

Rosettes.Fibrillae often in bundleswith clusters of cells.

|Rosettes.|Fibrillae often in bundles

with clusters of cells.

|Rosettes.Fibrillae often in bundlesjwxith clusters of cells.

INodular. Cell clusters.,Rosettes. Fibrillar stroma.jZebra appearance.

IEpithelioidI arrangement.|No fibrillar stroma.

|Lobulated. Rosettes.iFibrillar stroma.l

|As in C:ase I.lCut section has a variegatedIappearance.l

|As above.lAppearance is variegated.|

|Soft, cellular. Rosettes.Fibrillar matrix.l

|Rosettes. Fibrillar inatrix.|Alveolar design.Zebra appearance of cut|surfaces.l

Typical.|

|Nake(l nuclei, ver) rich inicbroiiiatin.

|NTakedl nuclei, very ricli inIcbromatiiii.

|Naked nuclei, very ricb in|chromatin.

|Large nuclei witb scantyprotoplasm.

|Small nuclei, rich in cbro-matin, but little c y t o -

Iplasm.

Large, pale nuclei, little|cytoplasm.

|Round nuclei, little or no|Icytoplasm.l

Round nuclei, little or nocytoplasm. Nuclei rich

1in chromatin.

|Nuclei rich in chromatin.|

S;mall epitheliod cells.

|Small round cells w i th|Iscanty protoplasm.

|As above. Some celsIIlarger, more protoplasm.|

|Large nuclei, much chro-|Imatin. Little protoplasm.

|Scanty cytoplasmn.INuclei rich in chromatin.|

|As above, except some|cells have more cbro-|

Imatin.l

|Large cbromatin. R i c h|inuclei. Scanty cyto-|Iplasm.l

1I-VuLLV%,>;ULVLa

its

dis

its

|Ganglioma.lSympathoma.IEmbryonale.

|Neurocytoma.

Malignant neuroblas-|tomla.I

Malignant neuroblas-|toma.i

Malignant neuroblas-|toma.I

Neuroblastoma.|

Sympathoblastoma.|

Malignant neuroblas-|toma.I

Parasyt

Mlalign

Lymphsarcoi

Lynipb

iNeuro)c

flemorrhages.Blood pigment.

|Hemorrhages.IBlood pigment.

|Hemorrhages.IBlood pigment.

|Hemorrhages.

Necrosis.IDegenerations.

|None.

|lHemorrhages.Necrosis.IFatty change.

|Hemorrhages.Necrosis.

Hemorrhages.Necrosis.

iHemorrhages. Ne-crosis. Also cal-cium deposits invessel walls.

Calcium deposits.Hemorrhages.

Characteristic structure is seen only in theIlung.

|Direct and indirect division forms are present.

|No fibrillar tissue between the cells. Doesnot properly belong to this group as it is the

Itype arising in the central nervous system.

|Aorta passes through the growth withoutIbeing compressed.

|Larger cells bave vesicular nuclei and aretransitional cells to ganglion cells. Many

Ifibrill2e.

|There is little fibrillar tissue. Thrombi of1tumor cells in many of the veins.

|Characteristic structures not present in primarytumor, but appeared in the 2d and 3d recur-

Irences. Frequent mitosis.

Lymphoid follicles. Fibrillae well developed.Nuclei often vesicular. Is the "1 walnut"part of the tumor.

Extended into spinal canal. Multinucleatedcells. Few young ganglion cells. Amitosis.Some rosettes blave small lumina.

the muscles.

spinal canal.

* = cases in which account was either incomplete or the original not accessible.

Author, Date.

Loretz, 1870.

*Axel Key, 5879.

Weichselbauin, iSSi

I3usse, 1897.

Knauss, 1598.

*Chiari 1595.

Schmidt, 1899.

*Cripps and Williamson,1899.

*Haenel 1599.

*Bruchanow, 1899.

*Borst, 1897.

Worcester, 190!.

Beneke Case I., 1901

Case II., 1901.

*l.osenl)acl) 1901.

*Ril)l)eit (2 cases), iyo4

Glockner, 1902.

*1'aljris, 1903.

Kredel and Beneke,1903.

Benda, 1904.

*(Jhse 1906.

*\\oo(ls 1906.

*(;lin,li 1900.

Oberodorfer, 1907.

Faik, 1907.

Verocay, I9oS.

.' Size.

diameter.

3'

Braun, 1908..

Oelsner, I 908.

Miller, i9o8.

Risel-Zwickaw, 1909 ...

*Jacobsthal, I909.

*Hagenbach, 1909.

Hook, 1910.

Wegelin, 1910.

Schminke,i9ro.I

*Schorr, 1910.

*Krauss.

Friederich, I91i.7I

Pick and Bielschowsky, 21911.

Sato, 1912.3I

I-f. McNaughton-Jones ii912(Casel.) I

(Case II.).3,F

Peters, 1913.3.

Martius, 1913.2.M

Freund, i913..3.jeter.

Gangli.yteuromaa.

Evidences

Capsulated.(?

Uncapsulated.

Metastases.

Retroperitoneal.

Retroperitoneal.

abdomina

Retroperitoneal.

Retroperitoneal.

tissue

Retroperitoneal.

Left adrenal.

One.

Retroperitoneal.

Retroperitoneal.

ganglion.

Retroperitoneal.

Pelvis.

Medulla.

1-4th lumbar verte.bra.

Retroperitoneal.

Sacrum.

Right kidney.

Root of neck.

Right side neck.

verte-

Source.

Sympathetic

Medulla.non-med.

Sympathetic

Sympatheticmedul-

.1 Sympatheticmedul.

Sympathetic

mpatheticnon-med.

Sympatheticnon-med.

. Sympatheticnon-med.

ullated.

CranialNon-medullated.

Sympathetic

Non-medullated.

Cervical

SympatheticNon-medullated.

patheticnon-med-

Entirenon-med.

Sympatheticnon-med.

system. ullated.

Non-medullated.

nervous

nervous

system.

nervous

system.

system.

Sympatheticsystem.

Sympatheticsystem.

Sympatheticsystem.

nervous

Medullated fibers.

'. ''

" " 7

Mostly non-med-ullated.

.on-medullated.

Variation in siMultinucleate

MultinucleateAmitosis ?

MultinucleatedVariation in siz

Large number.

Mitosis.

Multinueleated.

Multinucleated.Variation in size.Transitional cells

Amitosis.

Transitional cellsPresent.

" Present."

Multinucleated.

Multinucleated.

Multinucleated.

Multinucleated.

Variation in size.

Amitosis.Variation in size.Transitional cells.

Present.

Multinucleated.

Multinucleated.Mitosis.Transitional cells.

TV

A]

ransitbn.

stages.

non.medullated. Encapsulated.

,f Evidences of Degeneration.ri.

Myxomatous.

ze. -ci.

Myxomatous.

d. -

Hyaline changes.Vacuolar changes.Myelin globules.

Hemorrhages.e.

, Calcium deposits.

Calcium concretions.

Vacuolar degeneration. SiMyelin.

. Pigmentation.

Chromatolysis. P1Vacuolar degeneration.Myelin.

Present.

Hyaline degeneration. " IHydropic degeneration.Myelin degeneration.

Vacuolar degeneration. PlaMyelin degeneration. Lyi

Vacuolar degeneration. LyzHyaline degeneration. PlaMyelin degeneration.

Hyaline degeneration. LyrMyelin degeneration.Edema.

Vacuolar degeneration.Granular degeneration.Fatty degeneration ?

Vacuolar degeneration. SmaHyaline ? degeneration.Myelin ? degeneration.

Shrunken cells and nuclei.Calcium deposits.Granular degeneration.

Shrunken cells and nuclei.Calcium deposits.Granular degeneration.

Calcium deposits. LymHyaline degeneration.Hemorrhage and necrosis.

Present. Lym

" Lymj

* = cases in which account was either incomplete or the original not accessible.

Cells ofLymphoid Type.

Small round cells.

Plasma.Lymphocytes.

Lymphocytes.

tall round cells. XT(

asma and mast.ells.

.ymphoid tissue."

all round cells.

nphoid cells.

phoid-like cells.

Vascular Cha

.ssels have thivalls.

Mu.thi

Vesthichya

ularisekened.

Remarks.

Often 2-3 ganglion cells in a single capsule.

Oval and spindle cells occur and are higherstage of round cell. Sheath cells pro-liferating.

Ganglion cells have no capsule.

Tumors composed mainly of connective tissuefibers.

At first tumor was considered a fibroma.

Ganglion cells are mostly apolar.

Was not connected with the brain.

No axis cylinders.

Sheath cells a little increased in number.

Fat cells are present. Infiltrates the adjacentglands. Resembles embryonic nerve tissue.Sheath seem to form axis cylinder.

Cystic structures that are probably softenedfibroma.

in Has areas that resemble embryonic nervetissue.

Second tumor nodule is embedded in the wallofthe duodenum.

Cystic structures are present.

Fat cells are present. A few ganglion cells

are present in the lymph metastasis.

Has a glial ground substance.

Has a glial ground substance. Ganglion cellsand giant cells are in the liver metastasis.

. Fat cells are present.

Neurofibril1. are well differentiated. Nissl'sgranules are present.

Lymphoid cells are indifferent nerve cells thatform cells or even medullated nerve fibers.

Newly-formed smooth muscle fibers andvessels.

Nerve fibers can be traced to sheath cells.

Has a glial stroma. Nerve fibers have bulb-like enlargements but do not arise fromsheath cells.

Eosin staining granules are in the protoplasmof some of the ganglion cells. Nature?

Tumor contains friable areas in which thereseems to be transition to a fibrillo-cellulartissue or to nerve fibers.

Resembles the first cases.

Lymphoid cells in follicles? with germinalcenters are masses of embryonic nerve cells.

Has a fibrillar stroma. All transitions fromlymphoid cells to ganglion cells and fromfibrilla to nerve fihers. This applies onlyto the ganglioneuroma part of the growth.

Lymphoid cells considered to be glial cells.

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NEUROBLASTOMATA.

Tables of cases reported in the literature:

Table I. Ganglioneuromata.- In glancing over this tableit becomes at once evident that the recognition of this type ofgrowth is becoming more and more frequent. It is seen thatmost cases occur in the female sex (twenty-five out of forty),and at any age, though most of them (twenty-nine out of forty-seven) occurred before thirty years, and after forty they arecomparatively rare. They occur in any part of the body,but are far more frequent in the retroperitoneal and retro-pleural regions (twenty-nine out of forty-seven cases, ten inadrenal gland). They may arise in any part of the nervoussystem, occurring in the following order of frequency: sym-pathetic system (thirty-six), central nervous system (three),peripheral nerves (two), cranial ganglia (two), entire nervoussystem (one), doubtful (three).

Most of the growths are solitary and benign. Of theforty-seven cases five were multiple. Metastases were notedin all but three, infiltration into surrounding tissue in four,and in all of these embryonic and undifferentiated tissue waspresent.The degree of differentiation of cells is very variable.In almost all in which a complete description was accessi-

ble, degenerative changes in the ganglion cells were noted(often adjacent to marked proliferative changes), occurringin the following order of frequency: vacuolar (nine), mye-lin (eight), hyaline (seven), myxomatous (five), calciumdeposits (five). Active proliferation was noted in twenty ofthe cases in the following order of frequency: multinucleatedganglion cells (twelve), mitotic figures (two), direct divi-sion of nuclei of ganglion cells (three). These figures aresignificant if we recall that in sixteen instances the descrip-tion was very incomplete or not accessible, and seem toconfirm the opinion of many authors that the life history ofthese cells is markedly shortened. Most of the nerve fibersare non-medullated.

It is noteworthy that out of six cases in which a note wasmade on the condition of tlle vessels, in five there was

WAHL.

considerable thickening and hypertrophy of the vessel walls,often associated with hyaline changes.

In sixteen of the tumors, cells described as lymphoid-likeand small round cells occasionally grouped into lymphoid-like follicles were noted, and recent publications indicate thatthey are usually present, and that they are to be regarded asembryonic nerve cells; in fact, transitional cells to ganglioncells were described in nine of the cases.

Table II. Malignant neuroblastomata. - A study of thistable shows how very recent is the recognition of this tumor.It includes twenty-five cases, some of which were at firstdiagnosed as gliomata or sarcomata. The tumors occur asfrequently in the male as in the female. They almost alwaysoccur in very young children (twenty-three in children underten years and twelve in those less than one year old). Thetable seems to confirm Landau's conception that the youngerthe host the more embryonic, malignant, and extensive thegrowth.These tumors may occur in any part of the body, but are

most frequent in the adrenal glands (twelve cases), and thenin the retroperitoneal region (seven). But one case hasbeen described in the central nervous system, and all butthree had their origin in the sympathetic system. Degen-erative changes, necrosis, and hemorrhage are very frequent(nine).A point of special interest is the occurrence of more

highly differentiated cells. Chromaffine cells were noted intwo cases, young ganglion cells in four cases, and transitionalcells in three cases.

Table III. Chromaffine tumors (paragangliomata).-These tumors are also of very recent recognition. Of theseven cases in which the sex is noted, there were twice asmany females as males. The tumor apparently never occursbefore the age of thirty, and in fact usually in the lastdecades of life (four out of seven in persons over sixty).The tumors usually occur in the adrenal glands (ten out of

220

NEUROBLASTOMATA.

thirteen). They are always benign and solitary, and tend tobe smaller in size than the other nerve tumors of sympa-thetic origin. In five of seven cases in which a completedescription was available, sympathetic formative cells weredescribed. Fat cells were noted in two of these tumors.They were also noted in three of the ganglioneuromata.

In studying the literature of these three types of sympa-thetic nerve tumors, their interrelationship becomes appar-ent. Cases of purely one type are rare. Many of themcontained elements of two of the types, and one case(Martius) was composed of two distinct parts, each repre-senting a different type. All three elements were present inHedinger's case, and in one of Zuzuki's, but whether theywere newly formed or not, is doubtful. Theoretically, therecan be growths in which there are newly formed elements ofall three types, but up to date no such case has beendescribed. The following is undoubtedly such a case.

REPORT OF CASE.

Clinical history. - The case occurred in the practice of Dr. Price, ofGlyndon, Maryland, and was seen in consultation by Dr. J. H. MasonKnox, of Baltimore, to both of whom I am indebted for the clinical his-tory and the opportunity to do the autopsy. The patient was a girl 2iyears of age, who had been suffering from marked anemia and obscureabdominal symptoms for several months. During the last three weeks oflife there was an irregular low elevation of the temperature, associatedwith rapidly increasing abdominal distention and tenderness and enlarge-ment of the inguinal lymph glands. On deep palpation of the abdomen,an irregular, firm and immovable mass was felt in the umbilical region.A few years before a young sister of this child died of a disease that ranapparently the same clinical course.Autopsy (4 hours after death). - Unfortunately, only an incomplete

autopsy was allowed. The main changes on inspection are a markedgeneral anemia and pallor and a distended abdomen. The spleen isenlarged, reddish brown in color and firm in consistency. The liver isvery much enlarged, is pale yellowish brown in color, and its surfaceis studded with numerous opaque, white, round, tumor metastases (2-25millimeters in diameter), which also extend throughout the substance ofthe organ. The lymph glands at the hilum of the liver are much enlargedand grayish red in color. The right kidney has a few small tumor

;221

WAHL.

metastases surrounded by a small zone of intense congestion in the cor-tex. Otherwise the organ is pale and shows considerable cloudy swellingof the cortex. The right adrenal gland is normal in appearance and inposition.A strikingly variegated oval tumor mass is situated just below the

spleen and apparently closely connected with the upper, inner, andanterior aspect of the left kidney, occupying the position of the leftadrenal gland, which it seems to have replaced. It is well encapsulated,apparently adherent to the left kidney, and is readily removed with thelatter.The kidney itself presents the same appearances as the right one. Its

capsule strips off readily, except anteriorly and medially, where it is fuseddirectly with the tumor tissue.The tumor tissue fuses with the anterior part of the capsule of the kid-

ney, and passes down into the hilum of the kidney as a firm, dense, white,bipartite stalk, enclosing the renal vessels, but does not enter the kidneysubstance (Fig. 3). This tumor tissue is composed of two distinct parts,an outer thin portion enclosing an inner egg-shaped mass, which is easilyshelled out, remaining attached to the outer layer only at its upper andinner part, where a yellow band of tissue J millimeter in thickness and8 millimeters wide passes from a process of the left adrenal gland, deeplybut loosely embedded in this tissue, and spreads out over the white smoothsurface of the inner mass or tumor proper.The inner mass measures 6.8 x 4.4 x 4 centimeters and weighs 6o

grams (Fig. i). It has a variegated appearance and a lobulated structure,being composed of nodules that vary considerably in size (4-25 millime-ters in diameter), in color (dark gray, reddish gray, yellow, etc.), and inconsistency (soft, spongy, friable, elastic, gritty), and that are heldtogether by firm white connective tissue, which is apparently considerablyincreased in amount towards the base of the pedicle. There is a smallarea in the dense white tissue about the base of the pedicle which seemsto be canalized, giving it the appearance of a finely meshed sponge.The capsule of the outer portion of the tumor tissue varies considerably

in thickness. The anterior and medial surface is thin, and composed ofa semitransparent membrane .5 millimeter in thickness, which, at thesides, becomes abruptly thickened to form a collar of white dense tissuemeasuring 5-15 millimeters in thickness, being largest at the upper pole.This tumor is also nodular in structure and variegated in appearance.Some of the nodules are composed entirely of yellow necrotic tissue. Itsinner surface and larger part is mottled dark gray or red in color, and softand spongy in consistency. Its posterior surface is composed of densewhite fibrous tissue, into which several small nerves enter from above.The left adrenal gland is loosely embedded in the thicker upper part of thecapsule, and appears normal, except that its posterior part tapers downand forms the pedicle of the inner tumor mass. It is attached to the cap-sule at two points, one where a nerve passes out from its hilum and entersthe compact elastic white adjacent tissue of the capsule, and the other

222

NEUROBLASTOMATA.

where a large collapsed blood vessel (3 millimeters in diameter) leaves thegland and plunges into the firm white tissue of the capsule. This vesseldoes not end in the adrenal gland, but passes along its border into thepedicle of the tumor, and breaks up into numerous large branches in thetumor. The tumor capsule is attached only to the capsule and vessels ofthe kidney (Figs. 2 and 3).At the root of the small mesentery there is another irregular, lobulated

mass which extends from a point just above the coeliac axis to within2 centimeters of the bifurcation of the aorta, completely encloses this partof the aorta and its branches, and lies over the bodies of the lumbar ver-tebra a little to the left of the median line. The inferior vena cavapasses loosely over its anterior and right sides. It is not connected withthe tumor tissue arising in the left adrenal gland. Because of its intimaterelation to the aorta it is henceforth referred to as the periaortic tumor.It measures 8 x4.5 x 7 centimeters, and weighs 72 grams. It has thesame nodular structure, variegated appearance and variable consistencyas the tumor mass, situated over the left kidney. Many of the nodulesare yellow in color and entirely necrotic. Several small nerves enter vari-ous parts of this mass running into the firm fibrous tissue framework ratherthan the individual nodules of softer and grayer tissue. Enlarged graylymph glands are loosely adherent to the surface of this mass.The lumbar and iliac lymph glands are enlarged (1.5 centimeters in

diameter), soft and gray in color.

Microscopical description.- Liver: Outside of the metastases thereis considerable fatty change in the parenchyma, most marked in thecentral zone of the lobule.

Spleen: Capsule is thickened and the connective tissue is increased.There is a large amount of brown (blood) pigment scattered throughout,the lymph sinuses are prominent, the endothelial cells swollen, and thelymphocytes in the pulp decreased in amount, while there are numerouslarger round cells often with eosinophilic granules in the cytoplasm, sug-gesting both myelocytes, myeloblasts of the bone marrow, and polymor-phonuclear leucocytes. There is also considerable congestion.

Kidneys: Both organs showed cloudy swelling of the epithelium of theconvoluted tubules. There are a few scattered small metastases in thecortex.The right adrenal gland was unfortunately lost in the transference of

the material.Tumor tissue: Owing to the fact that the structure of the tumor tissue

is very complicated and confusing, no two areas being exactly alike, yetapparently composed of a varying differentiation of the same mother cell- the neurocyte- and in order to obviate needless repetition the descrip-tion will be given under three main divisions according to the type of tis-sue present in the four parts of the tumor tissue: (i) tumor, (2) tumorcapsule, (3) periaortic tissue, and (4) metastases, viz.: (a) the differen-tiated nerve tissue, comprising the ganglioneuroma; (b) the differentiated

223

chromaffine tissue making up the paraganglioma, and (c) the undifferen-tiated tissue forming the largest part of the tumor tissue, and comprisingthe malignant neuroblastoma.

(a) Differentiated nerve tissue (ganglioneuroma): This tissue is pres-ent in three parts of the tumor tissue, but does not occur in the metas-tases. Grossly, it has the appearance of dense, elastic, closely-meshed,white tissue, and is most abundant in the tumor proper, where it is massedabout the root of the pedicle, and in a radius of 2 centimeters from it.In the capsule it forms an elongated compact area in the thick portionnear the adrenal gland; and in the periaortic tumor it is present in scat-tered foci and blends with the connective tissue framework of this part.

This tissue has a very complicated and variable structure in the tumorproper. There are at least eight main types of architecture with varyingcombinations of these. They consist in areas composed (i) of a com-bination of a focus of ganglion cells and nerve fibers bearing a relation toeach other that suggests a small sympathetic ganglion (Fig. 20); (2) alarge number of irregular large ganglion-like cells lying naked in a scantyfibrillar stroma into which some of the protoplasmic processes of the cellsare lost (Fig. 21); (3) interlacing bundles of nucleated fibrille, suggest-ing a plexus of non-medullated nerve fibers (Fig. 24); (4) irregular,nucleated, fibrillar, fine-meshed reticulum; (5) loose edematous anddegenerated nerve tissue containing large and small, rounded, atypical,multinucleated ganglion cells (Fig. 22); (6) a variable number of cystoidformations (noted macroscopically as having a canalized or honeycombedspongy appearance) embedded in a fibrillated ground substance (Fig. 30) ;(7) stratified pattern due to alternate layers of compressed ganglion cellsand bundles of sparingly nucleated fibrillae, and (8) scattered, degeneratedand hyaline ganglion cells, embedded in a fibrillar stroma (Fig. 23).

Nerve fibers: These run in parallel bundles or interweave irregularlywith each other. They are almost all non-medullated. The sheathnuclei do not generally show much evidence of proliferation, but in a fewareas this is not true, since there are here many sheath nuclei, showingvarious stages in direct division, budding, swelling, and hyperchromaticity.The dividing nucleus. also shows what is apparently a preceding divisionof the nucleolus. Some of the sheath nuclei are very much elongatedand ribbon-like (Fig. 44).

Ganglion cells: These cells show great variations in size, distribution,relations, development, and appearance. In size, they vary from I5.9 /U to8i [, the degenerated forms being usually the largest. They may be inlarge masses of cells, or small foci or nests of five to twenty cells or theymay be isolated in a plexus of non-medullated nerve fibers or in a fibrillarmatrix. Most of them are unencapsulated. They are round or unipolar inshape, but usually more angular in shape giving off one to four proto-plasmic processes, one of which may often be traced into a bundle ofnerve fibers or occasionally directly into a simple nerve fiber. The cyto-plasm is large in amount, stains faintly with eosin, is finely granular andoften tends to shrink away from the fibrillar ground substance. The

224 WAHL.

NEUROBLASTOMATA.

nucleus is usually large, round, and vesicular, containing a large, round,eccentrically-placed nucleolus and a delicate reticulum, in which a fewscattered chromatin granules are embedded. In some nuclei the chromatinis more diffused and the nuclear membrane shrunken and often absent.

Degenerated ganglion cells are very frequent and predominate in threelocations, viz.: (a) in areas where they are isolated in the fibrillarstroma, (b) in the cystoid structures, and (c) along the surface of thetumor, where they are undergoing a pressure atrophy. The most com-mon forms of degeneration are the granular and hyaline types. In someplaces they stain diffusely with hematoxylin with little or no differentia-tion. The cytoplasm often shows considerable shrinkage and vacuolardegeneration. The nuclei are often very large, swollen and hyperchro-matic or very much shrunken and pycnotic, and may stain irregularly,occasionally giving a signet ring appearance. Some nuclei show karyor-rhexis. Very frequently, the nucleus has disappeared leaving a clear zonein the more or less hyaline cytoplasm.

Proliferative changes in the ganglion cells are also frequent. Many ofthe ganglion cells, even the small forms, contain two or more large typicalvesicular nuclei, and in fact some of the cells are so packed with nucleithat little cytoplasm can be seen (often six to twelve characteristic nucleiin a single cell). In some areas these multinucleated cells are apparentlyfused together giving the appearance of a nucleated syncytium (Figs. 21and 22). In these areas there are many small round cells very rich inchromatin and various transitions between these cells and the ganglioncells. No mitotic figures are present in the nuclei of the multinucleatedganglion cells, but direct division is frequent and is apparently precededby direct division of the nucleolus, as shown by the occurrence of two orthree large definite nucleoli in a single nucleus (Fig. 46). In some nucleithere was a protrusion of the nucleolus through the nuclear membrane inthe cytoplasm. Scattered chromatin granules, surrounded by a narrowclear zone, or a slight reticulum, and occasionally also a partial nuclearmembrane are present in the cytoplasm of some of the ganglion cells.This unusual appearance about intracytoplasmic chromatin material maybe due to the fact that several nuclei in multinucleated cells have been cuttangentically, so that only small bits of chromatic material instead ofwhole nuclei appear in the cells. This is unlikely. A second possibilityis the occurrence of a localized edema about bits of chromatic material orNissl's substance. A third interpretation, and one on which we areinclined to lay some stress, is that in some of these cells true nuclei arebeing formed from extranuclear chromatin material analogous to what isknown to occur in certain protozoa.

In one large area in which there is marked edema and granular degen-eration there are many large, round, multinucleated cells, in which thenuclei are often shrunken, pycnotic, and very rich in chromatin, so thatthe cells have more the appearance of large multinucleated giant cellsthan ganglion cells, but there are various transitions between typical

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ganglion cells and these atypical cells, hence they represent most prob-ably degenerative forms of multinucleated ganglion cells (Fig. 22).

Specific nerve staining methods: In preparations obtained by the useof Bielchowsky's method for neurofibrils, two or three black neurofibrillxcould often be seen in a single nerve fiber (Figs. 25-28). Some of themcould be traced through the fiber into a ganglion cell, where they endabout the nuclei. The atis cylinders stain black and lie at one side of thenerve fiber close to a sheath cell nucleus, and often show varicosities intheir course. Some of the ganglion cells are surrounded by a plexus ofthese black fibrillm.

After Weigert's myelin sheath stain myelin droplets were noted in thecytoplasm of a few of the ganglion cells. This stain also showed anoccasional degenerated myelin sheath about some of the nerve fibers, butthey are very uncommon. No definite Nissl's granules were demonstratedin the ganglion cells with any of the specific stains for these structures(except a few fine granules near the border of some cells). The fibrillxin the stroma did not take any of the specific neuroglial stains, character-istically, nor did they behave like collaginous fibers.

In the capsule, the nerve elements are of two types, one representingundoubtedly a hyperplasia and hypertrophy of normal sympathetic ganglia,incorporated in the tumor tissue, and the other consisting in a definite newformation of ganglion cells and nerve fibers, such as exists in the tumor(the latter contains no normal nerve tissues). In the normal but hyper-plastic ganglia the ganglion cells are uniformly arranged, rounded inshape, are usually mononuclear and bear the usual relation to enteringnerve fibers, seen in sympathetic ganglia.The newly formed nerve elements resemble those in the tumor, but

present a few minor differences. The ganglion cells are more rounded andgive off usually no discernible protoplasmic processes. No connectionbetween them and the nerve fibers can be traced as in the tumor. The cyto-plasm of these cells often appears vacuolated, in fact, entire foci of ganglioncells (2o-30 cells) may show the same degree of vacuolar degenerationand disintegration, which as it becomes more and more marked leads tothe formation of the cystoid formations, noted also in the tumor; thedevelopment and fate of these cystic spaces is much better illustrated inthe capsule than in the tumor, for -in the former there are various stagesfrom slight vacuolar and edematous degeneration of a focus of ganglioncells (Fig. 29), more or less fully differentiated, to the cystic formations,containing remains of disintegrated nerve cells, both undifferentiated ordifferentiated. The fate of these structures may be twofold. Eitherthey become enlarged, often by the coalescence of several of them, andgive the area a honeycombed or cavernous appearance, suggesting ahygroma or a cavernous angioma, if hemorrhage occurs in them as it oftendoes (Fig. 32); or they may become obliterated by an ingrowth of youngfibrous tissue from the wall (Fig. 31), so that finally an area composed oflighter and darker patches of fibrillated tissue is obtained (Fig. 33), the

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lighter areas often containing remnants of ganglion cells, such as shrunkennuclei, and representing the remains of cystic spaces. Finally, the entiretissue becomes transformed into a dense fibrillated nucleated tissue.The ground substance in which the newly formed ganglion cells are

embedded consists in an interlacing mesh of fibrilla, some of which arearranged parallel in bundles suggesting embryonic nerves. The edema-tous degeneration affecting the ganglion cells foci often also involves thestroma.

In the periaortic tumor there are no new-formed ganglion cells, butthere are many scattered foci of hyperplastic differentiated nerve tissuerepresenting sympathetic ganglia that have been incorporated in the tumortissue, and have undergone hypertrophy, some measuring as much as2 X I5 millimeters, and all in definite relation to some non-medullatednerve fibers. One of these ganglia is the site of a marked local edema,in which the ganglionic elements are widely separated, but are not them-selves disintegrated. In other ganglia the ganglion cells are shrunken andstain very poorly.

Secondary changes: In the first place these may be vascular in nature.Hemorrhage occurs, but is not abundant, except at the boundary betweenthe differentiated and undifferentiated tissues. The vessels show atendency to sclerosis and partial obliteration, which is most marked inthe arteries and blood sinuses. In some vessels there is marked swellingand irregular proliferation of the endothelial cells, resulting in an irregularlumen. In the arteries the intima is swollen, edematous, often withincreased fibrous tissue, and frequently has undergone hyaline changes, orin other vessels is vacuolated. The media is thickened in some vessels;in others the muscle fibers appear swollen and vacuolated. The elasticfibers are increased in some vessels and not changed in others. Theadventitia is comparatively little affected. In some vessels the lumina arealmost completely obliterated (Fig. 42). These sclerotic changes aremost marked in the fibrous tissue of the capsule and of the periaortictumor.In the second place there are degenerative changes involving more than

the individual elements, such as deposition of calcium salts seen best inthe tumor, and vacuolar and edematous degeneration of considerable areasleading to the cystoid structures as noted above.

Finally, there are secondary changes of an inflammatory character.Perhaps the edema is as largely inflammatory as degenerative. There is,however, a marked infiltration of cells of the white blood cell series insome areas; in fact this is so extensive that it may form the main featureof the section (Figs. 37-41). It is about thin-walled vessels and radi-ating out from them in large numbers that these infiltrating cells occur inlarge numbers. They are often arranged in parallel columns held inelongated meshes of a delicate reticulum. In contradistinction to theindifferent tumor cells, they are rounded in shape with a smooth borderand considerable protoplasm. They show, however, a marked variation

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in size and appearance, and apparently include all varieties of cells seenin myeloid tissues (Figs. 37-41). A large number of the cells containeosinophilic granules in their protoplasm, and have the appearance ofmyelocytes. There are also many cells that resemble myeloblasts, transi-tional cells, large and small lymphocytes, plasma cells, polymorphonuclearcells, a few nucleated red blood cells and scattered typical megalokaryo-cytes, measuring 14.7 to 25 ,u in diameter, with large annular lobulatednuclei (Fig. 4I). These infiltrating white blood cells are much smallerand more uniform in size and appearance than the undifferentiated tumorcells. A few young ganglion cells are scattered among them. Theseinflammatory foci are present chiefly in the capsule of the tumor and inthe differentiated nerve tissue. A small focus of striated muscle fibers(2 millimeters in diameter) is present in a part of the capsule.

(b) Undifferentiated nerve tissue (malignant neuroblastoma). -Thisportion of the tumor tissue is represented in the gross by gray, dark gray,reddish gray or yellow, soft, more or less friable areas, and occupies by farthe most extensive part in each of the four main divisions of the tumortissue; in fact, it is the only portion that forms the metastases. The cellsand the stroma form a variable combination due largely to the degree ofdifferentiation of the former, which, in turn, is dependent on the rapidityof growth, thus giving rise to six main types of architecture, viz.: (I) verycellular pattern with few or no intercellular fibrillk (Fig. 8); (2) a loosespongy alveolar design broken up into compartments by capillaries andstrands of connective tissue, to which the cells are loosely attached (Fig. 4);(3) peritheliomatous pattern, composed of large, dilated, thin-walled ves-sels, surrounded by a thick zone of small round cells outside of which thetissue is necrotic (Fig. 5); (4) syncytial pattern of a more or less fibrillarnature, depending on the relative amount of cytoplasm about the cells(Fig. 7), which varies considerably; (5) solid and hollow balls of cells, thelatter having the appearance of Kuster's rosettes (Fig. I3), and formed bythe polarization of the cells in several concentric rows about a mesh ofdelicate interlacing fibrillae, many of which are continuous with the proto-plasmic processes of the surrounding cells (Fig. 6). Serial sections provethese masses to be spheres, the cells forming the shell, while the interioris filled with this fibrillar mesh. There are various transitions from these"rosettes" to solid balls of cells embedded in a fine fibrillar stroma.Often such a ball of cells is separated by a clear space from the adjacentfibrillar stroma, except at one small point where it is attached to the latterby a small pedicle composed of the same fibrillke that interlace betweenthe cells (Fig. io). Lastly (6) a pattern that consists of parallel bundlesof fibrillm about which (especially at the ends) numerous small indifferentcells cluster. Between these architectural types there are various grada-tions and combinations, but in a given nodule the arrangement and struct-ure is generally the same throughout.The cellular elements are characterized by the relatively large propor-

tion of the nucleus as compared with the cytoplasm; by the abundant

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chromatin material in the nucleus; by the tendency of the scanty cyto-plasm to run out into one or more delicate slender processes, which tendto blend with those of adjacent cells, and by the tendency of the cells topolarize about masses of fibrilla (Figs. 13-19). Some of the nuclei arenaked; others are surrounded by an irregular narrow zone of cytoplasm.Often the cytoplasm is polarized at one end of the nucleus and serves toanchor the cells to surrounding structures. The nuclei are round or ovaland are divided in two types. One is small (4-6.7 , in diameter), roundin shape and contains a large amoitnt of chromatin that is diffused through-out. The other is larger, round or irregular in shape, and contains lesschromatin, which is collected in small granules. There are various grada-tions between these two types, with sometimes one and then the otherpredominating in a given area. Mitotic figures are extremely rare, thoughdirect division of the nuclei is frequently encountered. The nuclei areoften very much enlarged, hyperchromatic and often give off bud-likeprocesses, taking on very bizarre forms. Karyorrhexis is fairly common.Some nuclei are more vesicular, forming transitional nuclei to ganglioncell nuclei. In some areas, especially adjacent to the differentiated tissue,there are a few larger cells with vesicular nuclei, each containing a largeintranuclear body, suggesting young ganglion cells (Figs. 13-19).The intercellular substance is fibrillar, and varies considerably in amount,

being almost entirely absent in some areas and very prominent in others.These fibrille are often connected with the cells and often join severalcells together; in fact, in some foci this fact gives rise to a fibrillo-proto-plasmic syncytium, becoming more or less protoplasmic or fibrillardepending on the relative amount of cytoplasm present. Some of the iso-lated cells with the slender protoplasmic processes suggest neuroglial cells,but the intercellular fibrillm do not stain characteristically after any of theneuroglial stains.The vessels are thin-walled, very numerous, and dilated. In the peri-

theliomatous areas they are very distended with fibrin, serum, and a fewred blood cells, and calcium salts are deposited in the walls of some ofthese vessels.

In the capsule the undifferentiated tissue presents the same characteris-tics. There are no peritheliomatous areas, but there are many placesconsisting of dense fibrous tissue infiltrated with cords and columns of theindifferent cells, presenting much the appearance of a rapidly infiltratingscirrhus carcinoma.The periaortic mass is composed mostly of nodules of this type of tissue,

each nodule presenting some combination of the types of architecturenoted above.The metastases consist entirely of cells of the indifferent type, having

the same characteristics, even "rosette" formation, as in the tumor.The architecture is usually of the loose alveolar type. In the liver smallclumps of indifferent cells are present in the peripheral zone of the liverlobules and in the portal veins as tumor emboli. Cords of compressedliver cells may be recognized right in the center of the metastases.

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These indifferent cells often actively invade the differentiated tissues,especially along the boundary line between them (Fig. ii). They arealso present as larger or smaller foci right in the center of this developednerve tissue.Of the secondary changes hemorrhage and necrosis are very prominent,

especially hemorrhage where the indifferent cells are invading adjacentnormal or tumor tissue. Often entire nodules show a caseous necrosis.The vessels are very thin-walled. Necrosis is not present in the metas-tases. There are considerable deposits of calcium salts in the walls ofmany of the vessels. Infiltration of white blood cells is not prominent,though it does occur and suggests the same condition as in the capsulebut of a much smaller grade.

(c) Chromaffine tissues.- This type of differentiated nerve tissue ispresent in isolated foci in all parts of the tumor tissue except in the metas-tases, and is most abundant in the denser tissues of the tumor proper.The left adrenal gland is normal except that it has a minimal amount of

medullary tissue. The cortex is normal except for a small metastasis ofindifferent tumor cells. The cells of the medulla show no brown pigmen-tation after preliminary fixation in chrome salts (all tissues were preservedin formalin).The pedicle of the tumor is a direct prolongation of a part of the adrenal

gland, being composed of adrenal cortex surrounding a finely fibrillar con-nective tissue core, in which the large blood vessel supplying the tumor isembedded. No medullary tissue is present in the pedicle. At one end ofthe section there are irregular bundles of non-medullated nerve fibers cutin cross section, and at one side of the large vessel there is a large focusof undifferentiated nerve cells (Fig. 12). At its base the pedicle is sepa-rated by bands of connective tissue into three distinct zones, in the centralone of which the vessel breaks up into several sinusoid branches. Thetwo outer zones continuous with the cortical layer of the pedicle divergeand spread out over the inner surface of the tumor, while the middle zoneenlarges and blends with the dense fibrillo-cellular tissue just beneath thebase of the pedicle.

Chromaffine cells. - Deep within the fibrillo-cellular tissue lyingbeneath the pedicle and showing no connection with the adrenal cells ofthe pedicle, there are nests and foci of cuboidal epithelioid cells that havethe structure and arrangement of the cells of the normal medulla (Figs. 47and 53). The cell masses may be arranged in solid columns, or alveoli,in anastomosing cords of cuboidal cells, giving the focus a reticularstructure, or in a syncytium in which the cell boundaries are obscure.The cells are mostly cuboidal and swollen and often appear to be infiltrat-ing the surrounding fibrillar tissue. They are of two types. In one thecytoplasm stains faintly, and may be vacuolated or shrunken, and thenuclei are distended and vesicular containing a few chromatin granules,scattered in a delicate nuclear reticulum. The outlines of these cells may

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be obscure and the cytoplasm often blends with the surrounding tissue.The second type of cell is smaller, with a small, often shrunken nucleusvery rich in chromatin diffused throughout, resembling closely the indif-ferent nerve cells. There are various transitions between this type andthe first type. Nests of undifferentiated nerve cells occur in these regions(Fig. 47), and with increasing amounts of cytoplasm show various transi-tions to the nests of chromaffine cells. Several attempts were made toimpregnate these apparent medullary or chromaffine cells, along with theadrenal gland as a control, with chrome salts, but without success, duemost probably to preliminary fixation in formalin, followed by alcohol.

In the capsule foci of cells, resembling chromaffine cells, were noted intwo locations, each at least I centimeter from the adrenal gland, and in noway connected with it. One is a boot-shaped area composed of parallelcolumns of cuboidal cells, embedded in a fibrillated tissue, containingmore or less numerous indifferent nerve cells (Fig. 48). The other is amass of small undifferentiated nerve cells, in which short columns andclusters of much larger, more faintly staining cells with a cuboidal shapeare embedded (Fig. 49). Transitional cells between these cuboidal cellsand the small indifferent nerve cells occur.

In the periaortic tumor mass there are several foci of epithelioid (chromaf-fine) ceils, one area being of especial interest. It consists in a fibrillarreticulated stroma, extensively infiltrated with undifferentiated tumor cellsand, within it, there is a lighter zone of tissue composed of a wide-meshed, fibrillo-protoplasmic syncytium in which chromatin-rich, roundedor slightly shrunken nuclei are embedded. At one side of this tissue thereis an L-shaped cluster of large cuboidal cells (Fig. 50), the cytoplasm ofwhich is considerable in amount, granular, and stains deeply with eosin.The nuclei are swollen and vesicular, and the outlines of the cells aregenerally obscure, but in a few places they are sufficiently distinct to showthat the cells are cuboidal in shape. The cytoplasm of some of the epithe-lioid cells blends with that of the fibrillar syncytium; in fact, some of thenuclei far out in this syncytium are swollen and vesicular like those of theepithelioid cells, and are embedded in a broader, more cytoplasmic sub-stance, that is finely granular and stains more intensely with eosin thanthe rest of the syncytium, suggesting a transitional stage to the epitheli-oid cells in the L-shaped area (Figs. 5t and 52). These cells are mostprobably chromaffine cells.

It should be emphasized that there is no sharp distinction between areasshowing the ganglioneuroma, the chromaffine cells, and the malignantneuroblastoma. In some areas only one element is represented; in othersvarying amounts of two or all three types are present, and in most allsections nests of undifferentiated nerve cells occur. Often the latter canbe seen infiltrating into the differentiated nerve tissues like a malignantgrowth, but always retaining their tendency to form fibrilla and to polarizeinto "1 rosettes."

In summary, the tumor tissue in my case is composed of three distinct

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parts - periaortic mass, tumor proper, and the capsule of the tumor-each forming a primary growth in itself; each intimately associated withthe sympathetic system, each (with the exception of the periaortic mass),composed of all three types of growths that arise from the sympatheticsystem - the ganglioneuromata, the chromaffine tumor, and the malignantneuroblastomata, with various transitional cells to each of the other twotypes; each containing a benign and a malignant part, the latter invadingthe former; and each presenting the same morphological and structuralcharacteristics.

Anatomical diagnosis. - Malignant neuroblastoma of the sympatheticsystem, arising in the left adrenal gland and the celiac plexus, withmetastases in the liver, lymph glands, kidneys, and left adrenal gland;ganglioneuroma of the left adrenal gland; paraganglioma (chromaffinetumor) of the left adrenal gland; hyperplasia and hypertrophy of theabdominal sympathetic ganglia; general anemia; chronic splenitis; acuteparenchymatous degeneration of the liver and kidneys.

DISCUSSION. -The study of the different parts of thetumor tissue shows that each part (though distinct ana-tomically) is composed of elements representing varyingdegrees of differentiation of a common mother cell, theleast differentiated form being most extensive and mostmalignant. Two facts show that this mother cell is thesympathetic formative cell or " Bildungszelle." First thelocation of the tumor tissue and its intimate connection withsome part of the sympathetic nervous system shows that ithas its origin in the latter. In the second place, the sympa-thetic origin is indicated by the structure, the tumor tissuebeing composed of cell elements that correspond in relations,morphology, arrangement and degree of differentiation tothose of the developing sympathetic nervous system. Inboth, the cell elements are of two main types, in one of whichthey are more or less highly differentiated, while in the otherthey are of an embryonic and indifferent character. Theformer are again subdivided into two distinct types, one con-sisting of cuboidal epithelioid cells (chromaffine cells), andthe other comprising the ganglion cells and their adnexa.

In the tumor tissue the differentiated nerve elements areagain subdivided into two classes, one forming a true newformation of nerve cells, the other representing a hyper-plasia of normal ganglia incorporated in the tumor tissue.

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Degenerative changes are noted even in the hyperplasticganglia indicating a lower degree of the same blastomatouschange associated with general instability and lack of equilib-rium in even the normal elements, incorporated in the tumortissue.The blastomatous nerve tissue is distinguished from the

hyperplastic type in its irregular and variable architecture,in the abnormal proportion of ganglion cells; in the atypi-cal cell elements; in their relations and their degenerativetendency on the one hand and proliferative one on theother. It forms a typical ganglioneuroma. Specific nervestains, as Beilschowsky's neuro-fibril stain and Weigert'smyelin sheath stain, leave no doubt as to the nervous natureof these cells.The mode of proliferation of such highly differentiated

cells as the ganglion cells is quite clearly illustrated in thistumor. They do not develop from the division of fullydifferentiated preexisting ganglion cells or as the result ofan anaplasia or " Entdifferenzierung" with subsequent redif-ferentiation, but they arise as a more or less atypical differ-entiation of rapidly proliferating embryonic sympatheticnerve cells before they are recognizable as such. On theother hand, when these nerve cells have once assumed theiradult form, their growth is apparently always incomplete,consisting in growth of cytoplasm and division of the nucleionly, giving rise to multinucleated cells (Fig. 22). Through-out the tumor proper there are various transitional stagesbetween young indifferent nerve cells and fully developedganglion cells. Indifferent nerve cells and transitional cellsare similarly frequently noted in the ganglioneuromatareported in the literature.

While the adult ganglion cells do not proliferate as such,yet they show abundant evidence of rapid growth in sizeand of depression, physiological degeneration, and death.Their attempt to overcome this depression is shown by thenumerous nuclei in a single cell (four to twelve); more oftenlarge, irregular, nucleated masses of protoplasm apparentlycrawling through the fibrillar stroma; the occurrence of

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direct division in the nucleus (no mitotic figures were seen),and by the protrusion of nuclear material including thekaryosomes through the nuclear membrane into the cyto-plasm, producing a true chromidiosis. These regulatoryphenomena are, however, inadequate as evidenced by thepresence of so many degenerating cells, vacuolated cells, andhyaline anuclear or shrunken ganglion cell remains. Insome areas the pathological differentiation and degenerationof these nerve cells is so marked that they are scarcelyrecognizable, appearing often as multinucleated giant cellswith shrunken and degenerated nuclei and cytoplasm (Fig.22). Such atypical forms are most frequent in the morerapidly growing part of the differentiated nerve portion,indicating that growth is excessive at the expense of differ-entiation. The cytoplasm in the growing ganglion cells doesnot keep pace with the nuclear growth nor does it divide,thus upsetting the nuclear plasma relation in favor of thenucleus with rapid degeneration and death of the cell. Thefrequency of multinucleated and of degenerated ganglioncells in other ganglioneuromata (Table I.) shows that suchchanges are characteristic in these tumors.As in other tumor cells, in these ganglion cells the kary-

osome takes a prominent part in nuclear division; in fact,initiates the direct division of the nuclei, as also noted byHoward and Schulz, suggesting a primitive type of nucleardivision seen in some protozoan forms. In a few ganglioncell nuclei, the karyosome was broken up into what had theappearance of intranuclear mitotic figures, such as theequatorial plate or diaster stages as described by Schulz.

Nerve fibers.-As in the case of the ganglion cells thenerve fibers have no definite arrangement with each other,and no uniform pattern or common course, but interminglein a more or less haphazard fashion. The relation of thenerve fibers to the ganglion cells opens up the much disputedproblem of the origin of the nerve fibers. They may ariseeither as direct outgrowths of the ganglion cells, or as adifferentiation of sheath cells secondarily united to the

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ganglion cells. I shall limit myself only to the evidence thatmy case gives on this question from the standpoint of tumorformation. Most authors who have recently describedganglioneuromata have taken up this question, but with con-siderable disparity of opinion. Some (Beneke, Pick andBielschowsky, Peters, Wegelin, Knauss) maintain that allnerve fibers are derived primarily from the ganglion cells.Some (Schminke, Falk, Oberndorfer, Friederich, Martius,Verocay, Durck) hold just the opposite view and describevarious transitions from the sheath cells to elongated nucle-ated protoplasmic bands, within which fibrille are developed,and to the differentiation of these intraprotoplasmic fibrillkinto axis cylinders and neurofibrilla. The evidence in mytumor is mostly in favor of the central origin of the niervefibers. There were no nucleated protoplasmic bands orfibrillar differentiation in the latter, such as described bySchminke. Many parallel fibrillk were noted, often inti-mately associated with indifferent cells, but, in an early stagein development of the sympathetic system, cells that aredestined to form ganglion cells cannot be distinguished fromthose that develop into sheath cells, so that these fibrillemay represent processes of indifferent ganglion cells as wellas a differentiation in the cytoplasm of a fused mass of sheathcells. No transition of nerye fibers to sheath cells, and noaxis cylinders passing directly out of sheath nuclei as Fried-erich described was noted in this tumor. The preponderanceof nerve fibers over the ganglion cells in parts of my tumorand in many other ganglioneuromata is due not to a differ-entiation of nerve fibers from sheath cells, but is to beascribed more to the fragility of the ganglion cells whichhave degenerated and disappeared, leaving large numbers ofnerve fibers representing the processes of ganglion cells ofall generations that have developed, degenerated, and disap-peared as well as those still existing.On the other hand, naked axis cylinders without any sheath

cells can be traced directly into ganglion cells, most of whichare also naked and unprovided with a nucleated capsule(Fig. 28). It is very improbable that, if the axis cylinder

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developed from sheath cells, there would be no trace of thelatter left. Fibrillm, many of which can be traced into thecytoplasm of undifferentiated nerve cells, cannot be dis-tinguished from embryonic connective tissue fibers, thoughtheir arrangement, appearance, and staining reaction arevery much like those seen in the adrenal medulla or in thesympathetic ganglia of a young human embryo. The paral-lel fibrillae are most probably processes of embryonic andundifferentiated ganglion cells, while the nuclei embeddedamong them are between rather than in the individualfibrilla. It may well be that while the nerve fibril is adefinite offshoot of the ganglion cell, the cytoplasm of one ormore sheath cells may later enclose or fuse with it, and assistin its nourishment and growth, thus acting as nurse cells.The stroma is a finely fibrillar mesh with small round nuclei

at the nodal points, and resembles neuroglial tissue, but doesnot react characteristically to the specific stains for neuroglialfibers, indicating either that the specificity had been lostbefore tissue was fixed, or that the specific substance had notdifferentiated, the stroma being of the nature of an embryonictissue capable of differentiating later into true neuroglial ornerve fibers as in Verocay's neurinomata.The cystoid formations are evidently due to an edema

and a vacuolar degeneration involving foci of both differen-tiated and undifferentiated ganglion cells and secondarily thefibrillar stroma. Vacuolar degeneration and edema arefairly characteristic of blastomatous and even hyperplasticnerve tissue. In the periaortic tumor, one of the incorpor-ated ganglia showed very extensive edema. Cystoid struct-ures were noted in three ganglioneuromata reported in theliterature and in several more a myxomatous tissue wasdescribed, but no detailed description was given.

,Myeloid tissue. - In most cases of ganglioneuromata anote is made of foci of small deeply staining round cells.At first they were interpreted as lymphoid cells, but mostrecent authors regard them as undifferentiated nerve cells.It is probable that foci of both cells occur. In addition to

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indifferent nerve cells in my case there are, in the capsule ofthe tumor, considerable foci of small round cells of anentirely different type that apparently bear no relation toganglion cell formation. They lie in the meshes of a loosefibrillar reticulum, supporting a rich network of capillariesadjacent to an area of hemorrhage or necrosis, and from theirdistribution, their uniform appearance, their striking ten-dency towards mitotic division, their staining reactions, theirmorphology and their relation to the blood vessels, it is evi-dent that they form a new type of cells belonging to a differ-ent tissue from that of nerve cells, and that the cells aresimilar to, if not identical with, myeloid cells (Figs. 37, 38,39, 41). If it is granted that these cells are myeloid cells,as they most probably are, their occurrence in such an oddposition can be explained in three ways. In the first place,the tumor tissue may represent an embryoma, arising fromtoti- or multi- potential cells capable of producing severaltypes of tissue with ectodermal nerve cells predominating.This is unlikely for several reasons, including the fact thatsome of the foci appear more like white cells of blood, andare not present in all four parts ot the tumor tissue, at leastonly strikingly marked in the capsule. However, it is quitepossible that the tumor tissue is composed of a mass ofembryonic nerve cells, which instead of retrogressing at thenormal period have increased their vegetative activity, incor-porating indifferent mesodermal elements, which later havebecome differentiated into different types of mesodermalcells, such as myeloid cells, fat cells, and muscle cells. Ametaplasia of tumor cells is also possible, but equallyunlikely as the first explanation.The most probable explanation is that these myeloid cells

represent an inflammatory infiltration and reaction with asecondary hyperplastic growth of young and plastic whiteblood cells in loco, this occurring in an individual with aseverely taxed and plastic bone marrow, as indicated by theclinical history of a severe and intractable anemia, blood pig-ment, and myelocytes in the spleen. This fact associatedwith edema and hemorrhage and necrosis caused a mild

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exudation of white blood cells, including immature bonemarrow cells which, finding a suitable environment forgrowth, took on a growth in situ. At this point it is worthyof note that myeloid nodules have been produced experi-mentally in the liver of rabbits by excising the spleen withsubsequent administration of a severe hemolytic toxin, eg.,sapotoxin, resulting in the production of nodules of typicalmyeloid cells. If the latter can thus be produced experi-mentally, there is no reason why, under similar conditions ofthe bone marrow, such a growth should not occur in such avascular tumor as this one, especially if initiated by aninflammatory infiltration of these cells. Borst, Schmieden,Albrecht and Gierke have all described tumors containingnodules of myeloid cells or true marrow tissue. Schultz(I912) reported the presence of considerable myeloid tissuein the hilum of the kidney.

Chromaffine tissues. - The other type of differentiatedtissue is the chromaffine tissue, i.e., foci of ill-definedcuboidal epithelioid cells that have the morphology, relation,and appearance of the cells of the medulla of the adrenalgland. There are various transitions between small islandsof indifferent nerve cells, embedded in a fibrillar matrixand connected with each other by delicate protoplasmicprocesses to a nucleated protoplasmic syncytium havinga vacuolated appearance, to the development of cuboidalcells within this syncytium (Figs. 50-52). These epithe-lioid cells resemble normal medullary cells in every respectexcept that the chromaffine reaction was not obtained,probably because of previous fixation in formaline, for it wasalso absent in the medulla of the adrenal gland itself.

In the tumor proper and in the capsule these foci may beaccessory or incorporated chromaffine tissues and hence arenot necessarily blastomatous, though in the tumor they areactively proliferating. But it is in the periaortic tumor thatthe best and most convincing evidence ofchromaffine tissue andits mode of development is evident. In this position wherenormally there are no epithelial structures nor chromaffine

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tissues, there are several large foci of cuboidal epithelialcells, apparently differentiating from a nucleated protoplasmicsyncytium, which in turn shows transitions to masses ofundifferentiated cells (Figs. 50-52). Such a picture couldbe possible as a result of degeneration of a mass of epithe-lial cells, but none of these cells appear degenerated; on thecontrary, they are large and full; then, too, it is much moreprobable that these cuboidal cells are differentiated fromcells clearly proven to have this power than a degenerationof cells not known to exist here normally. The only objec-tion to classifying these cells as chromaffine cells is theabsence of the chromaffine reaction, yet, even if the tissuehad been fixed immediately in the solution of chrome salts,the reaction of the true tissue would not necessarily haveshown, because this cell in a tumor is not, at best, a fullydifferentiated (functionally) cell, owing to its blastomatousnature. The chief reasons for considering these cellschromaffine cells are because of their morphology andbecause they are embedded in a neurogenous tissue, theindifferent elements of which are known to differentiate, inpart, into chromaffine cells, and this transition can be tracedthrough an intermediate syncytial stage to the indifferent cells.After differentiating, these chromaffine cells, like the ganglioncells, do not divide.

Cellular undifferentiated tissue. -This portion forms themalignant element of this tumor, and has the same charac-teristic structure and architecture, wherever it is present, inthe tumor, capsule, periaortic mass, or metastases. The cellunit is a small cell with a relatively large nucleus, very richin chromatin, surrounded by little and, in some places, nodiscernible cytoplasm, and embedded in a more or lessdelicate fibrillar stroma (Figs. 15-19). The variations inthe arrangements of these cells, in the relation of their cyto-plasm to the stroma and to the connective tissue bands; andin the occurrence of secondary changes such as necrosis,hemorrhages, and degenerations, gives rise to a variegatedappearance and numerous architectural designs, six types of

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which were described and any combination noted, giving onepart a very different appearance and structure from anotherpart. In the fibrillo-syncytial type the fibrilla becamerelatively very prominent, and often there are small elongatedirregular foci of sparingly nucleated parallel fibri1la con-sidered by Martius and Peters as embryonic nerves. Noextensive fibrillated structure noted by these authors was inthis part of the tumor.The cells vary markedly in size and shape and are malig-

nant in character. They actively infiltrate adjacent beriignand differentiated blastomatous nerve tissue and metastasizeextensively in the liver. There are various types of nuclearand cellular depression, such as extensive direct nucleardivision, nuclear budding, hyperchromatism, and chromidio-sis. The prevalence of direct nuclear division illustrates thefact that these embryonic nerve cells are similar to manyother tumor cells in the mode of nuclear division. Wherethe growth is less rapid the cells tend to form a syncytiumthat is fibrillar or cytoplasmic, depending on the relativeamount of protoplasm that is present. In general, theindifferent cells tend to join each other by delicate proto-plasmic processes that polarize into rosettes, parallel bundlesof fibrilla and embryonic nerves. The young nerve elementsseem to differentiate from a syncytial basis, at first fibrillarand later mnore cytoplasmic.

In connection with the study of this case several humanfetal adrenal glands were examined (from four centimeters inlength, up), and the cells of the medulla of the adrenalsand neighboring sympathetic structures compared with theindifferent cells in this tumor, and very striking resemblanceswere noted, especially the presence of " rosettes" anid bun-dles of parallel fibrilla, connecting clusters of small roundcells, thus confirming the findings of Wright and others andwarranting the conclusion that the indifferent cells of mytumor are sympathetic formative cells. Some of the indiffer-ent cells have retained considerable power of differentiationin that they may become a little larger with more vesicularnuclei, forming an intermediate stage (Poll's sympathoblast)

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between the indifferent cell and the ganglion or chromaffinecell. These intermediate cells are uncommon in the undiffer-entiated nerve tumors, but more frequent in the ganglio-neuromata, a relation that is also true in the differentportions of my case. A tumor containing a large numberof transitional cells has been described but once- Martius(9I3).The fibrillar stroma does not react to appropriate stains as

well defined collagenous fibers nor as neuroglial fibers, yetthis does not preclude their being of a glial nature, becausethe specificity of the stains is soon lost after death, orbecause these fibers may not be fully developed, and havenot acquired their specific attributes. They may, accord-ingly, be embryonic nerve fibers, neuroglial fibers, or youngconnective tissue fibrilla, and probably all three are repre-sented.

There are various transitions between solid balls of indiffer-ent cells, embedded in a fibrillar mesh to "rosettes " andfrom these through separation of each half of a " rosette "to bundles of parallel fibrilla, connecting clusters of indiffer-ent cells at each end. These fibrillae represent undoubtedlyembryonic nerve fibers, for many can be traced into thecytoplasm of the indifferent cells clustered about their endsjust as in the fetal sympathetic system. The more undiffer-entiated the cells, the fewer are the fibrilla, and withincreased differentiation the fibrilla accordingly becomemore and more prominent. The separation of the rosetteinto two parts connected by parallel fibrils suggests this as amode of formation of nerves from " rosettes."

Vascular changes.- In the differentiated tissues and in thefibrous part of the capsule the vessels, especially arteriesincorporated in the growth, show a very marked tendencytowards endothelial hyperplasia and obliterating sclerosisoften associated with thickening and edema of the intima andvacuolar or hyaline degeneration of the media. Some vesselsshow a unilateral thickening of the intima and endotheliallining. Apparently, there is first a thickening and hyperplasia

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of the muscles of the media followed by edema andfibrosis in the intima and atrophy of the elastic fibers, andlater vacuolar and hyaline degeneration of the muscle fibers inthe media. Sclerosis of the vessels was noted in five cases ofganglioneuromata reported recently in the literature, andseems to be a not infrequent condition. It may mean thatthere is considerable unrecognized chromaffine tissue (espe-cially since in my case scattered foci were found) embeddedin the nerve tissues, giving the specific functional effect ofthis tissue on surrounding vessels, resulting in chronic hyper-tonus of the arterial walls, their hypertrophy, and ultimatelyto the exhaustion and ddgeneration of the muscle fibers.However, it would be hazardous to lay much stress on thisrelation without further evidence. On the other hand, it isquite possible that the sympathetic cells supplying thesevessels have become involved in the blastomatous change,resulting either in loss or perversion of their functionalactivity, and it may well be that these sclerotic changes arebut trophic manifestations of this change in the sympatheticcells controlling the vessels in question, as Todd has sug-gested in explanation of other forms of vascular sclerosis.

Nature of the tumor as a whole and its relation to nervetumors.- Without doubt the tumor is of neuroectodermalorigin, the mesodermal elements playing but a secondarypart. At first one would be inclined to regard this case asexhibiting two distinct types of tumors each having a verydifferent origin, one benign, a ganglioneuroma and of neuro--ectodermal origin, and the other malignant, a peculiar typeof a sarcoma and of mesodermal origin; but a careful studyshows that both arise from the neuroectoderm, and thatthe former is but a high degree of differentiation of the latter,owing (i) to the intimate relation between the two parts;(2) to transitional structures between the two; (3) to theconnection of both with the sympathetic nervous system, and(4)to the similarity of the structures in both types to variousstages in differentiation of the fetal sympathetic system andadrenal medulla. The cells of the different parts of the

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tumor show varying degrees of differentiation, from the indif-ferent nerve cells to the fully differentiated ganglion or chro-maffine cell, showing that in a way the tumor represents theentire physiological development and differentiation of thesympathetic " Bildungszellen." The indifferent cells of thetumor are, accordingly, classed as sympathetic formative cells,first because of their location, being almost invariably con-nected with the sympathetic system, and secondly, becauseof their close similarity in structure, arrangement, and differ-entiation to the sympathetic " Bildungszellen."Why one part of this tumor is malignant and invading

another portion that is benign, as well as the normal tissuesof the abdomen; why there are three separate and distinctparts, each with the same peculiar characteristics, and whythere is such an intimate relation and yet, in a way, distinctseparation between the tumor proper, its capsule and theleft adrenal gland, - are queries that are readily explainedby reference to the development of the sympathetic tissues.Examination of a human fetus, four centimeters in length(ten weeks) showed masses of sympathetic formative cells,partly surrounding the cortical part of the adrenal glands,and extending from the hilum of one kidney to that of theother, more or less completely enclosing this part of theabdominal aorta. These cells and their ground substancebore a close resemblance to the clusters of indifferent cellsand the fibrillar stroma of the malignant part of the tumor.In this fetus there was no medullary substance in the centerof the adrenal gland except a small number of indifferentcells, but sympathetic "1 Bildungszellen" were migratingsingly and in clusters, often as " rosettes " (Figs. 35 and 36),through the cortical substance and converging toward thecenter of the gland. The mass of cells about the aortajoining one adrenal to the other forms the abdominal para-ganglion first described by Kohn, who also pointed out thatthese fetal organs (paraganglia) reach their greatest extentduring fetal life, and have undergone considerable retrogres-sion by the termination of this period, parallel with corre-sponding progressive differentiation of the sympathetic

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elements, so that in man little more remains than ganglia,nerves, and chromaffine cells. Accordingly, at the height ofdevelopment of the paraganglia there is a mass of formativecells entirely enclosing the cortical part of the adrenalglands, another portion accumulated in the center of theadrenal gland, and a third large, irregular mass, extendingfrom that about one adrenal to that about the other part,enclosing the aorta. In the human fetus this stage occursrelatively early, as little trace of the paraganglion or forma-tive cells was seen in fetuses older than five or six months.The peculiar relations of the different tumor portions is

most probably referable to a blastomatous change in theparaganglia at the height of the latter's development, certainof the cells in entirely different areas behaving abnormallyand instead of retrogressing in the normal manner retainedtheir vegetative activity, and failed to develop their full dif-ferentiating power, resulting in tumor formation. It is veryprobable that a partial retrogression did occur in placesallowing sufficient differentiation to go on to form fullydeveloped nerve cells or a portion of the cells may havebecome dormant and later become active and gone on tofurther differentiation, while the larger part of the indifferentcells retained their vegetative activity. In the medulla of theleft adrenal gland some of the indifferent cells retained theirdifferentiating power, giving a large mixed tumor containinga mass of differentiated tissue, including ganglion cells andchromaffine cells overgrown by a malignant part made up ofindifferent cells, all joined in a large lobulated tumor con-nected with the left adrenal by a flat pedicle of corticaladrenal tissue. There was simultaneously a new growth ofthe indifferent cells, surrounding the adrenal gland givingrise to the thick tumor capsule within which the adrenal andthe inner tumor mass is embedded. At about the same timethere was a marked hyperplasia or blastomatous change inthe cells of the paraganglion over the aorta resulting in theperiaortic tumor. The lobulated structure of the latterindicates a partial retrogression with the formation of islandsof embryonic sympathetic cells separated by bands of

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connective tissue, and differentiated nerve tissues, followed laterby a blastomatous change in the isolated nodules of indiffer-ent nerve cells, each nodule developing by itself into its owncharacteristic architecture, though joined by connective tis-sue framework with similar nodules into a conglomeratetumor mass. The same process accounts for the lobulationin the tumor and in its capsule. It is quite probable thatfor a time the entire growth was slow, associated with moreor less complete differentiation of some of the cells whensome cause excited all the tumor cells to more rapid growth,the differentiated cells becoming more and more atypical andthe indifferent cells assuming more and more malignantproperties. The cells still retain some specificity and powerof differentiation in that even in the metastases they tend topolarize in clusters and rosettes and to form fibrille.The blastomatous change in the paraganglia may well be

regarded as a system disease involving a greater or less por-tion of the sympathetic system, but not so extensive as inVerocay's case, though more extensive than in the casesreported by Landau and Martius. In my tumor the changeapparently involves only the abdominal segment of the sym-pathetic system on the left side, but since the examinationof the child was unfortunately incomplete, there may or maynot have been further involvement of the sympatheticsystem.The simplest type of nerve tumor is the neurocytoma

composed of medullary neuroblasts, and described but once(by Marchand, I907), made up solely of embryonic cellswith no fibrillar differentiation, and with an epithelioid char-acter. The next stage is the malignant neuroblastoma, com-posed ofsympathetic formative cells, and between this type andthe fully differentiated ganglioneuroma and chromaffine tumorthere are the sympathoblastoma and the phaochromoblas-toma. Though the latter has not been described, yet it mayoccur not infrequently, being composed of cells that are simi-lar in morphology and genesis, but have not acquired thespecificity for chrome salts, the absence of which renders thediagnosis difficult. Its relation to the sympathetic system,

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the morphology and histogenesis of its cells, and the pres-ence of other sympathetic elements should aid in its recogni-tion, and it may well be that such cases will be reported inthe future. The genetic relationship of the different typesof nerve tumors to each other is illustrated in the followingscheme:

Neurocytoma { Medullary neuroblasts,Marchand (I9o7).

Sympathetic system. V Cerebro-spinal system.

Malignant neuroblastoma of Ganglioneuroma.the sympathetic (Landau).

Sympathoma embryonale (Pick).

vsI I-0 (. Sympathoblastoma Phaochromoblastoma (Poll)

(Martius). (undescribed by itself). |p

.:3 VV. ' Ganglioneuroma Paraganglioma or chromaffine

2 I or cell tumor (Zuzuki).l Ganglioglioneuroma. Phaochromocytoma (Poll). j

An analysis of the cases in the literature and my caseshows that in nerve tumors the older the host the more differ-entiated and benign the tissue growths as a rule, the malig-nant neuroblastomata usually occurring in young children,the ganglioneuroma in the first half of the normal life spanand the chromaffine tumor in the latter half. Evidently thechromaffine tumor is the last type to become blastomatous,but this may be only apparent, as it is the easiest to overlookif it has not been fixed in a solution of chrome salts. Thedegree of differentiation bears the same relation to true nervetumors as to tumors of other tissues. High differentiation isusually confined to benign tumors, while the more malignantthe tumor becomes, the lower the degree of differentiation asa rule. It is, par excellence, in these nerve tumors com-posed of tissue of widely varying degrees of differentiation

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that important facts in normal histogenesis of nerve tissuemay be established.

Nomenclature. - There is some confusion in the use ofterms applied to the different types of neurogenic growths.It would simplify their classification if all true nerve tumorswere regarded as neuroblastomata and these subdivided andnamed according to their location and degree of differentia-tion. Ihe undifferentiated neuroblastoma of the cerebro-spinal systenT has been termed a neurocytoma (Marchand),a term that should be retained. The embryonic tumor ofthe sympathetic system is almost invariably malignant, andis appropriately called a malignant neuroblastoma of thesympathetic system. Pick and Bielchowsky's term for thistype of growth is the "sympathoma embryonale," or the" ganglioma sympathoma embryonale," but the latter termis inaccurate because it implies the presence of ganglioncells when none are recognizable as such, and the indifferentcells may give rise to chromaffine cells, nerve sheath cellsand glial cells, just as well. The chromaffine tumor is some-times called a paraganglioma or phaochromocytoma (Poll).

Diagnosis of neuroblastoma. -The ganglioneuroma pre-sents little difficulty in its recognition because of its invari-able connection with some part of the nervous system, andbecause of the unmistakable morphology and arrangementsof its elements. The chromaffine tumor is easily recognizedbecause of its connection with the sympathetic system andthe affinity that its cells have for chrome salts, but if thetissue has not been fixed in solution of chrome salts within afew hours after death, this reaction is often absent, therecognition is more difficult, and the identification of thecells depends then on the relation of the tissue to the sympa-thetic system and the morphology and arrangement of thecells, especially if other epithelial structures can be excluded.

Anatomically the recognition of the tundifferentiated typeof nerve tumor is often very difficult, because some partsmay simulate a round cell or alveolar sarcoma and a single

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section may be very misleading, while a second section fromanother portion of the tumor may show the characteristicstructures. When the cells show a low degree of differenti-ation, few or no fibrilke are present, and the only cue to itsnature is its connection with some part of the nervous systemor the presence of a more characteristic structure in anotherpart of the same tumor. The fact that over one-half of thecases reported in the literature were noted in the past fouryears suggests both the frequency with which these tumorshave probably been overlooked and the more commonrecognition of them in the future. In fact, sarcomatoustumors in the adrenal or retroperitoneal region of very youngchildren should be regarded with suspicion. In a lobulatedvariegated tumor, the presence mostly of cells with compara-tively large round nuclei, very rich in chromatin, surrounded bya very small amount of cytoplasm tending to flow out into oneor more processes; the tendency of the cells to polarize aboutmasses.of fibrillw forming rosettes and other cell aggrega-tions; the occurrence of bundles of parallel fibrille connect-ing clusters of small round cells of a fibrillar matrix stainingneither as collagenous nor as glial fibers; of considerablevariation in the architecture, of frequent degenerative changes(necrosis and hemorrhage) and the occasional occurrence ofmore highly differentiated cells are decisive points in thehistological diagnosis. A definite connection with thesympathetic system makes the diagnosis much more certain.

Clinically, the ganglioneuromata are difficult to recognize,for a large percentage of the cases were discovered atautopsy or at operation with no sympathetic symptoms inlife. A mass in the retroperitoneal space in a child or youngperson should be suggestive. The same facts apply tochromaffine tumors except that they are rarely large insize and usually occur in very elderly individuals. Themalignant neuroblastoma is more easily recognized, clini-cally, than the other two types, because of its usual occur-rence in very young individuals, its rapid malignant course,and the rapid painful enlargement of the abdomen withoutascites or with the appearance of tumor nodules in the

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bones, especially of the skull with exophthalmus (Hutchin-son's type). The clinical data given in most cases are someager that it is impossible to give more details on theclinical course. A tumor in a young child, especially if itrun a malignant course and occurs in the adrenal glands orconnected with some part of the sympathetic system, shouldsuggest a malignant neuroblastoma of the sympatheticsystem before a sarcoma or any other malignant growth.

SUMMARY AND CONCLUSION.

Nerve tissue may give rise to new growths, which areproperly called neuroblastomata. They may occur in anypart of the nervous system and are of two types, accordingas they are composed chiefly of differentiated or undiffer-entiated elements. The neurocytoma is the undifferentiatedtype. arising in the cerebro-spinal nervous system. Thecorresponding type derived from the sympathetic system isthe malignant neuroblastoma of the sympathetic nervoussystem or the " sympathoma embryonale." The ganglioneu-roma and the chromaffine tumor represent the differentiatednerve growths, the latter taking its origin only in the sympa-thetic nervous system, the former arising also in the cerebro-spinal nervous system. Most neuroblastomata especially ofthe undifferentiated type arise in the sympathetic nervoussystem.

Most of the neuroblastomata of the differentiated typecontain both mature and immature cell elements, one typegreatly predominating over the other. Foci of indifferentcells are usually present in both ganglioneuromata and inchromaffine tumors. Differentiated elements occur, but lessfrequently, in the undifferentiated neuroblastomata. Theremay be any combination of differentiated and undifferentiatedelements in these nerve tumors.Though the nerve tumors of the sympathetic system

malignant neuroblastomata, ganglioneuromata and chromaf-fine tumors -show very marked differences in appearance,behavior, and morphology, they are closely related geneti-cally, being varying differentiations of the same mother cell

249

- the sympathetic formative cell (" Bildungszelle ")which normally differentiates into ganglion cells, peripheralglial cells, and chromaffine cells of the sympathetic system.The infrequency with which pure neuroblastomata of anyone type occur, the occasional occurrence of nerve tumors,composed of two distinct portions each composed of adifferent form of nerve cells with transitions between themand my tumor containing all three elements actively partici-pating in the growth, establishes the intimate relationship ofthese tumors to one another. Accordingly, the ganglioneu-roma and the chromaffine tumor are the differentiated coun-terparts of the malignant neuroblastoma.

Neuroblastomata are manifestations of a pathologicalcondition more or less localized or diffused in the whole orpart of the nervous system. If localized to one focus, as isusually the case, the result is a solitary nerve tumor(ganglioneuroma); if generalized, multiple tumors result.Intermediate stages and varieties occur frequently. In thepresent case apparently only a segment of the abdominalsympathetic system was involved, resulting in three primarygrowths, each of which was composed of the three elementsof the sympathetic system (ganglion cells, chromaffine cells,and indifferent nerve cells). Derivatives of the mesoderm(myeloid cells, fat tissue, and striated muscle foci) may beaccidentally incorporated in the tissue of these tumors.The neuroblastoma is derived from the neuroectoderm and

shows variations in differentiation, the degree of whichapparently varies directly with the age of the host, while themalignant properties bear an inverse proportion to age.The cellular elements of the neuroblastomata, like those of

other tumors, composed of differentiated cells, retrogress andrevert to the embryonic condition of the mother (nerve)tissue as the growth becomes more undifferentiated andmalignant.The ganglioneuroma usually occurs in young individuals,

but may occur at any age. The life history of the blastoma-tous ganglion cells is very short and the cells are very proneto degenerative changes. They are incapable of complete

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division after full differentiation, but manifest a limited growth,however, by division of the nuclei and increase in the amountof the cytoplasm. The nuclei apparently divide only bydirect division, a process that seems to be initiated by pre-liminary direct division of the nucleolus. Ganglion cells do,however, multiply rapidly in their indifferent stage, when theyare not recognizable as such. Clusters of ganglion cells,whether differentiated or not, occasionally undergo anedematous degeneration, resulting in cystoid structures thatmay lead to an angiomatous architecture or to sclerosis.The nerve fibers or axis cylinders arise apparently only as

outgrowths of the ganglion cells without an active participa-tion of the sheath cells.The chromaffine tumor as in the ganglioneuroma is

benign in character, tends to occur more frequently in thefemale sex, but usually occurs very late in life. The cellularelements differentiate from masses of indifferent sympathetic" Bildungszellen," through an intermediate nucleated proto-plasmic syncytium, indicating that in these tumors as in manyothers cells may differentiate from a syncytium. Blastoma-tous chromaffine cells may not have acquired the specificityfor chrome salts, though having the characteristic morphology,location, relations, and genesis, thus making their recognitiondifficult.The undifferentiated type of neuroblastoma is almost

always malignant, occurs usually in very young children, hasa lobulated structure and a variegated appearance and is atype of nerve tumor apparently peculiar to the synmpatheticnervous system, the corresponding tumor of the cerebro-spinal system being very rare, less malignant, and havingmore an epithelioid character (neurocytoma). It is charac-terized, histologically, by the similarity of certain parts of itstissue with certain phases in the development of the adrenalmedulla and sympathetic ganglia; by its round cells with itsnuclei very rich in chromatin and with scanty cytoplasm thatgives off delicate processes which unite with those of adjacentcells to form a delicate syncytium; by the tendency of thecells to polarize about fine meshes of fibrillae, about

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252 WAHL.

capillaries, and about strands of connective tissue; and bythe peculiar fibrillar ground substance.Owing to the extensive variation in the degree of differen-

tiation of the cellular and fibrillar structures in the undiffer-entiated type of nerve tumors different portions of a malignantneuroblastoma may differ widely in their appearance, bothgrossly and microscopically, some parts resembling a scir-rhus carcinoma, others a round cell sarcoma, glioma, lympho-sarcoma or alveolar sarcoma, but the possession of thefibrillar matrix with its peculiar staining reaction, the tendencyof the cells to give off delicate protoplasmic processes thatunite with adjacent cells to give a fibrillar syncytium and theformation of " rosettes" is distinctive.The fibrilla so characteristic of the undifferentiated nerve

tumors stain neither as collagenous nor as neuroglial fibers;are derived from the protoplasmic processes of the indifferentcells, and serve as precursors of the nerve fibers, in factmay well be embryonic nerve fibers.The malignant neuroblastoma of the sympathetic system

metastasize rapidly and extensively and are especially proneto invade the liver, lymph glands, and bones, but often showcomparatively little infiltration into the surrounding tissues.These metastases occur most often by way of the bloodstream, but may also follow the lymph channels. There isusually a marked tendency to the formation of extensiveareas of necrosis and hemorrhage.

All forms of neuroblastomata are undoubtedly much morefrequent than has been generally recognized, their identifica-tion being often easily overlooked.

BIBLIOGRAPHY.

Ganglioneuromata.I. Axel Key. Virchow's Hirches Jahresb., i88i, ix 2992. Aschoff. Ergebnis. d. allg. Path., v, I9oo.3. Benda. Verhandl. d. Path. Gesell., I904, Heft. i, 266.4. Beneke. Zeigler's Beitriige, xxx, I9OI.S. Borst. Geschwulstlehre, I904.6. Braun. Arch. f. Klin. Chirurgie, lxxxvi, 3 Heft.7. Bruchanow. Zeitschr. f. Heilkunde, xx, 40.

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8. Bruns. Arch. f. Klin. Chirurg., xlii, I892.9. Chiari. Verhandl. d. Naturforscherversammlungen. Diisseldorf.,

I898.I0. Cripps and Williamson. Brit. Med. Jour., I899, ii, io.iI. Fabris. Arch. p. 1. sc. med., xxvii, I903.I2. Falk. Zeigler's Beitrage, xl.13. Freund. Frankerfurter Zeitschr. fur Pathologie, xiii, 2 Heft.14. Friederich. Frankerfurter Zeitschr. fur Pathologie, x, 456.I. Glinski. Referat in Zentralblatt f. Chirurgie, I906.i6. Glockner. Arch. f. Gynaecologie, lxiii.17. Goldman. Beitrage v. Bruns., x, I892.i8. Graupner. Zeigler's Beitrage, xxiv.I9. Haenel. Arch. f. Psychiatrie, I899, xxxi.20. Hagenbach. Deutsche Zeitschrift f. Chirurgie, 19o9, xlix, 570.21. Hook. Frankfurter Zeitschr. fur Pathologie, vii, I9I0.22. Jacobsthal. Verhandl. d. d. Path. Gesell., I909.23. Kaufman. Lehrbuch d. speziellen Pathologie, 1908.24. Krause. Bericht uber die 36 Versamml. der Ophthalm. Gesell.,

Heidelberg, 19II, 337.25. Kredel and Beneke. Deutch. f. Chirurgie, lxvii, 239.26. Loretz. Archiv. f. Virchow, xlix, 435.27. Busse. Arch. f. Virchow Suppl., cli, 66.28. Knauss. Archiv. f. Virchow, i898, cliii.29. McNaughton-Jones. Proc. Roy. Soc. Med., London, I9I1-1912,

299.30. Martius. Frankfurter Zeitschr. fur Path., 1913, xii.31. Miller. Archiv. f. Virchow, 1908, clxli, 41.32. Ohse. Bruns, Beitriige f. Chirurg., 1, I906, 667.33. Oelsner. Munch. med. Wochenschr., I908, 2488.34. Oberndorfer. Beitrage f. Zeigler, 1907, xl.35. Ribbert. Geschwulstlehre, I9o4.36. Risel. Verhandl. d. d. Path. Gesell., I909.37. Peters. Frankfurter Zeitschr. fur Path., 1913, xiii, 117.38. Rosenbach. Verhandl. d. d. Gesell. f. Chirurg., I882, i, 134.39. Sato. Arch. f. klin. Chirurg. Berl., 1912, XCVii, 177.40. Schminke. Beitrage f. Virchow, 1910, xli, 267.41. Schorr. Verhandl. des Russichen Gesell. f. Path., I910.42. Schmidt. Arch. f. Virchow, I899, clv.43. Verocay. Beitrage f. Zeigler, xlvi, 403.44. Weichselbaum. Archiv. f. Virchow, I88i, lxxxv, 554.45. Wegelin. Beitrage f Zeigler, I910, xlvi, 403.46. Worcestor. Jour. Med. Research, i, 59.47. Pick u. Bielschowsky. Zeitschr. f. d. Gesell. f. iNeurol. u. Psychi-

atrie, I91I, vi, H. 4.48. Woods. Prager. med. Wochenschrift, i906, 646.

Maligxant Neuroblastomata.49. Alezais u. Imbert. Compt. Rend. d. la Soc. d. Biol., x9o7.So. Alezais u. Peyron. Compt. Rend. d. Ia Soc. d. Biol., I9o8.

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Si. Amberg. Archiv. of Pedriat., I9o4.52. Askanasy. Verhandl. d. d. path. Gesell., xi, Dresden, i9o7.53. Askanasy. Zeitschr. f. Krebsforsch, ix.'54. Bashford. Berl. Klin. Wochenschr., 1909, I637.55. Borst. Sitzungsbericht d. physick med. Gesell. in Wiirzberg, I89756. Bruck. Jahrb. f. Kinderheilk., lxii.57. Dalton. Trans. Path. Soc., London, I898, XXXvi.58. Gierke. Beitriige f. Zeigler, I905, Suppl. Festschr. f. Arnold.59. Heaton. Trans. of Path. Soc., London, I898, xlix.6o. Hecht. Wienerklin. Wochenschr., I909, 324.6i. Hutchinson. Quart. Journ. of Med., I907.62. Kretz. Ergebn. d. Path., viii, I902, 532.63. Kuster. Archiv. f. Virchow, 1905, clxxx.64. Landau. Verhandl. d. Internat. Path. Cong. Turin, I91I.65. Landau. Frankfurter Zeitschr. f. path., I9I3, xi, Heft. I.66. Lapointe u. Lecene. Arch. d. med. exp., I9o7, xix.67. Marchand. Arch. f. Virchow, lxxxi.68. Marchand. Festschr. f. Virch. Internat. Beit. zur. Wissen. (Med.,

I89I, i).69. Marchand. Festschrift f. Rindfleisch, 1907.70. Marchand. Verhandl. d. internat. Pathol. Kongress. Turin, I9II.71. Pepper. Am.Journ. Med. Sci., I9OI, cxxi.72. Pick u. Bielschowsky. Berl. Klin. Wochenschr., 1913, N. I and 2,

i6.73. Pitt. Trans. of Path. Soc. of London, I898, xlix.74. Richards. Guy's Hospital Reports, 1905.75. Risel. Verhandl. d. d. Path. Gesell., Leipsig, I909, xiii.76. Ruyter. Arch. f. klin. Chirurg, xl.77. Schilder. Frankf. Zeitschr. f. pathol., iii.78. Shukowsky. Jahrb. f. Kinderheilk., lxix.79. Thomas. Beitriige f. Zeigler, l.8o. Tileston and Wolbach. Am. Journ. Med. Sci., I908, cxxxv.8i. Verocay. Festschr. f. Chiari, I908.82. Virchow. Die krankhaften Geschwulste, I864, ii, 150.83. Wiesel. Archiv. f. Virch., I905, clxxx, 553.84. Wright, J. H. Journ. Exp. Med., 1910, xii, 556.85. Anitschkow. Arch. f. Virchow, ccxiv, I37.

Chromaffne Tumors.86. Berdez. Arch. d. med. exp. et. d'anat. path., iv, 182.87. Dagonet. Zeitscher. f. Heilkunde, i885, Vi, 23.88. Hedinger. Frankfurter Zeitschr. f. Path., vii, I909.89. Kawashima. Arch. f. Virchow, cciii.go. Manasse. Arch. f. Virchow, cxxxiii, 391.9I. Marchette. Arch. f. Virchow, clxxvii.92. May, R. Arch. f. Virchow, cviii.93. Monkeberg. Zeigler's Beitriige, xxxviii.94. Simmonds. Arch. f. Virchow, cliii.95. Stangl. Verhandl. d. d. pathol. Gesell., v, Karlsbad, 1902.

NEUROBLASTOMATA. 25 5

96. Stilling. Arch. f. Virchow, cix.97. Vecchi, Bindo de. Arch. f. Virchow, i905 clxxxii.98. Wegelin. Verhandl. d. d. pathologischen Gesell., 19I2, 255.99. Zuzuki. Berl. klin. Wochenschr., i9o9, No. 36, I644.ioo. Zuzuki. Berl. klin. Wochenschr., I9IO, No. 35.

Myeloid Tissue.IOI. Borst. Die Lehre von den Geschwulste, I902.102. Fischer. Frankfurter Zeitschr. f. path., 1913, xii, 409.I03. Fischer. Frankfurter Zeitschr. f. path., 1913, Xii.Io4. Fischer. Miinsch. med. Wochenschr., 1911, xlii, 2244.I05. Gierke. Zeigler's Beitrage, Suppl. Festerschrift f. Arnold, i9o5.io6. Ribbert. Geschwulst Lehre, I9o4.Io7. Schultze, W. H. Verhandl. d. d. Gesell., 1912, 47.io8. Verse. Verhandl. d. d. path. Gesell., 1912, 62.

Gliomata.IO9. Bonome. Arch. f. Virchow, clxiii.I IO. Enrich. Brain, 1897, xx.iii. Hardesty. Am. Journ. Anat., ii.112. Homberger. Frankfurter Zeitsch. f. path., ii, I909.113. Landau. Frankfurter Zeitsch. f. path., I9IO, v, Heft 3.I14. Mueller. Arch. f. Mikroscop. Anat., lv, 99.i15. Reinke. Arch. f. Microscop. Anat., 1, 243.ii6. Schridde. Ergebn. d. Path., x, I904, 5.117. Storch. Arch. f. Virchow, clvii.i i8. Stroebe. Zeigler's Beitrage, xviii, 6o5.II9. Stumpf. Zeigler's BeitraLge, lij I91i.

Development of the Sympathetic System and the Adrenals; alsoMiscellaneous Topics.

120. Bruce, Alex., and J. W. Dawson. Rev. of Neurol. and Psychiat.,1913, Xi, 235.

I21. Courvoisier. Die Neurome., Basel, i886.122. Held. Die Entwickl. des Nervengewebes bei den Wirbeltieren,

Leipzig, I909.123. Howard and Schultz. Monograph, Rockefeller Institute for

Medical Research, No. I i.124. Kohn. Ergeb. d. Anat. u. Entwicklungschr., xii.I25. Kohn. Arch. f. mikroscopic. Anat., lxii.I26. Kohn. Arch. f. mikroscopic. Anat., lxx.127. Kuntz. Journ. Comp. Neurol., xxi, 177.128. Streeter. Keibel and Mall's Human Embryology, 19II, 1912.129. Todd, T. Wingate. Journ. of Nerv. and Ment. Dis., xl, No. 7.I30. Poll. Entwickelung der Nebennierensysteme. In Hertwig's

Handbuch d. Entwickelungsgesch.131. Wiesel. Anat. Hefte., xvi.132. Wiesel. Anat. Hefte., xix.

WAHL.

DESCRIPTION OF PLATES.

PLATE XX., FIG. I.- Drawing of the tumor proper showing its pedicle.FIG. 2.- Drawing of the capsule of the tumor showing its relation to

the left kidney and the left adrenal gland.FIG. 3.- Drawing of a posterior aspect of the capsule of the tumor

showing its relation to the renal vessels and to the pelvis of the ureter.

PLATE XXI. - Photomicrograph illustrating various appearances of theundifferentiated nerve tissue under low magnification.

FIG. 4.- Iron hematoxylin stain. Shows the alveolar type of archi-tecture which prevails in the metastases and in the periaortic tumor mass.Smaller areas of this type are present in the tumor and its capsule. Notethe tendency of the cells to polarize about capillaries or strands of con-nective tissues. Note also the protoplasmic processes arising from thecells and joining them together. x 87.

FIG. S. - Hematoxylin and eosin stain. Illustrates the perithelioma-tous pattern, very characteristic of the undifferentiated part of the maintumor mass. Note the dilated vessels, also the diffuse, pale-stained areasof necrosis. x 43.

FIG. 6.- Photomicrograph taken from a large focus of undifferentiatednerve cells embedded in the main portion of the tumor. Shows the ten-dency of the cells to arrange in characteristic clusters and aggregationsforming the " rosettes " so peculiar to this type of growth. x 43.

FIG. 7.- Illustrates a fibrillar type of architecture. Shows cells looselyembedded in a matrix of fibrille. Note the presence of a well-formed" rosette " near the center of the figure, and a more solid aggregation ofcells (" glial ball") .

FIG. 8. -Illustrates the very cellular type of architecture. Note thetendency of the cells to polarize about round spaces suggesting " rosettes."x 62.

FIG. 9. - Illustrates a metastasis of the indifferent nerve cells into alymph gland. The lighter stained areas represent the remains of lymphoidtissue; the darker stained sections correspond to the tumor tissue. Notethe tendency of the cells of the latter to form " rosettes." x 87.

FIG. IO. -Photomicrograph of a solid cluster of cells projecting intothe space in the fibrillar ground substance (" glial ball "). Note that thismass of cells is connected with the surrounding fibrillar tissue by thenarrow pedicle of fibrilll. x 87.

FIG. II. - Photomicrograph through the boundary zone between thedifferentiated (ganglioneuroma) and the undifferentiated portion of thetumor tissue in the main tumor, showing the invasion of the area con-taining the ganglion cells and nerve fibers by the indifferent nervecells. x 87.

FIG. I2.- Photomicrograph of the larger part of the pedicle of thetumor. Note the large vessel that supplies the tumor, the mass of darkindifferent nerve cells at one end of the vessel, and the bundles of unmedul-lated nerve fibers at the pointed end of the pedicle. x 23.

256

NEUROBLASTOMATA.

PLATE XXII. - Photomicrographs illustrating various appearances ofthe indifferent nerve cells (sympathetic Il Bildungszellen ").

FIG. 13. - Iron hematoxylin stain. Shows several typical " rosettes."Note the fibrillar mesh about which the cells are polarized. Note also thatsome of the fibrillse can be traced into the cytoplasm of some of the sur-rounding cells. x 69o.

FIG. 14.- Van Gieson stain. Shows the fibrillar syncytium in whichthe nuclei of the indifferent cells are embedded. Note that, on one side,the cells are apparently polarizing about a mass of fibrille suggesting theformation of a "rosette." x 360.

FIG. I5. -Iron hematoxylin stain. Shows the detailed appearance andstructure of the indifferent cells. Note the smaller and larger types ofcells, the fibrillo-protoplasmic syncytium in which they are embedded, andthe direct division of the nucleus of one of the cells. Note also the scantyamount of cytoplasm, if any, about the nuclei. x 6go.

FIG. i6. - Photomicrograph, showing a mass of indifferent tissue,embedded in the ganglioneuromatous portion of the tumor proper. Ironhematoxylin stain. Shows an early degree of differentiation of the indif-ferent cells. There is more protoplasmn in the syncytium than usual.The nuclei are more vesicular than those of the indifferent cells, and afew of them have the appearance of ganglion cell nuclei. x 360.

FIG. 17.-From a metastasis in the liver, showing the appearance ofthe individual tumor cells about some atrophied liver tissue. Note alsothat the cells are larger than in other regions. x 690.

FIG. I8. - From a metastasis in a lymph gland, showing the delicateprotoplasmic processes of the cells. Stained after Mallory's phospho-tungstic-acid-hematoxvlin method for neuroglia fibers. x 690.

FIG. I9.- From capsule of the tumor. Shows the tendency of the cellsto polarize loosely about capillaries. x 690.

PLATE XXIII. - Photomicrographs illustrating the ganglioneuromatousportion of the tumor.

FIG. 20. -Iron hematoxylin-eosin stain. Shows a small cluster of gan-glion cells and a nerve entering at the left side and breaking up amnongthe cells. Note that only one of the ganglion cells is encapsulated, andthat only in part; also note the presence of two or more nuclei in someof the ganglion cells, and the occurrence of scattered small cells, many ofwhich are indifferent or but slightly differentiated nerve cells. x 430.

FIG. 21. - Iron hematoxylin stain. Shows a cluster of very irregularganglion cells, lying naked in the fibrillar stroma. Many of the cells aremultinucleated and some are apparently fused together. x 87.

FIG. 22. -Iron hematoxylin-eosin stain. From an area of the edemain a focus of ganglion cells and granular disintegration of the fibrillarmatrix, showing atypical multinucleated giant ganglion cells. Note theapparent direct division of the nucleolus of a ganglion cell in the upperleft corner of the figure. Some of the giant cells consist of irregularmasses of ganglion cell nuclei. Note the striking variation in size. x 430.

FIG. 23.- Iron hematoxylin stain. Shows numerous ganglion cells

257

WAHL.

that have become degenerated and hyaline with absence of many of thenuclei. There are also many unmedullated nerve fibers. x 87.

FIG. 24. -Iron hematoxvlin stain. Shows interlacing bundles ofmedullated nerve fibers. x 87.

FIG. 25. -Bielschowsky's stain for neurofibrille. Shows a small clusterof ganglion cells with delicate black nerve fibers entering it. Note thebundles of nerve fibers within the surrounding tissue. x 87.

FIG. 26.- Bielschowsky's stain for neurofibrillhe. Shows a ganglioncell with a long process containing an axis cylinder. Note the absence ofsheath cells about this nerve fiber arising directly from the ganglion cell.Also note the presence of scattered indifferent cells. x 69o.

PLATE XXIV., FIG. 27.- Photomicrograph of a Bielschowsky's silverpreparation showing three ganglion cells and many nerve fibers. Notethe relation of the sheath cells to the nerve fibers. Note also the occa-sional presence of two or even three neurofibrillm in a single nerve fiber.Preparation was counterstained with hematoxylin to bring out the nuclei.x 690.

FIG. 28. -Same as Fig. 27. Shows an axis cylinder, leaving a smallganglion cell, and at the other end breaking up among several ganglioncells. x 69o.

FIG. 29. - Photomicrograph of several foci of ganglion cells in the cap-sular part of the tumor tissue. Shows considerable edema in the foci,disintegrating the ganglion cells from each other, especially marked inthe upper foci, where there is a partial cyst formed. x 62.

FIG. 30.-Photomicrograph from same region, but showing the cys-toid structures. Note the disintegrated ganglion cells in these cysticspaces. x 62.

FIG. 31.- Photomicrograph showing partial obliteration of the cysticspaces, with loose connective tissue derived from the surrounding walls.x 62.

FIG. 32.- Photomicrograph illustrating the transformation of an areacontaining many cystic spaces into a cavernous angiomatous appearancewith red cells, degenerated ganglion cells, fibrin and cellular ddbris in thelumina. x 62.

FIG. 33. Photomicrograph illustrating the transformation of areas ofcystoid formations to patchy areas of fibrosis. x 62.

FIG. 34. - Photomicrograph of an area of indifferent cells showing theformation of embryonic nerves represented by the lighter areas withparallel running nuclei. Compare with next figure. x 4o.

FIG. 35.- Photomicrograph taken of a part of the anlage of the adrenalgland in a human fetus about ten weeks old. Note the separation of thetissue on left two-thirds of figure into upper and lower parts; lower onerepresenting the cortical part of the adrenal, the upper part the paragan-glion composed of sympathetic " Bildungszellen." Note the presence oftwo embryonic nerves in the upper part of this section. Also note a" rosette " embedded in the lower left quadrant, indicating the migrationof the cells of the paraganglion to the center of the cortical anlage in theform of " rosettes." Also note in the upper right corner a sheath-like

258

NEUROBLASTOMATA.

arrangement of cells (not well focused), which is apparently the separa-tion of a " rosette " into two unequal halves connected by parallel fibrille.x 40.

FIG. 36. - Photomicrograph of a " rosette " composed of indifferent cells,embedded in the anlage of the cortex of the adrenal gland in a humanfetus at about io weeks. x 360.

PLATE XXV., FIGS. 37 and 38. - Photomicrograph of myeloid cellstaken from an area of myeloid tissue in the capsular part of the tumortissue. Note a mitotic figure in each photomicrograph. Note a diasterstage near the center of Fig. 37 and an equatorial plate stage in upperright corner of Fig. 38. Note variation in the size and morphology ofthe cells. The two large cells in the lower part of Fig. 38 containedeosinophilic granules in the cytoplasm. Note also that the cells are sur-rounded by a delicate reticulum. x 690.

FIG. 39.- Photomicrograph of an area of myeloid tissue. Note theradial arrangement of the cells about the blood vessels. x 87.

FIG. 40.- Photomicrograph of a metastasis into a lymph gland, showinglymphoid tissues on one side and indifferent tumor cells on the other.Compare these cells with the cells in Figs. 36 and 37, and note the strikingdissimilarity between them. x 69o.

FIG. 4I.- Photomicrograph of a giant megalokaryocyte present in themyeloid tissue. x 69o.

FIG. 42.- Photomicrograph of a very sclerotic and thickened bloodvessel in the capsular portion of the tumor tissue. Note that the lumenis almost obliterated. x 87.

FIG. 43.- Camera lucida drawing of a nerve fiber, showing the relationof the sheath nucleus to the nerve fiber and the axis cylinder. Bielschow-sky preparation, counterstained with hematoxylin. x 1240.

FIG. 44. -Camera lucida drawing of a nerve fiber showing a markedelongated ribbon-like sheath nucleus frequently seen along the nerve fibersin the tumor tissue. x 1240.

FIG. 45. - Camera lucida drawing of a ganglion cell with neurofibrillepassing out along its single large process. Note that the latter is split intwo parts at its base. Note also the presence of three neurofibrille in thenerve process, and that they disappear in the neighborhood of thenuclei. They are not equally sharply focused in one plane. Bielschow-sky preparation. x 1240.

FIG. 46.- Camera lucida drawing of a ganglion cell showing partialdirect division of the nucleus with the presence of three distinct nucleoli.Note the indentations of the nuclear membrane suggesting beginningdivision, corresponding to the three nucleoli. Bielschowsky preparation.X I240.

PLATE XXVI. - Photomicrographs illustrating the chromaffine tissuesof the tumor.

FIG. 47.-Iron hematoxylin stain. Shows clusters of indifferent cellsand nests of chromaffine cells, embedded in a fibrillar matrix beneath the

259

base of the pedicle of the tumor. A large nest of the chromaffine cells isshown in the lower right quadrant. x 62.

FIG. 48.- Hematoxylin and eosin stain. Shows columns of chromaffine(?) cells, embedded in the capsule of the tumor at least one centimeterfrom the adrenal gland. x 87.

FIG. 49.- Iron hematoxylin stain. Shows foci of chromaffine cells,embedded in a dense cellular mass of indifferent tumor cells in theperiaortic mass. x 360.

FIG. 50.- Hematoxylin and eosin stain. Shows an irregular L-shapedarea of cuboidal epithelial cells (chromaffine cells), embedded in a massof indifferent tissue in the periaortic tumor mass. Note the syncytium inthe angle of the L; and that the cells are lighter and surrounded by moreprotoplasm than the indifferent cells at the periphery. x 87.

FIG. 5I.- From same preparation as Fig. 50, showing two large chrom-affine cells apparently developing from the surrounding nucleated proto-plasmic syncytium. x 69o.FIG. 52. -From same preparation as Figs. 5o and Si, taken through

the mass of epithelial cells showing their 6tructure and cuboidal shape.X 9IO.

FIG. 53.- From same preparation as Fig. 47, showing one of the nestsof chromaffine cells under higher magnification. Note their cuboidalshape, but obscure outlines, their tendency to a reticular arrangement,and the presence of many indifferent cells scattered among them. Notealso the surrounding fibrillar matrix. x 360.

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