I.E., Growths Consisting of Specific Nerve Tissue Elements, May * Received for Publication Feb

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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 and Lakeside 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 neuroblastoma). C - Chromaffine tissues (paraganglioma). (d) Summary; (e) anatomical diagnosis. IV. DIscusSION: (a) Relation of the tumor to the sympathetic system; (b) differentiated nerve tissue elements (ganglioneuroma); (c) cystoid formations; (d) myeloid tissue; (e) undifferentiated nerve tissue elements (malignant neuroblastoma); (f) vascular changes; (g) nature of the tumor tissue as a whole and its relation to nerve tumors in general; (h) nomenclature; (i) diagnosis. V. SUMMARY AND CONCLUSION.

INTRODUCTION.- It is becoming recognized, especially in the last four or five years, that the most highly differentiated tissue of the body - the nerve tissue - may and does frequently undergo blastomatous change. True nerve tumors, i.e., growths consisting of specific nerve tissue elements, may * Received for publication Feb. 25, I914. (205) 206 WAHL. occur in any part of the nervous structure, but by far the greater number of them have their origin in the sympathetic system. 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 most frequent and best illustrated in the sympathetic system. The former includes the ganglioneuromata and the chromaffine tumors, in both of which the cells are more or less highly differentiated -depending on the rapidity of their growth and their location. The latter is represented in the central nervous system by the gliomata. Outside of the rentral nervous system, this form was not generally recognized until the last four or five years. It originates in a blastomatous change of undifferentiated and embryonic nerve cells. In the peripheral ganglia it forms what Marchand has termed the neurocytoma. In the sympathetic system, where almost all of the reported cases, especially the more malignant ones, have been found, often associated with the adrenal gland, it is composed of the embryonic formative cells (" Bildungszellen") of the sympathetic system. The development of the present knowledge concerning these true nerve tumors is outlined in a very brief review of the literature.

REVIEW OF THE LITERATURE: (a) Ganglioneuromata. - The term neuroma was first used by Odier, in I803, to designate " deep-seated tumors which are characterized by painful swellings of the nerve involved." Later, it was employed more loosely, being applied to any tumor in relation to a nerve, and indicated an overgrowth of the connective tissue sheaths of the nerve. Then it became entirely a clinical term regardless of whether the tumor to which it was applied was an inflammatory swelling, a metastatic growth, or a new formation of nerve tissue, and it was not until I863 that the pathology of neuromata was placed on a histological rather than a clinical basis. In this year Virchow cleared up the confused status of the neuromata and made a sharp NEUROBLASTOMATA. 207 distinction between the true and the false forms. Accord- ingly, the true neuromata arise in the nerve tissue, and are composed essentially of nerve elements. The false neuromata have their origin in the interstitial connective tissue of the nerves. Virchow sub-divided the true neuromata into: (i) the neuroma gangliocellulare, containing newly formed ganglion cells; (2) the neuroma fibrillare amyelini- cum, consisting chiefly of non-medullated nerve fibers; and (3) the neuroma fibrillare myelinicum, composed mainly of medullated fibers. He also pointed out that undoubtedly the nervous nature of many neuromata had been overlooked, because the non-myelinated fibers were mistaken for connective tissue fibers, and many of the ganglion cells and nerve fibers had disappeared through pressure atrophy and degeneration, and had been replaced by fibrous tissue. While Virchow admitted the possibility, he did not believe that a true neuroma containing proliferating ganglion cells had been carefully described and proved to be such without question. Gunzberg in I847 reported such a case, but Virchow did not consider his description sufficiently complete 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 Axel Key's case in i879 and Weichselbaum's ganglioneuroma in adrenal gland in I88I. No cases were reported for the next eighteen years until I 897, when Busse and Borst each described a typical ganglioneuroma. From this time on similar tumors were reported with gradually increasing frequency. The following year Chiari and Knauss each reported a case. The latter gave the first careful description of multiple neuromata situated in the subcutaneous tissues all over the body. Knauss believed that all of the tumors of his case bore a direct relation to the blood vessels, and that they were derived from the sympathetic cells embedded in the sympathetic plexus about these vessels. He maintained that most, if not all, true neuromata had their origin in the sympathetic system, a view also held by 208 WAHL.

Czerny, and suggested that many multiple neuromata containing only newly-formed nerve fibers probably had ganglion cells that either were overlooked or had gone to pieces in some stage of their development. In I9OI Beneke reported two cases of considerable interest. The tumor in his first case was a retroperitoneal pelvic growth, containing nerve fibers and ganglion cells that varied in size from that of small lymphocytes to fully developed large ganglion cells. Beneke believed that all of the nerve elements - sheath cells, ganglion cells, and nerve fibers- were actively proliferating. He also pointed out that the ganglion cells had no specific functional activity, because the fibers had no end organs. Furthermore, he maintained that in pathological new growths of nerve tissue a true new formation of fibers can arise only in relation to the ganglion cells. Beneke's second tumor is interesting in that it illustrates the malignant transformation of a ganglioneuroma with metastases into the surrounding lymph glands. The tumor enclosed the aorta and metastasized into the surrounding lymph glands. Many of the ganglion cells were scarcely recognizable, being large, irregular and more or less packed with nuclei, giving the appearance of multinucleated giant cells. Typical and atypical ganglion cells were present in the metastases. Beneke pointed out that in the metastases the cells have acquired an epithelioid tendency to line the alveolar framework, and that the ganglioneuromata were associated only with the sympathetic system, and were due to 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 author believed that the ganglion cells in his tumor arose from small round cells with very little cytoplasm and a nucleus so rich in chromatin that no structure could be made out. He regarded these small cells as having an indifferent character, and as being capable of developing into nerve cells or glial cells. In I907, Oberndorfer, in describing a case of a ganglioneuroma involving the adrenal gland, emphasized the intimate !EROBLASTOMATA. 209 association of the ganglioneuromata with the sympathetic system, maintaining that with a true new formation of nerve fibers there must also be newly formed ganglion cells and that every true neuroma must of necessity be a ganglioneuroma. In the same year Falk from a brief review of the literature concluded that in all cases there was a growth of nerve fibers and ganglion cells as well as glial cells and sheath cells; that most cases occurred in individuals under thirty years of age; and that the size of the tumor bore an inverse ratio to the age of the host. He also pointed out that with but two exceptions (Haenel and Axel Key) all the tumors arise in the sympathetic system. He did not believe that there was a ganglion cell for each nerve fiber, explaining the great preponderance of nerve fibers over the ganglion cells in three ways: (a) The nerve fibers represent the product of all generations of ganglion cells that had existed and gone to pieces since the growth began; (b) a new growth of nerve fibers long after the ganglion cells have degenerated, and lastly (c) the development of nerve fibers from the sheath cells. He is thus the first of many workers on nerve tumors to support the cell chain theory of the origin of peripheral nerve fibers. He described many nerve fibers as arising from the cells of the sheath of Schwann through the continuous growth and differentiation of the protoplasm of the latter. In I908 Verocay described the case of a man with an endothelioma of the dura, many subcutaneous neurofibromata, several true neuromata involving spinal nerves, gliomata in the brain stem and a true neuroma arising in the trunk of the sympathetic system. He pointed out that multiple nerve tumors (the so-called neurofibromata) are not made up of connective tissue, but of true neurogenous tissue formed by nerve fiber cells (sheath cells) or by corresponding cells so altered that they are unable to produce the normal elements of nerve tissue. He explained the presence of sheath cells, ganglion cells, and nerve fibers as being due to a varying differentiation of a misplaced mother cell - the 210 WAHL.

neurocyte - and looked upon all of the cases of multiple nerve tumors as manifestations of a "Systemerkrankung" of the entire nervous system. To these growths, derived from nerve fiber cells (neurocytes) and composed of a peculiar tissue that is distinguished from connective tissue by its staining reaction, by the formation of peculiar nucleated bands, and by the pale fibrilla arranged in bundles resembling nervous and glial tissue, but identical with neither typical nerve fibers nor typical glial tissue, he gave the name of neurinomata, meaning, literally, fibrous tumors of a nerve tissue nature. Verocay's case suggests some relation between multiple neurofibromata (at least of one type) and true ganglioneuromata, and gives some basis for his conception that most so-called false neuromata begin as true neuromata, that the ganglion cells and other specific elements sooner or later disappear through degeneration or other processes, and that the only difference between a single true neuroma and multiple neuromata is that in the former the blastomatous change is merely local, whereas in the latter it is pleuricentric. Contrary to previous authors, Verocay did not limit these tumors to the sympathetic system. Schminke's case (I9IO) established the fact that true neuromata occur in the central nervous system. He noted the presence of nests of young cells having the morphology of neurocytes grouped about vessels. These nests he called " Bildungsnester " and " Proliferationszentren." He described all transitions from sheath cells to nerve fibers, thus supporting the theory of the peripheral origin of nerve fibers even in the central nervous system, and noted the presence of young nerve forming tissue in the form of syncytial neuro- blastic masses and their differentiation into non-medullated nerve fibers, an unusual condition for the central nervous system. He believed that the tumor was a further development of a part of the brain that was separated from the rest of the cerebrum in an early period of fetal life, and that the nerve tracts in the brain are developed normally in much the same way. NEUROBLASTOMATA. 2I11

In the following year, Friederich reported a ganglioneuroma in which he maintained that the nerve fibers were a direct continuation of the sheath nuclei, i.e., that the sheath cells were capable of further differentiation into nerve fibers and their adnexa. His conception of the multicellular origin of 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 ganglioneuroma of the central nervous system, and introduced a new and accurate classification of true neuromata. Accord- ing to these authors all true neuromata have their origin in embryonal malformations and displacements of cells in the form of multipotential embryonal neurocytes, according to the degree of differentiation of which a " reifende" or i "unreifende " type of a neuroma is obtained. The former is the ganglioneuroma and occurs most frequently in the sympathetic system. On account of the multipotential power of the cells from which the tumor has arisen, glial tissue may be formed in all three groups. These tumors are almost always benign. On the other hand, the growths of the " unreifende " type are almost always more or less malignant and include (i) the pure cellular neurocytoma of the cerebro-spinal system first described by Marchand in 1907; (2) ganglioma embryonale sympathoma (Wright's neurocytoma, Schilder's malignant glioma); (3) "Hirnschlerose; " and (4) the neurinomata of Verocay, for the peculiar neurogenous fibrillar tissue of these tumors is identified in no way with glial tissue nor with amyelinic nerve tissue and may contain newly-formed ganglion cells. They did not agree with Friederich's conception that the sheath cells may form nerve fibers. The following year McNaughton-Jones described a tumor composed of areas containing differentiated nerve elements (" reifende"), alternating with patches of undifferentiated cells. Peters in I913 described a highly differentiated retroperitoneal nerve tumor containing tissue with few cells and many nerve fibers, alternating with areas very rich in small 212 WAHL. undifferentiated nerve cells. Peters noted, for the first time, nodules of lymphoid-like cells with larger faintly staining cells in the center, resembling lymphoid nodules with germinal centers. He believed that the cells in these lymphoid nests represented different developmental stages of the same indifferent nerve cells, showing a continuous cycle of lymphoid-like cells, differentiating into fully developed ganglion cells, and that the lymphoid-like cells are really " sympathogonien" (Poll). He pointed out that foci of lymphoid-like cells were characteristic of ganglioneuromata, and that of late years they have been generally interpreted as being not lymphocytes, but embryonic nerve forming cells. He denied 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 in the cervical part of the sympathetic trunk, one of which was. benign and composed of well differentiated elements, and the other malignant and made up of undifferentiated nerve cells. The former was a typical ganglioneuroma, the latter a malignant neuroblastoma. This case illustrates the close- relationship between the ganglioneuroma and the malignant neuroblastoma, a fact that Kohn, Wiesel, Poll, and Held hadt anticipated in their embryological researches, and which Pick and Bielchowski suggested but which hitherto had not: been described. As this relation is still more strikingly illustrated in my case, a very brief account of the embryological researches that throw considerable light on this case andi other related nerve tumors will be given preliminary to a brief survey on the literature on these recently recognizedl embryonic nerve growths. In his paper on the development of the sympathetic system, Kohn (1905) pointed out that the embryonic sympathetic cells (" Bildungszellen") are not migrating- preformed ganglion cells, but are simple neurocytes formedi in situ that have, locally, a different power of differentiation: from elsewhere, in that they become differentiated, on the one hand, to ganglion cells, capsule cells, nerve fibers, and NEUROBLASTOMATA. 213 sheath cells and even glial cells, and on the other hand, to chromaffine cells. He pointed out that peripheral ganglion cells are seen in many organs, e.g., the tongue, and are described in clusters in the brachial plexus, and maintained that such cells do not arise from preformed ganglion cells, but from the indifferent cells (neurocytes) of embryonal nerves that have lain dormant in these locations and later taken on growth and differentiated into ganglion cells, and suggested the same mode of origin for the pathological new formation of ganglion cells. Kohn's paper on the paraganiglion is of special interest, especially in connection with my case. In this article he described a new intrinsic tissue, hitherto unrecognized, which he called the " Paraganglion" (chromaffine bodies) which genetically and anatomically is a derivative of the sympathetic nervous system, and which attains its greatest development during fetal life with more or less marked retrogression shortly before cessation of this period. This paraganglion is characterized: ( i ) by its peculiar origin, arising from the formative 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 in all stages, and in all vertebrates. The medulla of the fetal adrenal contains mostly undifferentiated formative cells, which at first cannot be distinguished from young sympathetic nerve cells. Later some of these cells differentiate into chromaffine cells. Kohn maintained that chromaffine cells may be found all over the body wherever there is a part of the sympathetic system; and that they may give rise to pathological new growths, especially in the retroperitoneal region. This work of Kohn was confirmed by Wiesel in his paper on the development of the adrenal glands. Poll gave a very exhaustive account of the development and comparative embryology of the adrenal glands and the chromaffine system. He showed that throughout the entire vertebrate series the chromaffine cells arise from the sympathetic system, and has named the small embryonic undifferentiated sympathetic cell the " sympathogonion." 21I4 WAHL. These cells he held become differentiated either into the elements of the sympathetic system-ganglion cells, nerve fibers, sheath or glial cells, or into chromaffine cells, but, in doing so, always pass through an intermediate stage, which he called the sympathoblast or phaochromatoblast, as the case may be. The genetic relation of the different nerve elements may be expressed in the following scheme (modified from Poll and Landau):

Neuroectoderm of the medullary tube.

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

Sv,nnathetic-. -- r-X- - - system./-J __ V Chromaffine system.

I I I Sympathoblasten (Poll). Phaochromoblasten (Transition cells.) Peripheral glial cells (Poll). (Held). V Ganglion cells Phaochromocytes and (Poll). Sheath cells. (Chromaffine cells.)

Malignant neuroblastomata. - Marchand ( I 89 I ) reported the first neuroblastoma of the undifferentiated type. He described a small tumor of the adrenal medulla composed of small, round, deeply-stained, lymphoid-like cells, containing very little protoplasm and embedded in a finely fibrillar ground substance, making the whole tissue resemble a soft cellular glioma. In fact, he noted that Virchow regarded as gliomata, tumors occupying the same region. He believed that, because the cells in his case so closely resembled those in the medulla of the fetal adrenal, they represented the cells of the medulla in an indifferent stage of development, and that these may later give rise to definite ganglion cells. He also pointed out that the growth of these cells may be so NEUROBLASTOMATA. 2I5 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 gland and the liver, frequently reported in very young children, are really derived from formative sympathetic cells normally present on the under surface of the fetus. In 1905 Kuster reported two peculiar medullary adrenal tumors, which he concluded were gliomata. Both were characterized by being made up of a very large number of small round chromatin rich nuclei, surrounded by little or no protoplasm, embedded in a fine mesh of delicate fibrillk and showing a marked tendency to polarize in two or three rows about a round mass of this fibrillar ground substance, forming a characteristic structure that he called a "rosette." He believed that the growths were derived from a misplaced tissue that had the potential power of forming glial tissue. At the same time Wiesel reviewed these cases and came to very different conclusions, maintaining that since these tumors are located in the sympathetic part of the adrenal glands, and since the sympathetic formative cells have the same morphology and the same tendency to form " rosettes," Kuster's cases are really growths of the "' Bildungszellen " of the sympathetic system, i.e., malignant neuroblastomata. Marchand (1907) reported another tumor, which he described as a neurocytoma of the Gasserian ganglion. This was a small tumor composed of neurocytes having an epithelial character, without any fibrillar differentiation in the ground substance. It represented probably the earliest and purest type of cellular neuroblastomata. In i910 Wright collected twelve of these tumors (four of his own) and described them as a distinct tumor entity, confirming and elaborating the views of Wiesel and Marchand. He pointed out that the cells composing the growths were indifferent nerve cells or neurocytes because (i) they are more or. less associated with delicate fibrils that do not stain like neuroglia, collagenous or fibroglia fibers by Mallory's method, and are, therefore, like the fibrillae that occur in the 2 I6 WAHL. anlage of the sympathetic system; and (2) the tumor cells and the fibrillae have the same morphology and arrangement as the formative cells and fibrille of the sympathetic system and of the medulla of the adrenal glands in an early stage of their development. He noted the presence of two very characteristic aggregations of cells and fibrille, and was the first to emphasize the similarity of these structures to the masses 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 the ends of these bundles and the other is the ball-like structure composed of two or three concentric rows of nuclei, surrounding a central mesh ofdelicate fibrillae (Kuster's rosettes). Wright postulated that owing to the occurrence of indifferent nerve cells which have migrated out from the central nervous system in any part of the body, these neurocytomata, as he called these tumors, may also occur in any part of the body. The fact that he had recognized four of these tumors in one year led him to believe that this type of growth is rare, not in its occurrence, but in its recognition, and he suggested that possibly the so-called adrenal sarcomata collected by Pepper and Hutchinson belong properly to this group. Pick and Bielchowski (1912) pointed out that the malignant neuroblastoma is the " unreifende" counterpart of the " reifende" true neuroma (ganglioneuroma), and that, in its substance, there are scattered throughout, structures that represent physiological stages in the development of the adrenal gland or of the sympathetic ganglia; and that the cells in these structures are but variations from the physiological course of development in that they have not produced a fully differentiated nerve tissue. They adhere closely to Held's idea that, for the anatomical basis of all neuroblastomata, one must go back to the embryonal malformation and cell division in the differentiating qualities of multipotential neurocytes. They call these indifferent nerve tumors arising in the sympathetic system the "ganglioma embryonale sympathicum," homologous with a similar NEUROBLASTOMATA. 2I7 growth of the Gasserian ganglion (Marchand's neurocytoma), which they termed " ganglioma embryonale nervo- rum or cranialum." A ganglioneuroma of the sympathetic trunk they would term a " ganglioma adultum sympathicum." Furthermore, they pointed out that all small round celled medullary sarcomata or alveolar sarcomatoid or carcinoma- toid tumors, occurring in early childhood, have a special significance as being possible embryonic nerve tumors. They also believed that these tumors may contain any combination of differentiated or undifferentiated nerve elements. Landau (I913) described three interesting cases in which he showed that fibril formation is not necessarily present since it represents only the degree of differentiation of the cells, for he pointed out that the fewer the fibrilla the younger and less differentiated is the tissue, and the more nearly does it approach the appearance of a sarcoma. He considered the fibrillm as a primitive differentiation of the plasma of neuroectodermal cells; that is, as embryonic nerve fibers. He pointed out that ganglion cells may occur in chromaffine tumors and vice versa, and sympathetic formative cells in both, while in the embryonic nerve tumors various transitional types of cells may occur. In conclusion, Landau gave the following three main characteristics of these tumors, viz.: (a) congenital anlage; (b) appearance of malignancy in early childhood; (c) genetic relation to the neuroectoderm; and laid stress on the direct relation of the tissue differentiation of the tumors, the character of the growth, and the age of the host, with each other, such that differentiation increases with age, while malignity decreases and the growth assumes more the appearance of a malformation. 1artius (1913) reported a unique case, composed of two distinct parts, one a fully differentiated ganglioneuroma and the other a partially differentiated malignant neuroblastoma. The two suggestive features of the latter were the high degree of differentiation of the fibrillae and the presence of many cells that correspond to Poll's sympathoblasts, which represent an intermediate stage between the undifferentiated 218 WAHL.

formative cell and the ganglion cells. Since these cells formed the predominating cell in the tumor, Martius called this tumor a sympathoblastoma, and looked upon it as affording the missing link between the ganglioneuroma and the malignant neuroblastoma.

Chromaffine tumors. -The third type of growth derived from the sympathetic system is the chromaffine tumor, or paraganglioma, as it is often called, because of its origin from the paraganglia. But very few of these tumors have been reported, and these only in the last five years. Hed- inger (I909) reported the first case, calling it a "struma medullaris cystica suprarenalis." Ganglion cells, sympathetic formative cells, non-medullated nerve fibers and fat tissue were noted in addition to chromaffine cells. An extract of this tumor gave a " typical reaction for adrenalin." Hedinger pointed out that this tumor could well be called a paraganglioma derived from the adrenal medulla. The following year Zuzuke collected from the literature six cases which were otherwise classified, but which he believed should be called chromaffine tumors. In addition he reported three cases of his own, all of which he looked upon as paragangliomata. Kawashima (I9Ii) reported a case of a small tumor of the medulla of the adrenal gland, associated with multiple cutaneous fibromata and patchy pigmentation of the skin, and believed that the cutaneous lesions bore a direct relation to the chromaffine tumor in the adrenal gland, that this case represents a disease of the sympathetic system and the adrenal gland, and that the chromaffine tumor is not an accidental complication, but a part of von Recklinghausen's disease. Wegelin (I i 2) nioted many "sympathognien" in his tumor with various transitions to chromaffine cells. TABLE II. 11falignant Neiiroblastomata.

I I~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Author, Date. Age, Sex. Size. Location. Source. I Metastasis. Structure. 'l tiior Cells. Secotidary Changes. Diagnosis.I Remarks.

Dalton, I885 ...... 6 weeks. Circumference |Left adrenal. ILiver. Alveolar design. Sinall roundI cells. MIucoidl (legenera- IL,Nmphht sarcom)a. Fib)rous stroma 1livides the growth into alveoli. MN. 19.5 in. Rosettes? Fibrillar stroma. tion. Ilemorrha- Sympathetic n e r v o u s ges. system. Marchand, I 89I ...... g months.I "Cherry." |Right adrenal. None. Resembles Rtoundl cells with v e F. glio-ma. iy Henioriliages. SeurocN cvtom-a? Resenmbles fetal brain or sympathetic gang- Finely fibrillar lrnatrix. scanty cytoplasm. lion of a fetus. *Haberfeld, I909..... 7 weeks. M. (Sympathetic ne rv ou s -IGliosarrcoma. Reported in the discussion of Hecht's case system.) and wvas very similar to it. Amberg, I904 ...... 2 montbs. 2 5-I1*3-2-5 cm. Left kidney. Liver. Alveolar F. design. Simall roundl cells, scantv Hemorrhages. iMSaligniant tumor of Noted resemblance of cells to those of the Right adrenal ? Rosettes r e s e m b I e 6; cytoplasm a n d1 (I ar k acdrennial medulla. m-edulla of a six iiionths' fetus. Medulla. months' fetus. nuclei. (Sympathetic nervous ;. *Bruck, 1904 ...... 14montbs. I "Apple." |Rigbt adrenal. system.) Liver. Pancreas. ? F. 81ll~Siiall roundI cells. rrhagic round Cells resembled lymphocytes. Skull. cell s-'arcoiiia. Medulla. Lymph gland. (Sympathetic nervous Richard, I905 ...... 2 weeks. | 2-1! 5 cm- |Left adrenal. system.) Liver. |Vascular sarcoma. .1 ssi i M. .;Small r('oun(l celled sar- Very vascular. Lymph gland. jRosettes? coma. | RetroperitohticnervouMedulla. (Sympathetic nervous Kuster, 1905 (Case I.) I4 weekss. | "Watch." |Right adrenal. system.)l Liver. |Resembles glioma. |Nake(l nuclei, ver) rich in _Glioma, l. ~~~Afewr cells are present that resemble ganglion Left adrenal. Rosettes. Fibrillar stroma. icbroiiiatin. AMedulla.| cells. (Sympathetic nervous Case II...... 34 years. Left adrenal. system.)l None. |Alveolar design. |NTakedl nuclei, very ricli in Has muiltinucleated cells, also some large cells hi. IAs in Case I. Icbromatiiii. NN w ith vesicular nuclei and protoplasml that edulla.| ~~~~~~~ss tended to give off processes. | Cerebellum.tem(Sympathetic nervous and I9 Lapointe Lecene, mIontbs "Two fists." system.) Lymph gland. Resembles glioma. |Naked nuclei, very ricb in I907 ...... F. Had infiltrated the diapbragm. Later the Mediastinum. 1Rosettes. |chromatin. authors called this a parasympathoma. Bewel Sympathetic( ne rv ou s Alezais and 6 system.) Peyron, years. r " Nut." None. Rosettes. Fibrillar stroma. |Large nuclei witb scanty 1907...... M. and rectum. Parasytmpathoma. Seemedl to be associated with the coccygeal I Sympathetic n e r v o u s protoplasm. Igland. Isystem.I Schildler, il909...... 7 days. 113-7-5 mm.n IRosettes. Glial stroma. |Small nuclei, rich in cbro- F. Attacbed to 2d left flemorrhages. Mlaligniant glioma. Contains ganglion and chromaffine cells, but matin, but little c y t o - Blood pigment. no newly formed ones. lnfiltrates the adja- vertebra. |Sympathetic n e r v o u s Iplasm. I system.l cent tissues. Hecbt, igog ...... g years. |Large. Adrenal ? Liver. Resembles sarccoma an F. d Large, pale nuclei, little Lymphio- or g I i o - In discussing this case Haberfeldt believed Lymph gland. |glioma. |cytoplasm. sarcoima. that it arose from the "1 Bildungszellen " of |Sympathetic n e r v o u s Duodenum. |Fibrillar stroniaa. the sympathetic system. Isystem. Tileston and WVolbach, I6 nIonlths cm- |13-8-8 Bones an(l lymph Rosettes. |Round nuclei, little or no| ioma ? Cells resemble the I190 ...... M. and liver. Lynipb immature cells of the blood Iney glan(l . Reticular and fi b r i I I a r Icytoplasm.l series. hIlitotic and amitotic figures present. |Sympathetic n e r v o u s| Istromna. I system.l Wright, I9Io (Case II.) I day. Both adrenals. |Rosettes. Round nuclei, little or no iNeuro)c,vtoma. M. iFibrillae often in bundlles cytoplasm. Nuclei rich 1I-VuLLV%,>;ULVLa |Sympathetic n e r v o u s| 1with clusters of cells. 1in chromatin. Isystem. l Case II...... Adult. Liver. Rosettes. |Nuclei rich in chromatin.| its Characteristic structure is seen only in the M. Fibrillae often in bundles Ilung. with clusters of cells. |Hemorrhages. Case III...... IBlood pigment. Sympathetic n e r v o u s None ? |Rosettes. dis system.? |Fibrillae often in bundles with clusters of cells. |Hemorrhages. IBlood pigment. Case IV...... i6 montbs. Nlediastinum. |Rosettes. its F. Retroperitoneal. Liver. Pelvis ? Fibrillae often in bundles Skull. |Sympathetic n e r v o u s| jwxith clusters of cells. system. |Hemorrhages. Pick and 23 years. Bielschowsky,l Large. Liver. INodular. Cell clusters. |Direct and indirect division forms are I912 ...... F. Iligament. |Ganglioma.l present. Crna Lymph gland. ,Rosettes. Fibrillar stroma. Necrosis. Sympathoma. gagia jZebra appearance. IDegenerations. IEmbryonale. Marchand, I907...... 56 years. |Gasserian ganglion. Sympatheticnerv us Infiltration i n t o IEpithelioidI arrangement. S;mall epitheliod cells. |None. |No fibrillar tissue between M. l |Neurocytoma. the cells. Does system. surrounding tis- |No fibrillar stroma. not properly belong to this group as it is the sues. None. Itype arising in the central nervous system. Landau, 19 I 3 (Case I.) 8 montbs. 7-7-3.5 cm- |Retroperitoneal. Liver. |Lobulated. i'. Rosettes. |Small round cells wi th| |lHemorrhages. Malignant neuroblas-| |Aorta passes through the growth without iFibrillar stroma.l Iscanty protoplasm. Necrosis. tomla.I Ibeing compressed. |Sympathetic n e r v o u s L IFatty Isystem. l change. Case II...... 2.5 years. " Fist." |Right adrenal. Liver. |As in F. C:ase I.l |As above. Some c elsI |Hemorrhages. Malignant neuroblas-| |Larger cells bave vesicular nuclei and are Cut section has a variegated Ilarger, more protoplasm.| Necrosis. toma.i transitional cells to ganglion cells. Many 1~~~~E Kidlney. Bones. Iappearance.l Ifibrill2e. Case III...... X day. Large. |Left adrenal. |Sympathetic ne rv o us |LL,iver.I |As above.l nuclei, much chro-| F. adrenal ? |Large Hemorrhages. Malignant neuroblas-||There is little fibrillar tissue. Thrombi of IRight system. LLymph gland. Appearance is variegated.| Imatin. Little protoplasm. Necrosis. toma.I 1tumor cells in many of the veins. SymnPrs, TAT-3 .... Smal. ISpinal nerves. Nqone.| M. |Soft, cellular. Rosettes. |Scanty cytoplasmn. iHemorrhages. Ne- Neuroblastoma.||Characteristic structures not present in primary Fibrillar matrix.l INuclei rich in chromatin.| crosis. Also cal- tumor, but appeared in the 2d and 3d recur- cium deposits in Irences. Frequent mitosis. vessel walls. Martius, 9139I ...... 2.5 years. Walnut Sympathetic n e r v o u s |I] WI. |Rosettes. Fibrillar inatrix.| |As above, except som e| Calcium deposits. Sympathoblastoma.| Lymphoid follicles. Fibrillae well developed. (Weight, I 7 gins. ) . Right side. system. the muscles. Alveolar design. cells have more cbro-| Hemorrhages. Nuclei often vesicular. Is the "1 walnut" Zebra appearance of cut| Imatin.l part of the tumor. surfaces.l Anitschkow, I1g9I3 .... 4 months. Very large. Sympathetic nervousI F. Lumbar Typical.| |Large cbromatin. R i c h| Malignant neuroblas-| Extended into spinal canal. Multinucleated region. system. spinal canal. inuclei. Scanty cyto-| toma.I cells. Few young ganglion cells. Amitosis. Iplasm.l Some rosettes blave small lumina. -~~~~~~~~~~

* = cases in which account was either incomplete or the original not accessible. .' Size. Gangli.yteuromaa. Author, Date. Evidences Metastases. Source. ri.,f Evidences of Degeneration. Cells of Loretz, 1870. Lymphoid Type. Vascular Cha Remarks. *Axel Key, 5879.

Weichselbauin, iSSi Often 2-3 ganglion cells in a single capsule.

Capsulated. (? Small round cells. I3usse, 1897. Oval and spindle cells occur and are higher stage of round cell. Sheath cells Retroperitoneal. proliferating. Uncapsulated. Knauss, 1598. Ganglion cells have no capsule. *Chiari 1595. Myxomatous. Tumors composed mainly of connective tissue fibers. Non-medullated. Schmidt, 1899. At first tumor was considered a fibroma. *Cripps and Williamson, Variation in size. - Multinucleate ci. Ganglion cells are mostly 1899. Retroperitoneal. apolar. Sympathetic *Haenel 1599. Myxomatous.

*Bruchanow, 1899. diameter. Was not connected with the brain. Medulla. non-med. *Borst, 1897.

Sympathetic Worcester, 190!.

Beneke Case I., 1901 Multinucleate d. - Amitosis ? No axis cylinders.

Sympathetic medul- Hyaline changes. Plasma. Case II., 1901. Vacuolar changes. Lymphocytes. Sheath cells a little increased in number. Myelin abdomina globules. .1 Sympathetic medul. Multinucleated Hemorrhages. Lymphocytes. *l.osenl)acl) 1901. Variation in size. Fat cells are present. Infiltrates the adjacent glands. Resembles embryonic nerve tissue. Retroperitoneal. Sheath seem to form axis cylinder. *Ril)l)eit (2 cases), iyo4

Sympathetic Glockner, 1902.

Retroperitoneal. mpathetic non-med. *1'aljris, 1903. Large number., Calcium deposits. Cystic structures that are probably softened Sympathetic non-med. fibroma. Kredel and Beneke,

1903. tissue . Sympathetic non-med. Benda, 1904. ullated. Mitosis.

Cranial Non-medullated. *(Jhse 1906. Multinueleated. Calcium concretions.

Retroperitoneal. Sympathetic *\\oo(ls 1906.

Non-medullated. *(;lin,li 1900.

Cervical Oberodorfer, 1907. Left adrenal. Sympathetic Non-medullated. Multinucleated. Vacuolar degeneration. Si Variation in size. tall round cells. XT(.ssels have Faik, 1907. Myelin. thiin Has areas that resemble embryonic nerve Transitional cells. Pigmentation. valls. tissue. Retroperitoneal. pathetic non-med- Amitosis. Chromatolysis. P1asma and mast Verocay, I9oS. Vacuolar degeneration. .ells. Second tumor nodule is embedded in the wall 3' Myelin. ofthe duodenum.

Entire non-med. Transitional cells Present. Present. Cystic structures are present. Braun, 1908..

Retroperitoneal. Sympathetic non-med.

system. " Oelsner, I 908. ullated. Present."

nervous Miller, i9o8.

nervous Fat cells are present. A few ganglion cells Multinucleated. Hyaline degeneration. " I.ymphoid tissue." Risel-Zwickaw, 1909 Hydropic degeneration. ... Myelin degeneration. are present in the lymph metastasis. ganglion. T cells. *Jacobsthal, I 909. all round V Has a glial ground substance. *Hagenbach, 1909. Multinucleated. Has a glial ground substance. Ganglion cells and giant cells are in the liver metastasis. Hook, 1910.

Wegelin, 1910. Multinucleated. Vacuolar degeneration. Pla Myelin degeneration. Lyi Mu. ularis . Fat cells are present. Retroperitoneal. thi ekened. Multinucleated. Vacuolar degeneration. Lyz Hyaline degeneration. Pla Neurofibril1. are well differentiated. Nissl's Schminke,i9ro.I Variation in size. Myelin degeneration. granules are present. system. A] Amitosis. Hyaline degeneration. Lyrnphoid *Schorr, 1910. Variation in size. Myelin degeneration. cells. Lymphoid cells are indifferent nerve cells that Transitional cells. form cells or even Pelvis. Edema. medullated nerve fibers.

*Krauss. Newly-formed smooth muscle fibers and vessels. Friederich, I91i.7 verte- I nervous Present. Vacuolar degeneration. Ves Pick and Granular degeneration. Nerve fibers can be traced to sheath cells. Bielschowsky, 2 Fatty degeneration thic 1911. Medulla. ? hya system.

Sato, Has a glial stroma. Nerve fibers have bulb- 1912.3 like enlargements but do not arise from I 1-4th lumbar verte. bra. Medullated fibers. ransitbn. sheath cells. Multinucleated. Vacuolar degeneration. Sma Eosin staining granules are in the I-f. McNaughton-Jones i Hyaline ? degeneration. protoplasm i912(Casel.) Myelin ? degeneration. of some of the ganglion cells. Nature? I Retroperitoneal. '. '' Shrunken cells and nuclei. (Case II.).3, Calcium deposits. Tumor contains friable areas in which there Sacrum. Granular degeneration. seems to be transition to a fibrillo-cellular F " " 7 tissue or to nerve fibers. system. Shrunken cells and nuclei. Peters, 1913.3. Calcium deposits. Resembles the first cases. Right kidney. Granular degeneration. Sympathetic Mostly non-med- system. ullated. Calcium deposits. Lym Martius, Hyaline degeneration. Lymphoid cells in follicles? with germinal 1913.2. Hemorrhage and centers are masses of embryonic nerve M Root of neck. Sympathetic necrosis. cells. .on-medullated. Multinucleated. system. stages. Present. Lym Mitosis. Has a fibrillar Transitional stroma. All transitions from Freund, cells. lymphoid cells to ganglion cells and from i913..3.j fibrilla to fihers. One. Right side neck. nerve This applies only eter. Sympathetic nervous to the ganglioneuroma part of the system. growth. non.medullated. Encapsulated. " Lymj phoid-like cells. Lymphoid cells considered to be glial cells.

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Tables of cases reported in the literature: Table I. Ganglioneuromata. - In glancing over this table it becomes at once evident that the recognition of this type of growth is becoming more and more frequent. It is seen that most cases occur in the female sex (twenty-five out of forty), and at any age, though most ofthem (twenty-nine out offorty- seven) occurred before thirty years, and after forty they are comparatively 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 in adrenal gland). They may arise in any part of the nervous system, occurring in the following order of frequency: sympathetic system (thirty-six), central nervous system (three), peripheral nerves (two), cranial ganglia (two), entire nervous system (one), doubtful (three). Most of the growths are solitary and benign. Of the forty-seven cases five were multiple. Metastases were noted in all but three, infiltration into surrounding tissue in four, and in all of these embryonic and undifferentiated tissue was present. The degree of differentiation of cells is very variable. In almost all in which a complete description was accessible, degenerative changes in the ganglion cells were noted (often adjacent to marked proliferative changes), occurring in the following order of frequency: vacuolar (nine), myelin (eight), hyaline (seven), myxomatous (five), calcium deposits (five). Active proliferation was noted in twenty of the cases in the following order of frequency: multinucleated ganglion cells (twelve), mitotic figures (two), direct division of nuclei of ganglion cells (three). These figures are significant if we recall that in sixteen instances the description was very incomplete or not accessible, and seem to confirm the opinion of many authors that the life history of these cells is markedly shortened. Most of the nerve fibers are non-medullated. It is noteworthy that out of six cases in which a note was made on the condition of tlle vessels, in five there was 220 WAHL. considerable thickening and hypertrophy of the vessel walls, often associated with hyaline changes. In sixteen of the tumors, cells described as lymphoid-like and small round cells occasionally grouped into lymphoid- like follicles were noted, and recent publications indicate that they are usually present, and that they are to be regarded as embryonic nerve cells; in fact, transitional cells to ganglion cells were described in nine of the cases.

Table II. Malignant neuroblastomata. - A study of this table shows how very recent is the recognition of this tumor. It includes twenty-five cases, some of which were at first diagnosed as gliomata or sarcomata. The tumors occur as frequently in the male as in the female. They almost always occur in very young children (twenty-three in children under ten years and twelve in those less than one year old). The table seems to confirm Landau's conception that the younger the host the more embryonic, malignant, and extensive the growth. These tumors may occur in any part of the body, but are most frequent in the adrenal glands (twelve cases), and then in the retroperitoneal region (seven). But one case has been described in the central nervous system, and all but three 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 in two cases, young ganglion cells in four cases, and transitional cells in three cases.

Table III. Chromaffine tumors (paragangliomata).- These tumors are also of very recent recognition. Of the seven cases in which the sex is noted, there were twice as many females as males. The tumor apparently never occurs before the age of thirty, and in fact usually in the last decades of life (four out of seven in persons over sixty). The tumors usually occur in the adrenal glands (ten out of NEUROBLASTOMATA. ;221

thirteen). They are always benign and solitary, and tend to be smaller in size than the other nerve tumors of sympathetic origin. In five of seven cases in which a complete description was available, sympathetic formative cells were described. 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 sympathetic nerve tumors, their interrelationship becomes apparent. Cases of purely one type are rare. Many of them contained elements of two of the types, and one case (Martius) was composed of two distinct parts, each representing a different type. All three elements were present in Hedinger's case, and in one of Zuzuki's, but whether they were newly formed or not, is doubtful. Theoretically, there can be growths in which there are newly formed elements of all three types, but up to date no such case has been described. The following is undoubtedly such a case.

REPORT OF CASE. Clinical history. - The case occurred in the practice of Dr. Price, of Glyndon, Maryland, and was seen in consultation by Dr. J. H. Mason Knox, of Baltimore, to both of whom I am indebted for the clinical history and the opportunity to do the autopsy. The patient was a girl 2i years of age, who had been suffering from marked anemia and obscure abdominal symptoms for several months. During the last three weeks of life there was an irregular low elevation of the temperature, associated with rapidly increasing abdominal distention and tenderness and enlargement 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 ran apparently the same clinical course. Autopsy (4 hours after death). - Unfortunately, only an incomplete autopsy was allowed. The main changes on inspection are a marked general anemia and pallor and a distended abdomen. The spleen is enlarged, reddish brown in color and firm in consistency. The liver is very much enlarged, is pale yellowish brown in color, and its surface is studded with numerous opaque, white, round, tumor metastases (2-25 millimeters in diameter), which also extend throughout the substance of the organ. The lymph glands at the hilum of the liver are much enlarged and grayish red in color. The right kidney has a few small tumor 222 WAHL. metastases surrounded by a small zone of intense congestion in the cortex. Otherwise the organ is pale and shows considerable cloudy swelling of the cortex. The right adrenal gland is normal in appearance and in position. A strikingly variegated oval tumor mass is situated just below the spleen and apparently closely connected with the upper, inner, and anterior aspect of the left kidney, occupying the position of the left adrenal gland, which it seems to have replaced. It is well encapsulated, apparently adherent to the left kidney, and is readily removed with the latter. The kidney itself presents the same appearances as the right one. Its capsule strips off readily, except anteriorly and medially, where it is fused directly with the tumor tissue. The tumor tissue fuses with the anterior part of the capsule of the kidney, 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 kidney substance (Fig. 3). This tumor tissue is composed of two distinct parts, an outer thin portion enclosing an inner egg-shaped mass, which is easily shelled out, remaining attached to the outer layer only at its upper and inner part, where a yellow band of tissue J millimeter in thickness and 8 millimeters wide passes from a process of the left adrenal gland, deeply but loosely embedded in this tissue, and spreads out over the white smooth surface 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 millimeters in diameter), in color (dark gray, reddish gray, yellow, etc.), and in consistency (soft, spongy, friable, elastic, gritty), and that are held together by firm white connective tissue, which is apparently considerably increased in amount towards the base of the pedicle. There is a small area in the dense white tissue about the base of the pedicle which seems to 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 of a semitransparent membrane .5 millimeter in thickness, which, at the sides, becomes abruptly thickened to form a collar of white dense tissue measuring 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. Its inner surface and larger part is mottled dark gray or red in color, and soft and spongy in consistency. Its posterior surface is composed of dense white fibrous tissue, into which several small nerves enter from above. The left adrenal gland is loosely embedded in the thicker upper part of the capsule, and appears normal, except that its posterior part tapers down and forms the pedicle of the inner tumor mass. It is attached to the capsule at two points, one where a nerve passes out from its hilum and enters the compact elastic white adjacent tissue of the capsule, and the other NEUROBLASTOMATA. 223 where a large collapsed blood vessel (3 millimeters in diameter) leaves the gland and plunges into the firm white tissue of the capsule. This vessel does not end in the adrenal gland, but passes along its border into the pedicle of the tumor, and breaks up into numerous large branches in the tumor. The tumor capsule is attached only to the capsule and vessels of the 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 within 2 centimeters of the bifurcation of the aorta, completely encloses this part of the aorta and its branches, and lies over the bodies of the lumbar vertebra a little to the left of the median line. The inferior vena cava passes loosely over its anterior and right sides. It is not connected with the tumor tissue arising in the left adrenal gland. Because of its intimate relation 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 the same nodular structure, variegated appearance and variable consistency as the tumor mass, situated over the left kidney. Many of the nodules are yellow in color and entirely necrotic. Several small nerves enter various parts of this mass running into the firm fibrous tissue framework rather than the individual nodules of softer and grayer tissue. Enlarged gray lymph 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 there is considerable fatty change in the parenchyma, most marked in the central 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 the lymphocytes in the pulp decreased in amount, while there are numerous larger round cells often with eosinophilic granules in the cytoplasm, suggesting both myelocytes, myeloblasts of the bone marrow, and polymorphonuclear leucocytes. There is also considerable congestion. Kidneys: Both organs showed cloudy swelling of the epithelium of the convoluted tubules. There are a few scattered small metastases in the cortex. 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, yet apparently composed of a varying differentiation of the same mother cell - the neurocyte - and in order to obviate needless repetition the description will be given under three main divisions according to the type of tissue present in the four parts of the tumor tissue: (i) tumor, (2) tumor capsule, (3) periaortic tissue, and (4) metastases, viz.: (a) the differentiated nerve tissue, comprising the ganglioneuroma; (b) the differentiated 224 WAHL. chromaffine tissue making up the paraganglioma, and (c) the undifferentiated tissue forming the largest part of the tumor tissue, and comprising the malignant neuroblastoma. (a) Differentiated nerve tissue (ganglioneuroma): This tissue is present in three parts of the tumor tissue, but does not occur in the metastases. Grossly, it has the appearance of dense, elastic, closely-meshed, white tissue, and is most abundant in the tumor proper, where it is massed about 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 portion near the adrenal gland; and in the periaortic tumor it is present in scattered foci and blends with the connective tissue framework of this part. This tissue has a very complicated and variable structure in the tumor proper. There are at least eight main types of architecture with varying combinations of these. They consist in areas composed (i) of a combination of a focus of ganglion cells and nerve fibers bearing a relation to each other that suggests a small sympathetic ganglion (Fig. 20); (2) a large number of irregular large ganglion-like cells lying naked in a scanty fibrillar stroma into which some of the protoplasmic processes of the cells are lost (Fig. 21); (3) interlacing bundles of nucleated fibrille, suggesting a plexus of non-medullated nerve fibers (Fig. 24); (4) irregular, nucleated, fibrillar, fine-meshed reticulum; (5) loose edematous and degenerated nerve tissue containing large and small, rounded, atypical, multinucleated ganglion cells (Fig. 22); (6) a variable number of cystoid formations (noted macroscopically as having a canalized or honeycombed spongy appearance) embedded in a fibrillated ground substance (Fig. 30) ; (7) stratified pattern due to alternate layers of compressed ganglion cells and bundles of sparingly nucleated fibrillae, and (8) scattered, degenerated and hyaline ganglion cells, embedded in a fibrillar stroma (Fig. 23). Nerve fibers: These run in parallel bundles or interweave irregularly with each other. They are almost all non-medullated. The sheath nuclei do not generally show much evidence of proliferation, but in a few areas this is not true, since there are here many sheath nuclei, showing various stages in direct division, budding, swelling, and hyperchromaticity. The dividing nucleus. also shows what is apparently a preceding division of the nucleolus. Some of the sheath nuclei are very much elongated and 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 to 8i [, the degenerated forms being usually the largest. They may be in large masses of cells, or small foci or nests of five to twenty cells or they may be isolated in a plexus of non-medullated nerve fibers or in a fibrillar matrix. Most of them are unencapsulated. They are round or unipolar in shape, but usually more angular in shape giving off one to four protoplasmic processes, one of which may often be traced into a bundle of nerve fibers or occasionally directly into a simple nerve fiber. The cytoplasm is large in amount, stains faintly with eosin, is finely granular and often tends to shrink away from the fibrillar ground substance. The NEUROBLASTOMATA. 225 nucleus is usually large, round, and vesicular, containing a large, round, eccentrically-placed nucleolus and a delicate reticulum, in which a few scattered chromatin granules are embedded. In some nuclei the chromatin is more diffused and the nuclear membrane shrunken and often absent. Degenerated ganglion cells are very frequent and predominate in three locations, viz.: (a) in areas where they are isolated in the fibrillar stroma, (b) in the cystoid structures, and (c) along the surface of the tumor, where they are undergoing a pressure atrophy. The most common forms of degeneration are the granular and hyaline types. In some places they stain diffusely with hematoxylin with little or no differentiation. The cytoplasm often shows considerable shrinkage and vacuolar degeneration. The nuclei are often very large, swollen and hyperchromatic or very much shrunken and pycnotic, and may stain irregularly, occasionally giving a signet ring appearance. Some nuclei show karyorrhexis. Very frequently, the nucleus has disappeared leaving a clear zone in the more or less hyaline cytoplasm. Proliferative changes in the ganglion cells are also frequent. Many of the ganglion cells, even the small forms, contain two or more large typical vesicular nuclei, and in fact some of the cells are so packed with nuclei that little cytoplasm can be seen (often six to twelve characteristic nuclei in a single cell). In some areas these multinucleated cells are apparently fused together giving the appearance of a nucleated syncytium (Figs. 21 and 22). In these areas there are many small round cells very rich in chromatin and various transitions between these cells and the ganglion cells. No mitotic figures are present in the nuclei of the multinucleated ganglion cells, but direct division is frequent and is apparently preceded by direct division of the nucleolus, as shown by the occurrence of two or three large definite nucleoli in a single nucleus (Fig. 46). In some nuclei there was a protrusion of the nucleolus through the nuclear membrane in the cytoplasm. Scattered chromatin granules, surrounded by a narrow clear zone, or a slight reticulum, and occasionally also a partial nuclear membrane are present in the cytoplasm of some of the ganglion cells. This unusual appearance about intracytoplasmic chromatin material may be due to the fact that several nuclei in multinucleated cells have been cut tangentically, so that only small bits of chromatic material instead of whole nuclei appear in the cells. This is unlikely. A second possibility is the occurrence of a localized edema about bits of chromatic material or Nissl's substance. A third interpretation, and one on which we are inclined to lay some stress, is that in some of these cells true nuclei are being formed from extranuclear chromatin material analogous to what is known to occur in certain protozoa. In one large area in which there is marked edema and granular degeneration there are many large, round, multinucleated cells, in which the nuclei are often shrunken, pycnotic, and very rich in chromatin, so that the cells have more the appearance of large multinucleated giant cells than ganglion cells, but there are various transitions between typical 226 WAHL. ganglion cells and these atypical cells, hence they represent most probably degenerative forms of multinucleated ganglion cells (Fig. 22). Specific nerve staining methods: In preparations obtained by the use of Bielchowsky's method for neurofibrils, two or three black neurofibrillx could often be seen in a single nerve fiber (Figs. 25-28). Some of them could be traced through the fiber into a ganglion cell, where they end about the nuclei. The atis cylinders stain black and lie at one side of the nerve fiber close to a sheath cell nucleus, and often show varicosities in their course. Some of the ganglion cells are surrounded by a plexus of these black fibrillm. After Weigert's myelin sheath stain myelin droplets were noted in the cytoplasm of a few of the ganglion cells. This stain also showed an occasional degenerated myelin sheath about some of the nerve fibers, but they are very uncommon. No definite Nissl's granules were demonstrated in the ganglion cells with any of the specific stains for these structures (except a few fine granules near the border of some cells). The fibrillx in the stroma did not take any of the specific neuroglial stains, characteristically, nor did they behave like collaginous fibers. In the capsule, the nerve elements are of two types, one representing undoubtedly a hyperplasia and hypertrophy of normal sympathetic ganglia, incorporated in the tumor tissue, and the other consisting in a definite new formation of ganglion cells and nerve fibers, such as exists in the tumor (the latter contains no normal nerve tissues). In the normal but hyperplastic ganglia the ganglion cells are uniformly arranged, rounded in shape, are usually mononuclear and bear the usual relation to entering nerve 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 and give off usually no discernible protoplasmic processes. No connection between them and the nerve fibers can be traced as in the tumor. The cytoplasm of these cells often appears vacuolated, in fact, entire foci of ganglion cells (2o-30 cells) may show the same degree of vacuolar degeneration and disintegration, which as it becomes more and more marked leads to the formation of the cystoid formations, noted also in the tumor; the development and fate of these cystic spaces is much better illustrated in the capsule than in the tumor, for -in the former there are various stages from slight vacuolar and edematous degeneration of a focus of ganglion cells (Fig. 29), more or less fully differentiated, to the cystic formations, containing remains of disintegrated nerve cells, both undifferentiated or differentiated. The fate of these structures may be twofold. Either they become enlarged, often by the coalescence of several of them, and give the area a honeycombed or cavernous appearance, suggesting a hygroma or a cavernous angioma, if hemorrhage occurs in them as it often does (Fig. 32); or they may become obliterated by an ingrowth of young fibrous tissue from the wall (Fig. 31), so that finally an area composed of lighter and darker patches of fibrillated tissue is obtained (Fig. 33), the NEUROBLASTOMATA. 227 lighter areas often containing remnants of ganglion cells, such as shrunken nuclei, and representing the remains of cystic spaces. Finally, the entire tissue 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 are arranged parallel in bundles suggesting embryonic nerves. The edematous degeneration affecting the ganglion cells foci often also involves the stroma. In the periaortic tumor there are no new-formed ganglion cells, but there are many scattered foci of hyperplastic differentiated nerve tissue representing sympathetic ganglia that have been incorporated in the tumor tissue, and have undergone hypertrophy, some measuring as much as 2 X I5 millimeters, and all in definite relation to some non-medullated nerve 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 and stain very poorly.

Secondary changes: In the first place these may be vascular in nature. Hemorrhage occurs, but is not abundant, except at the boundary between the differentiated and undifferentiated tissues. The vessels show a tendency to sclerosis and partial obliteration, which is most marked in the arteries and blood sinuses. In some vessels there is marked swelling and irregular proliferation of the endothelial cells, resulting in an irregular lumen. In the arteries the intima is swollen, edematous, often with increased fibrous tissue, and frequently has undergone hyaline changes, or in other vessels is vacuolated. The media is thickened in some vessels; in others the muscle fibers appear swollen and vacuolated. The elastic fibers are increased in some vessels and not changed in others. The adventitia is comparatively little affected. In some vessels the lumina are almost completely obliterated (Fig. 42). These sclerotic changes are most marked in the fibrous tissue of the capsule and of the periaortic tumor. In the second place there are degenerative changes involving more than the individual elements, such as deposition of calcium salts seen best in the tumor, and vacuolar and edematous degeneration of considerable areas leading 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 in some areas; in fact this is so extensive that it may form the main feature of 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 in large numbers. They are often arranged in parallel columns held in elongated meshes of a delicate reticulum. In contradistinction to the indifferent tumor cells, they are rounded in shape with a smooth border and considerable protoplasm. They show, however, a marked variation 228 WAHL.

in size and appearance, and apparently include all varieties of cells seen in myeloid tissues (Figs. 37-41). A large number of the cells contain eosinophilic granules in their protoplasm, and have the appearance of myelocytes. There are also many cells that resemble myeloblasts, transitional cells, large and small lymphocytes, plasma cells, polymorphonuclear cells, a few nucleated red blood cells and scattered typical megalokaryo- cytes, measuring 14.7 to 25 ,u in diameter, with large annular lobulated nuclei (Fig. 4I). These infiltrating white blood cells are much smaller and more uniform in size and appearance than the undifferentiated tumor cells. A few young ganglion cells are scattered among them. These inflammatory foci are present chiefly in the capsule of the tumor and in the 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). -This portion 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 far the most extensive part in each of the four main divisions of the tumor tissue; in fact, it is the only portion that forms the metastases. The cells and the stroma form a variable combination due largely to the degree of differentiation of the former, which, in turn, is dependent on the rapidity of growth, thus giving rise to six main types of architecture, viz.: (I) very cellular pattern with few or no intercellular fibrillk (Fig. 8); (2) a loose spongy alveolar design broken up into compartments by capillaries and strands of connective tissue, to which the cells are loosely attached (Fig. 4); (3) peritheliomatous pattern, composed of large, dilated, thin-walled vessels, surrounded by a thick zone of small round cells outside of which the tissue is necrotic (Fig. 5); (4) syncytial pattern of a more or less fibrillar nature, depending on the relative amount of cytoplasm about the cells (Fig. 7), which varies considerably; (5) solid and hollow balls of cells, the latter having the appearance of Kuster's rosettes (Fig. I3), and formed by the polarization of the cells in several concentric rows about a mesh of delicate interlacing fibrillae, many of which are continuous with the protoplasmic processes of the surrounding cells (Fig. 6). Serial sections prove these masses to be spheres, the cells forming the shell, while the interior is 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 adjacent fibrillar stroma, except at one small point where it is attached to the latter by a small pedicle composed of the same fibrillke that interlace between the cells (Fig. io). Lastly (6) a pattern that consists of parallel bundles of fibrillm about which (especially at the ends) numerous small indifferent cells cluster. Between these architectural types there are various grada- tions and combinations, but in a given nodule the arrangement and structure is generally the same throughout. The cellular elements are characterized by the relatively large proportion of the nucleus as compared with the cytoplasm; by the abundant NEUROBLASTOMATA. 229 chromatin material in the nucleus; by the tendency of the scanty cytoplasm to run out into one or more delicate slender processes, which tend to blend with those of adjacent cells, and by the tendency of the cells to polarize about masses of fibrilla (Figs. 13-19). Some of the nuclei are naked; others are surrounded by an irregular narrow zone of cytoplasm. Often the cytoplasm is polarized at one end of the nucleus and serves to anchor the cells to surrounding structures. The nuclei are round or oval and are divided in two types. One is small (4-6.7 , in diameter), round in shape and contains a large amoitnt of chromatin that is diffused throughout. The other is larger, round or irregular in shape, and contains less chromatin, which is collected in small granules. There are various grada- tions between these two types, with sometimes one and then the other predominating in a given area. Mitotic figures are extremely rare, though direct division of the nuclei is frequently encountered. The nuclei are often very much enlarged, hyperchromatic and often give off bud-like processes, taking on very bizarre forms. Karyorrhexis is fairly common. Some nuclei are more vesicular, forming transitional nuclei to ganglion cell nuclei. In some areas, especially adjacent to the differentiated tissue, there are a few larger cells with vesicular nuclei, each containing a large intranuclear 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 several cells together; in fact, in some foci this fact gives rise to a fibrillo-protoplasmic syncytium, becoming more or less protoplasmic or fibrillar depending on the relative amount of cytoplasm present. Some of the isolated cells with the slender protoplasmic processes suggest neuroglial cells, but the intercellular fibrillm do not stain characteristically after any of the neuroglial stains. The vessels are thin-walled, very numerous, and dilated. In the peritheliomatous areas they are very distended with fibrin, serum, and a few red blood cells, and calcium salts are deposited in the walls of some of these vessels. In the capsule the undifferentiated tissue presents the same characteristics. There are no peritheliomatous areas, but there are many places consisting of dense fibrous tissue infiltrated with cords and columns of the indifferent cells, presenting much the appearance of a rapidly infiltrating scirrhus carcinoma. The periaortic mass is composed mostly of nodules of this type of tissue, each nodule presenting some combination of the types of architecture noted 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 small clumps of indifferent cells are present in the peripheral zone of the liver lobules and in the portal veins as tumor emboli. Cords of compressed liver cells may be recognized right in the center of the metastases. 230 WAHL.

These indifferent cells often actively invade the differentiated tissues, especially along the boundary line between them (Fig. ii). They are also present as larger or smaller foci right in the center of this developed nerve tissue. Of the secondary changes hemorrhage and necrosis are very prominent, especially hemorrhage where the indifferent cells are invading adjacent normal or tumor tissue. Often entire nodules show a caseous necrosis. The vessels are very thin-walled. Necrosis is not present in the metastases. There are considerable deposits of calcium salts in the walls of many of the vessels. Infiltration of white blood cells is not prominent, though it does occur and suggests the same condition as in the capsule but of a much smaller grade. (c) Chromaffine tissues.- This type of differentiated nerve tissue is present in isolated foci in all parts of the tumor tissue except in the metastases, 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 of indifferent tumor cells. The cells of the medulla show no brown pigmentation after preliminary fixation in chrome salts (all tissues were preserved in 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 connective tissue core, in which the large blood vessel supplying the tumor is embedded. No medullary tissue is present in the pedicle. At one end of the section there are irregular bundles of non-medullated nerve fibers cut in cross section, and at one side of the large vessel there is a large focus of undifferentiated nerve cells (Fig. 12). At its base the pedicle is separated by bands of connective tissue into three distinct zones, in the central one of which the vessel breaks up into several sinusoid branches. The two outer zones continuous with the cortical layer of the pedicle diverge and spread out over the inner surface of the tumor, while the middle zone enlarges and blends with the dense fibrillo-cellular tissue just beneath the base of the pedicle.

Chromaffine cells. - Deep within the fibrillo-cellular tissue lying beneath the pedicle and showing no connection with the adrenal cells of the pedicle, there are nests and foci of cuboidal epithelioid cells that have the structure and arrangement of the cells of the normal medulla (Figs. 47 and 53). The cell masses may be arranged in solid columns, or alveoli, in anastomosing cords of cuboidal cells, giving the focus a reticular structure, or in a syncytium in which the cell boundaries are obscure. The cells are mostly cuboidal and swollen and often appear to be infiltrating the surrounding fibrillar tissue. They are of two types. In one the cytoplasm stains faintly, and may be vacuolated or shrunken, and the nuclei are distended and vesicular containing a few chromatin granules, scattered in a delicate nuclear reticulum. The outlines of these cells may N EUROBLASTOMATA. 2 3 I be obscure and the cytoplasm often blends with the surrounding tissue. The second type of cell is smaller, with a small, often shrunken nucleus very rich in chromatin diffused throughout, resembling closely the indifferent nerve cells. There are various transitions between this type and the first type. Nests of undifferentiated nerve cells occur in these regions (Fig. 47), and with increasing amounts of cytoplasm show various transitions to the nests of chromaffine cells. Several attempts were made to impregnate these apparent medullary or chromaffine cells, along with the adrenal gland as a control, with chrome salts, but without success, due most probably to preliminary fixation in formalin, followed by alcohol. In the capsule foci of cells, resembling chromaffine cells, were noted in two locations, each at least I centimeter from the adrenal gland, and in no way connected with it. One is a boot-shaped area composed of parallel columns of cuboidal cells, embedded in a fibrillated tissue, containing more or less numerous indifferent nerve cells (Fig. 48). The other is a mass of small undifferentiated nerve cells, in which short columns and clusters of much larger, more faintly staining cells with a cuboidal shape are embedded (Fig. 49). Transitional cells between these cuboidal cells and the small indifferent nerve cells occur. In the periaortic tumor mass there are several foci of epithelioid (chromaffine) ceils, one area being of especial interest. It consists in a fibrillar reticulated stroma, extensively infiltrated with undifferentiated tumor cells and, within it, there is a lighter zone of tissue composed of a wide- meshed, fibrillo-protoplasmic syncytium in which chromatin-rich, rounded or slightly shrunken nuclei are embedded. At one side of this tissue there is an L-shaped cluster of large cuboidal cells (Fig. 50), the cytoplasm of which is considerable in amount, granular, and stains deeply with eosin. The nuclei are swollen and vesicular, and the outlines of the cells are generally obscure, but in a few places they are sufficiently distinct to show that the cells are cuboidal in shape. The cytoplasm of some of the epithelioid cells blends with that of the fibrillar syncytium; in fact, some of the nuclei far out in this syncytium are swollen and vesicular like those of the epithelioid cells, and are embedded in a broader, more cytoplasmic substance, that is finely granular and stains more intensely with eosin than the rest of the syncytium, suggesting a transitional stage to the epithelioid cells in the L-shaped area (Figs. 5t and 52). These cells are most probably chromaffine cells. It should be emphasized that there is no sharp distinction between areas showing the ganglioneuroma, the chromaffine cells, and the malignant neuroblastoma. In some areas only one element is represented; in others varying amounts of two or all three types are present, and in most all sections nests of undifferentiated nerve cells occur. Often the latter can be seen infiltrating into the differentiated nerve tissues like a malignant growth, but always retaining their tendency to form fibrilla and to polarize into "1 rosettes." In summary, the tumor tissue in my case is composed of three distinct 232 WAHL.

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

Anatomical diagnosis. - Malignant neuroblastoma of the sympathetic system, arising in the left adrenal gland and the celiac plexus, with metastases in the liver, lymph glands, kidneys, and left adrenal gland; ganglioneuroma of the left adrenal gland; paraganglioma (chromaffine tumor) of the left adrenal gland; hyperplasia and hypertrophy of the abdominal sympathetic ganglia; general anemia; chronic splenitis; acute parenchymatous degeneration of the liver and kidneys. DISCUSSION. -The study of the different parts of the tumor tissue shows that each part (though distinct anatomically) is composed of elements representing varying degrees of differentiation of a common mother cell, the least differentiated form being most extensive and most malignant. Two facts show that this mother cell is the sympathetic formative cell or " Bildungszelle." First the location of the tumor tissue and its intimate connection with some part of the sympathetic nervous system shows that it has its origin in the latter. In the second place, the sympathetic origin is indicated by the structure, the tumor tissue being composed of cell elements that correspond in relations, morphology, arrangement and degree of differentiation to those of the developing sympathetic nervous system. In both, the cell elements are of two main types, in one of which they are more or less highly differentiated, while in the other they are of an embryonic and indifferent character. The former are again subdivided into two distinct types, one consisting of cuboidal epithelioid cells (chromaffine cells), and the other comprising the ganglion cells and their adnexa. In the tumor tissue the differentiated nerve elements are again subdivided into two classes, one forming a true new formation of nerve cells, the other representing a hyperplasia of normal ganglia incorporated in the tumor tissue. NEUROBLASTOMATA. 233

Degenerative changes are noted even in the hyperplastic ganglia indicating a lower degree of the same blastomatous change associated with general instability and lack of equilib- rium in even the normal elements, incorporated in the tumor tissue. 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 atypical cell elements; in their relations and their degenerative tendency on the one hand and proliferative one on the other. It forms a typical ganglioneuroma. Specific nerve stains, as Beilschowsky's neuro-fibril stain and Weigert's myelin sheath stain, leave no doubt as to the nervous nature of these cells. The mode of proliferation of such highly differentiated cells as the ganglion cells is quite clearly illustrated in this tumor. They do not develop from the division of fully differentiated preexisting ganglion cells or as the result of an anaplasia or " Entdifferenzierung" with subsequent redif- ferentiation, but they arise as a more or less atypical differentiation of rapidly proliferating embryonic sympathetic nerve cells before they are recognizable as such. On the other hand, when these nerve cells have once assumed their adult form, their growth is apparently always incomplete, consisting in growth of cytoplasm and division of the nuclei only, giving rise to multinucleated cells (Fig. 22). Through- out the tumor proper there are various transitional stages between young indifferent nerve cells and fully developed ganglion cells. Indifferent nerve cells and transitional cells are similarly frequently noted in the ganglioneuromata reported in the literature. While the adult ganglion cells do not proliferate as such, yet they show abundant evidence of rapid growth in size and of depression, physiological degeneration, and death. Their attempt to overcome this depression is shown by the numerous nuclei in a single cell (four to twelve); more often large, irregular, nucleated masses of protoplasm apparently crawling through the fibrillar stroma; the occurrence of 234 WAHL. direct division in the nucleus (no mitotic figures were seen), and by the protrusion of nuclear material including the karyosomes through the nuclear membrane into the cytoplasm, producing a true chromidiosis. These regulatory phenomena are, however, inadequate as evidenced by the presence of so many degenerating cells, vacuolated cells, and hyaline anuclear or shrunken ganglion cell remains. In some areas the pathological differentiation and degeneration of these nerve cells is so marked that they are scarcely recognizable, appearing often as multinucleated giant cells with shrunken and degenerated nuclei and cytoplasm (Fig. 22). Such atypical forms are most frequent in the more rapidly growing part of the differentiated nerve portion, indicating that growth is excessive at the expense of differentiation. The cytoplasm in the growing ganglion cells does not keep pace with the nuclear growth nor does it divide, thus upsetting the nuclear plasma relation in favor of the nucleus with rapid degeneration and death of the cell. The frequency of multinucleated and of degenerated ganglion cells in other ganglioneuromata (Table I.) shows that such changes are characteristic in these tumors. As in other tumor cells, in these ganglion cells the karyosome takes a prominent part in nuclear division; in fact, initiates the direct division of the nuclei, as also noted by Howard and Schulz, suggesting a primitive type of nuclear division seen in some protozoan forms. In a few ganglion cell nuclei, the karyosome was broken up into what had the appearance of intranuclear mitotic figures, such as the equatorial plate or diaster stages as described by Schulz.

Nerve fibers.-As in the case of the ganglion cells the nerve fibers have no definite arrangement with each other, and no uniform pattern or common course, but intermingle in a more or less haphazard fashion. The relation of the nerve fibers to the ganglion cells opens up the much disputed problem of the origin of the nerve fibers. They may arise either as direct outgrowths of the ganglion cells, or as a differentiation of sheath cells secondarily united to the NEUROBLASTOMATA. 235 ganglion cells. I shall limit myself only to the evidence that my case gives on this question from the standpoint of tumor formation. Most authors who have recently described ganglioneuromata have taken up this question, but with considerable disparity of opinion. Some (Beneke, Pick and Bielschowsky, Peters, Wegelin, Knauss) maintain that all nerve fibers are derived primarily from the ganglion cells. Some (Schminke, Falk, Oberndorfer, Friederich, Martius, Verocay, Durck) hold just the opposite view and describe various transitions from the sheath cells to elongated nucleated protoplasmic bands, within which fibrille are developed, and to the differentiation of these intraprotoplasmic fibrillk into axis cylinders and neurofibrilla. The evidence in my tumor is mostly in favor of the central origin of the nierve fibers. There were no nucleated protoplasmic bands or fibrillar differentiation in the latter, such as described by Schminke. Many parallel fibrillk were noted, often intimately associated with indifferent cells, but, in an early stage in development of the sympathetic system, cells that are destined to form ganglion cells cannot be distinguished from those that develop into sheath cells, so that these fibrille may represent processes of indifferent ganglion cells as well as a differentiation in the cytoplasm of a fused mass of sheath cells. No transition of nerye fibers to sheath cells, and no axis cylinders passing directly out of sheath nuclei as Fried- erich described was noted in this tumor. The preponderance of nerve fibers over the ganglion cells in parts of my tumor and in many other ganglioneuromata is due not to a differentiation of nerve fibers from sheath cells, but is to be ascribed more to the fragility of the ganglion cells which have degenerated and disappeared, leaving large numbers of nerve fibers representing the processes of ganglion cells of all generations that have developed, degenerated, and disappeared 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 which are also naked and unprovided with a nucleated capsule (Fig. 28). It is very improbable that, if the axis cylinder 236 WAHL. developed from sheath cells, there would be no trace of the latter left. Fibrillm, many of which can be traced into the cytoplasm of undifferentiated nerve cells, cannot be distinguished from embryonic connective tissue fibers, though their arrangement, appearance, and staining reaction are very much like those seen in the adrenal medulla or in the sympathetic ganglia of a young human embryo. The parallel fibrillae are most probably processes of embryonic and undifferentiated ganglion cells, while the nuclei embedded among them are between rather than in the individual fibrilla. It may well be that while the nerve fibril is a definite offshoot of the ganglion cell, the cytoplasm of one or more sheath cells may later enclose or fuse with it, and assist in 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 does not react characteristically to the specific stains for neuroglial fibers, indicating either that the specificity had been lost before tissue was fixed, or that the specific substance had not differentiated, the stroma being of the nature of an embryonic tissue capable of differentiating later into true neuroglial or nerve fibers as in Verocay's neurinomata. The cystoid formations are evidently due to an edema and a vacuolar degeneration involving foci of both differentiated and undifferentiated ganglion cells and secondarily the fibrillar stroma. Vacuolar degeneration and edema are fairly characteristic of blastomatous and even hyperplastic nerve tissue. In the periaortic tumor, one of the incorporated ganglia showed very extensive edema. Cystoid structures were noted in three ganglioneuromata reported in the literature and in several more a myxomatous tissue was described, but no detailed description was given.

,Myeloid tissue. - In most cases of ganglioneuromata a note is made of foci of small deeply staining round cells. At first they were interpreted as lymphoid cells, but most recent authors regard them as undifferentiated nerve cells. It is probable that foci of both cells occur. In addition to NEUROBLASTOMATA. 237 indifferent nerve cells in my case there are, in the capsule of the tumor, considerable foci of small round cells of an entirely different type that apparently bear no relation to ganglion cell formation. They lie in the meshes of a loose fibrillar reticulum, supporting a rich network of capillaries adjacent to an area of hemorrhage or necrosis, and from their distribution, their uniform appearance, their striking tendency towards mitotic division, their staining reactions, their morphology and their relation to the blood vessels, it is evident that they form a new type of cells belonging to a different tissue from that of nerve cells, and that the cells are similar 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 odd position can be explained in three ways. In the first place, the tumor tissue may represent an embryoma, arising from toti- or multipotential cells capable of producing several types of tissue with ectodermal nerve cells predominating. This is unlikely for several reasons, including the fact that some of the foci appear more like white cells of blood, and are not present in all four parts ot the tumor tissue, at least only strikingly marked in the capsule. However, it is quite possible that the tumor tissue is composed of a mass of embryonic nerve cells, which instead of retrogressing at the normal period have increased their vegetative activity, incor- porating indifferent mesodermal elements, which later have become differentiated into different types of mesodermal cells, such as myeloid cells, fat cells, and muscle cells. A metaplasia of tumor cells is also possible, but equally unlikely as the first explanation. The most probable explanation is that these myeloid cells represent an inflammatory infiltration and reaction with a secondary hyperplastic growth of young and plastic white blood cells in loco, this occurring in an individual with a severely taxed and plastic bone marrow, as indicated by the clinical history of a severe and intractable anemia, blood pigment, and myelocytes in the spleen. This fact associated with edema and hemorrhage and necrosis caused a mild 238 WAHL. exudation of white blood cells, including immature bone marrow cells which, finding a suitable environment for growth, took on a growth in situ. At this point it is worthy of note that myeloid nodules have been produced experi- mentally in the liver of rabbits by excising the spleen with subsequent administration of a severe hemolytic toxin, eg., sapotoxin, resulting in the production of nodules of typical myeloid cells. If the latter can thus be produced experi- mentally, there is no reason why, under similar conditions of the bone marrow, such a growth should not occur in such a vascular tumor as this one, especially if initiated by an inflammatory infiltration of these cells. Borst, Schmieden, Albrecht and Gierke have all described tumors containing nodules of myeloid cells or true marrow tissue. Schultz (I912) reported the presence of considerable myeloid tissue in the hilum of the kidney.

Chromaffine tissues. - The other type of differentiated tissue is the chromaffine tissue, i.e., foci of ill-defined cuboidal epithelioid cells that have the morphology, relation, and appearance of the cells of the medulla of the adrenal gland. There are various transitions between small islands of indifferent nerve cells, embedded in a fibrillar matrix and connected with each other by delicate protoplasmic processes to a nucleated protoplasmic syncytium having a vacuolated appearance, to the development of cuboidal cells within this syncytium (Figs. 50-52). These epithelioid cells resemble normal medullary cells in every respect except that the chromaffine reaction was not obtained, probably because of previous fixation in formaline, for it was also absent in the medulla of the adrenal gland itself. In the tumor proper and in the capsule these foci may be accessory or incorporated chromaffine tissues and hence are not necessarily blastomatous, though in the tumor they are actively proliferating. But it is in the periaortic tumor that the best and most convincing evidence ofchromaffine tissue and its mode of development is evident. In this position where normally there are no epithelial structures nor chromaffine NEUROBLASTOMATA. 239 tissues, there are several large foci of cuboidal epithelial cells, apparently differentiating from a nucleated protoplasmic syncytium, which in turn shows transitions to masses of undifferentiated cells (Figs. 50-52). Such a picture could be possible as a result of degeneration of a mass of epithelial cells, but none of these cells appear degenerated; on the contrary, they are large and full; then, too, it is much more probable that these cuboidal cells are differentiated from cells clearly proven to have this power than a degeneration of cells not known to exist here normally. The only objec- tion to classifying these cells as chromaffine cells is the absence of the chromaffine reaction, yet, even if the tissue had been fixed immediately in the solution of chrome salts, the reaction of the true tissue would not necessarily have shown, because this cell in a tumor is not, at best, a fully differentiated (functionally) cell, owing to its blastomatous nature. The chief reasons for considering these cells chromaffine cells are because of their morphology and because they are embedded in a neurogenous tissue, the indifferent elements of which are known to differentiate, in part, into chromaffine cells, and this transition can be traced through an intermediate syncytial stage to the indifferent cells. After differentiating, these chromaffine cells, like the ganglion cells, do not divide.

Cellular undifferentiated tissue. -This portion forms the malignant element of this tumor, and has the same characteristic structure and architecture, wherever it is present, in the tumor, capsule, periaortic mass, or metastases. The cell unit is a small cell with a relatively large nucleus, very rich in chromatin, surrounded by little and, in some places, no discernible cytoplasm, and embedded in a more or less delicate fibrillar stroma (Figs. 15-19). The variations in the arrangements of these cells, in the relation of their cytoplasm to the stroma and to the connective tissue bands; and in the occurrence of secondary changes such as necrosis, hemorrhages, and degenerations, gives rise to a variegated appearance and numerous architectural designs, six types of 240 WAHL. which were described and any combination noted, giving one part a very different appearance and structure from another part. In the fibrillo-syncytial type the fibrilla became relatively very prominent, and often there are small elongated irregular foci of sparingly nucleated parallel fibri1la considered by Martius and Peters as embryonic nerves. No extensive fibrillated structure noted by these authors was in this part of the tumor. The cells vary markedly in size and shape and are malignant in character. They actively infiltrate adjacent beriign and differentiated blastomatous nerve tissue and metastasize extensively in the liver. There are various types of nuclear and cellular depression, such as extensive direct nuclear division, nuclear budding, hyperchromatism, and chromidiosis. The prevalence of direct nuclear division illustrates the fact that these embryonic nerve cells are similar to many other tumor cells in the mode of nuclear division. Where the growth is less rapid the cells tend to form a syncytium that is fibrillar or cytoplasmic, depending on the relative amount of protoplasm that is present. In general, the indifferent cells tend to join each other by delicate protoplasmic processes that polarize into rosettes, parallel bundles of fibrilla and embryonic nerves. The young nerve elements seem to differentiate from a syncytial basis, at first fibrillar and later mnore cytoplasmic. In connection with the study of this case several human fetal adrenal glands were examined (from four centimeters in length, up), and the cells of the medulla of the adrenals and neighboring sympathetic structures compared with the indifferent cells in this tumor, and very striking resemblances were noted, especially the presence of " rosettes" anid bundles of parallel fibrilla, connecting clusters of small round cells, thus confirming the findings of Wright and others and warranting the conclusion that the indifferent cells of my tumor are sympathetic formative cells. Some of the indifferent cells have retained considerable power of differentiation in that they may become a little larger with more vesicular nuclei, forming an intermediate stage (Poll's sympathoblast) NEUROBLASTOMATA. 241 between the indifferent cell and the ganglion or chromaffine cell. These intermediate cells are uncommon in the undifferentiated nerve tumors, but more frequent in the ganglioneuromata, a relation that is also true in the different portions of my case. A tumor containing a large number of 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, yet this does not preclude their being of a glial nature, because the specificity of the stains is soon lost after death, or because these fibers may not be fully developed, and have not acquired their specific attributes. They may, accordingly, be embryonic nerve fibers, neuroglial fibers, or young connective tissue fibrilla, and probably all three are represented. There are various transitions between solid balls of indifferent cells, embedded in a fibrillar mesh to "rosettes " and from these through separation of each half of a " rosette " to bundles of parallel fibrilla, connecting clusters of indifferent cells at each end. These fibrillae represent undoubtedly embryonic nerve fibers, for many can be traced into the cytoplasm of the indifferent cells clustered about their ends just as in the fetal sympathetic system. The more undifferentiated the cells, the fewer are the fibrilla, and with increased differentiation the fibrilla accordingly become more and more prominent. The separation of the rosette into two parts connected by parallel fibrils suggests this as a mode of formation of nerves from " rosettes."

Vascular changes. - In the differentiated tissues and in the fibrous part of the capsule the vessels, especially arteries incorporated in the growth, show a very marked tendency towards endothelial hyperplasia and obliterating sclerosis often associated with thickening and edema of the intima and vacuolar or hyaline degeneration of the media. Some vessels show a unilateral thickening of the intima and endothelial lining. Apparently, there is first a thickening and hyperplasia 242 WAHL. of the muscles of the media followed by edema and fibrosis in the intima and atrophy of the elastic fibers, and later vacuolar and hyaline degeneration of the muscle fibers in the media. Sclerosis of the vessels was noted in five cases of ganglioneuromata reported recently in the literature, and seems to be a not infrequent condition. It may mean that there is considerable unrecognized chromaffine tissue (especially since in my case scattered foci were found) embedded in the nerve tissues, giving the specific functional effect of this tissue on surrounding vessels, resulting in chronic hyper- tonus of the arterial walls, their hypertrophy, and ultimately to the exhaustion and ddgeneration of the muscle fibers. However, it would be hazardous to lay much stress on this relation without further evidence. On the other hand, it is quite possible that the sympathetic cells supplying these vessels have become involved in the blastomatous change, resulting either in loss or perversion of their functional activity, and it may well be that these sclerotic changes are but trophic manifestations of this change in the sympathetic cells controlling the vessels in question, as Todd has suggested in explanation of other forms of vascular sclerosis.

Nature of the tumor as a whole and its relation to nerve tumors. - Without doubt the tumor is of neuroectodermal origin, the mesodermal elements playing but a secondary part. At first one would be inclined to regard this case as exhibiting two distinct types of tumors each having a very different origin, one benign, a ganglioneuroma and of neuro- -ectodermal origin, and the other malignant, a peculiar type of a sarcoma and of mesodermal origin; but a careful study shows that both arise from the neuroectoderm, and that the 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 the connection of both with the sympathetic nervous system, and (4)to the similarity of the structures in both types to various stages in differentiation of the fetal sympathetic system and adrenal medulla. The cells of the different parts of the NEUROBLASTOMATA. 243 tumor show varying degrees of differentiation, from the indifferent nerve cells to the fully differentiated ganglion or chromaffine cell, showing that in a way the tumor represents the entire physiological development and differentiation of the sympathetic " Bildungszellen." The indifferent cells of the tumor are, accordingly, classed as sympathetic formative cells, first because of their location, being almost invariably connected with the sympathetic system, and secondly, because of their close similarity in structure, arrangement, and differentiation to the sympathetic " Bildungszellen." Why one part of this tumor is malignant and invading another portion that is benign, as well as the normal tissues of the abdomen; why there are three separate and distinct parts, each with the same peculiar characteristics, and why there is such an intimate relation and yet, in a way, distinct separation between the tumor proper, its capsule and the left adrenal gland, - are queries that are readily explained by 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 the other, more or less completely enclosing this part of the abdominal aorta. These cells and their ground substance bore a close resemblance to the clusters of indifferent cells and the fibrillar stroma of the malignant part of the tumor. In this fetus there was no medullary substance in the center of the adrenal gland except a small number of indifferent cells, but sympathetic "1 Bildungszellen" were migrating singly and in clusters, often as " rosettes " (Figs. 35 and 36), through the cortical substance and converging toward the center of the gland. The mass of cells about the aorta joining one adrenal to the other forms the abdominal paraganglion first described by Kohn, who also pointed out that these fetal organs (paraganglia) reach their greatest extent during fetal life, and have undergone considerable retrogression by the termination of this period, parallel with corresponding progressive differentiation of the sympathetic 244 WAHL. elements, so that in man little more remains than ganglia, nerves, and chromaffine cells. Accordingly, at the height of development of the paraganglia there is a mass of formative cells entirely enclosing the cortical part of the adrenal glands, another portion accumulated in the center of the adrenal gland, and a third large, irregular mass, extending from that about one adrenal to that about the other part, enclosing the aorta. In the human fetus this stage occurs relatively early, as little trace of the paraganglion or formative 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 the paraganglia at the height of the latter's development, certain of the cells in entirely different areas behaving abnormally and instead of retrogressing in the normal manner retained their vegetative activity, and failed to develop their full differentiating power, resulting in tumor formation. It is very probable that a partial retrogression did occur in places allowing sufficient differentiation to go on to form fully developed nerve cells or a portion of the cells may have become dormant and later become active and gone on to further differentiation, while the larger part of the indifferent cells retained their vegetative activity. In the medulla of the left adrenal gland some of the indifferent cells retained their differentiating power, giving a large mixed tumor containing a mass of differentiated tissue, including ganglion cells and chromaffine cells overgrown by a malignant part made up of indifferent cells, all joined in a large lobulated tumor connected with the left adrenal by a flat pedicle of cortical adrenal tissue. There was simultaneously a new growth of the indifferent cells, surrounding the adrenal gland giving rise to the thick tumor capsule within which the adrenal and the inner tumor mass is embedded. At about the same time there was a marked hyperplasia or blastomatous change in the cells of the paraganglion over the aorta resulting in the periaortic tumor. The lobulated structure of the latter indicates a partial retrogression with the formation of islands of embryonic sympathetic cells separated by bands of NEUROBLASTOMATA. 245 connective tissue, and differentiated nerve tissues, followed later by a blastomatous change in the isolated nodules of indifferent nerve cells, each nodule developing by itself into its own characteristic architecture, though joined by connective tissue framework with similar nodules into a conglomerate tumor mass. The same process accounts for the lobulation in the tumor and in its capsule. It is quite probable that for a time the entire growth was slow, associated with more or less complete differentiation of some of the cells when some cause excited all the tumor cells to more rapid growth, the differentiated cells becoming more and more atypical and the indifferent cells assuming more and more malignant properties. The cells still retain some specificity and power of differentiation in that even in the metastases they tend to polarize 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 portion of the sympathetic system, but not so extensive as in Verocay's case, though more extensive than in the cases reported by Landau and Martius. In my tumor the change apparently involves only the abdominal segment of the sympathetic system on the left side, but since the examination of the child was unfortunately incomplete, there may or may not have been further involvement of the sympathetic system. 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 cells with no fibrillar differentiation, and with an epithelioid character. The next stage is the malignant neuroblastoma, composed ofsympathetic formative cells, and between this type and the fully differentiated ganglioneuroma and chromaffine tumor there are the sympathoblastoma and the phaochromoblastoma. Though the latter has not been described, yet it may occur not infrequently, being composed of cells that are similar in morphology and genesis, but have not acquired the specificity for chrome salts, the absence of which renders the diagnosis difficult. Its relation to the sympathetic system, 246 WAHL. the morphology and histogenesis of its cells, and the presence of other sympathetic elements should aid in its recognition, and it may well be that such cases will be reported in the future. The genetic relationship of the different types of nerve tumors to each other is illustrated in the following scheme: { Medullary neuroblasts, Neurocytoma 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 case shows that in nerve tumors the older the host the more differentiated and benign the tissue growths as a rule, the malignant neuroblastomata usually occurring in young children, the ganglioneuroma in the first half of the normal life span and the chromaffine tumor in the latter half. Evidently the chromaffine tumor is the last type to become blastomatous, but this may be only apparent, as it is the easiest to overlook if it has not been fixed in a solution of chrome salts. The degree of differentiation bears the same relation to true nerve tumors as to tumors of other tissues. High differentiation is usually confined to benign tumors, while the more malignant the tumor becomes, the lower the degree of differentiation as a rule. It is, par excellence, in these nerve tumors composed of tissue of widely varying degrees of differentiation NEUROBLASTOMATA. 27 that important facts in normal histogenesis of nerve tissue may be established.

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

Diagnosis of neuroblastoma. -The ganglioneuroma presents little difficulty in its recognition because of its invari- able connection with some part of the nervous system, and because of the unmistakable morphology and arrangements of its elements. The chromaffine tumor is easily recognized because of its connection with the sympathetic system and the affinity that its cells have for chrome salts, but if the tissue has not been fixed in solution of chrome salts within a few hours after death, this reaction is often absent, the recognition is more difficult, and the identification of the cells depends then on the relation of the tissue to the sympathetic system and the morphology and arrangement of the cells, especially if other epithelial structures can be excluded. Anatomically the recognition of the tundifferentiated type of nerve tumor is often very difficult, because some parts may simulate a round cell or alveolar sarcoma and a single 248 WAHL. section may be very misleading, while a second section from another portion of the tumor may show the characteristic structures. When the cells show a low degree of differentiation, few or no fibrilke are present, and the only cue to its nature is its connection with some part of the nervous system or the presence of a more characteristic structure in another part of the same tumor. The fact that over one-half of the cases reported in the literature were noted in the past four years suggests both the frequency with which these tumors have probably been overlooked and the more common recognition of them in the future. In fact, sarcomatous tumors in the adrenal or retroperitoneal region of very young children should be regarded with suspicion. In a lobulated variegated tumor, the presence mostly of cells with comparatively large round nuclei, very rich in chromatin, surrounded by a very small amount of cytoplasm tending to flow out into one or more processes; the tendency of the cells to polarize about masses.of fibrillw forming rosettes and other cell aggregations; the occurrence of bundles of parallel fibrille connecting clusters of small round cells of a fibrillar matrix staining neither as collagenous nor as glial fibers; of considerable variation in the architecture, of frequent degenerative changes (necrosis and hemorrhage) and the occasional occurrence of more highly differentiated cells are decisive points in the histological diagnosis. A definite connection with the sympathetic system makes the diagnosis much more certain. Clinically, the ganglioneuromata are difficult to recognize, for a large percentage of the cases were discovered at autopsy or at operation with no sympathetic symptoms in life. A mass in the retroperitoneal space in a child or young person should be suggestive. The same facts apply to chromaffine tumors except that they are rarely large in size and usually occur in very elderly individuals. The malignant neuroblastoma is more easily recognized, clinically, than the other two types, because of its usual occurrence in very young individuals, its rapid malignant course, and the rapid painful enlargement of the abdomen without ascites or with the appearance of tumor nodules in the NEUROBLASTOMATA. 249 bones, especially of the skull with exophthalmus (Hutchin- son's type). The clinical data given in most cases are so meager that it is impossible to give more details on the clinical course. A tumor in a young child, especially if it run a malignant course and occurs in the adrenal glands or connected with some part of the sympathetic system, should suggest a malignant neuroblastoma of the sympathetic system before a sarcoma or any other malignant growth.

SUMMARY AND CONCLUSION. Nerve tissue may give rise to new growths, which are properly called neuroblastomata. They may occur in any part of the nervous system and are of two types, according as they are composed chiefly of differentiated or undifferentiated elements. The neurocytoma is the undifferentiated type. arising in the cerebro-spinal nervous system. The corresponding type derived from the sympathetic system is the malignant neuroblastoma of the sympathetic nervous system or the " sympathoma embryonale." The ganglioneuroma and the chromaffine tumor represent the differentiated nerve growths, the latter taking its origin only in the sympathetic nervous system, the former arising also in the cerebro- spinal nervous system. Most neuroblastomata especially of the undifferentiated type arise in the sympathetic nervous system. Most of the neuroblastomata of the differentiated type contain both mature and immature cell elements, one type greatly predominating over the other. Foci of indifferent cells are usually present in both ganglioneuromata and in chromaffine tumors. Differentiated elements occur, but less frequently, in the undifferentiated neuroblastomata. There may be any combination of differentiated and undifferentiated elements in these nerve tumors. Though the nerve tumors of the sympathetic system malignant neuroblastomata, ganglioneuromata and chromaffine tumors -show very marked differences in appearance, behavior, and morphology, they are closely related genetically, being varying differentiations of the same mother cell 250 WAHL.

- the sympathetic formative cell (" Bildungszelle ") which normally differentiates into ganglion cells, peripheral glial cells, and chromaffine cells of the sympathetic system. The infrequency with which pure neuroblastomata of any one type occur, the occasional occurrence of nerve tumors, composed of two distinct portions each composed of a different form of nerve cells with transitions between them and my tumor containing all three elements actively partici- pating in the growth, establishes the intimate relationship of these tumors to one another. Accordingly, the ganglioneuroma and the chromaffine tumor are the differentiated coun- terparts of the malignant neuroblastoma. Neuroblastomata are manifestations of a pathological condition more or less localized or diffused in the whole or part of the nervous system. If localized to one focus, as is usually the case, the result is a solitary nerve tumor (ganglioneuroma); if generalized, multiple tumors result. Intermediate stages and varieties occur frequently. In the present case apparently only a segment of the abdominal sympathetic system was involved, resulting in three primary growths, each of which was composed of the three elements of the sympathetic system (ganglion cells, chromaffine cells, and indifferent nerve cells). Derivatives of the mesoderm (myeloid cells, fat tissue, and striated muscle foci) may be accidentally incorporated in the tissue of these tumors. The neuroblastoma is derived from the neuroectoderm and shows variations in differentiation, the degree of which apparently varies directly with the age of the host, while the malignant properties bear an inverse proportion to age. The cellular elements of the neuroblastomata, like those of other tumors, composed of differentiated cells, retrogress and revert to the embryonic condition of the mother (nerve) tissue as the growth becomes more undifferentiated and malignant. The ganglioneuroma usually occurs in young individuals, but may occur at any age. The life history of the blastomatous ganglion cells is very short and the cells are very prone to degenerative changes. They are incapable of complete NEUROBLASTOMATA. 2 5 I division after full differentiation, but manifest a limited growth, however, by division of the nuclei and increase in the amount of the cytoplasm. The nuclei apparently divide only by direct division, a process that seems to be initiated by preliminary direct division of the nucleolus. Ganglion cells do, however, multiply rapidly in their indifferent stage, when they are not recognizable as such. Clusters of ganglion cells, whether differentiated or not, occasionally undergo an edematous degeneration, resulting in cystoid structures that may 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 the female sex, but usually occurs very late in life. The cellular elements differentiate from masses of indifferent sympathetic " Bildungszellen," through an intermediate nucleated protoplasmic syncytium, indicating that in these tumors as in many others cells may differentiate from a syncytium. Blastoma- tous chromaffine cells may not have acquired the specificity for chrome salts, though having the characteristic morphology, location, relations, and genesis, thus making their recognition difficult. The undifferentiated type of neuroblastoma is almost always malignant, occurs usually in very young children, has a lobulated structure and a variegated appearance and is a type of nerve tumor apparently peculiar to the synmpathetic nervous system, the corresponding tumor of the cerebro- spinal system being very rare, less malignant, and having more an epithelioid character (neurocytoma). It is characterized, histologically, by the similarity of certain parts of its tissue with certain phases in the development of the adrenal medulla and sympathetic ganglia; by its round cells with its nuclei very rich in chromatin and with scanty cytoplasm that gives off delicate processes which unite with those of adjacent cells to form a delicate syncytium; by the tendency of the cells to polarize about fine meshes of fibrillae, about 252 WAHL. capillaries, and about strands of connective tissue; and by the peculiar fibrillar ground substance. Owing to the extensive variation in the degree of differentiation of the cellular and fibrillar structures in the undifferentiated type of nerve tumors different portions of a malignant neuroblastoma may differ widely in their appearance, both grossly and microscopically, some parts resembling a scirrhus carcinoma, others a round cell sarcoma, glioma, lympho- sarcoma or alveolar sarcoma, but the possession of the fibrillar matrix with its peculiar staining reaction, the tendency of the cells to give off delicate protoplasmic processes that unite with adjacent cells to give a fibrillar syncytium and the formation 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 indifferent cells, and serve as precursors of the nerve fibers, in fact may well be embryonic nerve fibers. The malignant neuroblastoma of the sympathetic system metastasize rapidly and extensively and are especially prone to invade the liver, lymph glands, and bones, but often show comparatively little infiltration into the surrounding tissues. These metastases occur most often by way of the blood stream, but may also follow the lymph channels. There is usually a marked tendency to the formation of extensive areas of necrosis and hemorrhage. All forms of neuroblastomata are undoubtedly much more frequent than has been generally recognized, their identification being often easily overlooked.

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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, I897 56. 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; also Miscellaneous 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. 256 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 the undifferentiated nerve tissue under low magnification. FIG. 4.- Iron hematoxylin stain. Shows the alveolar type of architecture which prevails in the metastases and in the periaortic tumor mass. Smaller areas of this type are present in the tumor and its capsule. Note the tendency of the cells to polarize about capillaries or strands of connective tissues. Note also the protoplasmic processes arising from the cells and joining them together. x 87. FIG. S. - Hematoxylin and eosin stain. Illustrates the peritheliomatous pattern, very characteristic of the undifferentiated part of the main tumor mass. Note the dilated vessels, also the diffuse, pale-stained areas of necrosis. x 43. FIG. 6.- Photomicrograph taken from a large focus of undifferentiated nerve cells embedded in the main portion of the tumor. Shows the tendency of the cells to arrange in characteristic clusters and aggregations forming the " rosettes " so peculiar to this type of growth. x 43. FIG. 7. - Illustrates a fibrillar type of architecture. Shows cells loosely embedded in a matrix of fibrille. Note the presence of a well-formed " rosette " near the center of the figure, and a more solid aggregation of cells (" glial ball"). FIG. 8. -Illustrates the very cellular type of architecture. Note the tendency of the cells to polarize about round spaces suggesting " rosettes." x 62. FIG. 9. - Illustrates a metastasis of the indifferent nerve cells into a lymph gland. The lighter stained areas represent the remains of lymphoid tissue; the darker stained sections correspond to the tumor tissue. Note the tendency of the cells of the latter to form " rosettes." x 87. FIG. IO. -Photomicrograph of a solid cluster of cells projecting into the space in the fibrillar ground substance (" glial ball "). Note that this mass of cells is connected with the surrounding fibrillar tissue by the narrow pedicle of fibrilll. x 87. FIG. II. - Photomicrograph through the boundary zone between the differentiated (ganglioneuroma) and the undifferentiated portion of the tumor tissue in the main tumor, showing the invasion of the area containing the ganglion cells and nerve fibers by the indifferent nerve cells. x 87. FIG. I2.- Photomicrograph of the larger part of the pedicle of the tumor. Note the large vessel that supplies the tumor, the mass of dark indifferent nerve cells at one end of the vessel, and the bundles of unmedullated nerve fibers at the pointed end of the pedicle. x 23. NEUROBLASTOMATA. 257

PLATE XXII. - Photomicrographs illustrating various appearances of the 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 that some of the fibrillse can be traced into the cytoplasm of some of the surrounding cells. x 69o. FIG. 14.- Van Gieson stain. Shows the fibrillar syncytium in which the nuclei of the indifferent cells are embedded. Note that, on one side, the cells are apparently polarizing about a mass of fibrille suggesting the formation of a "rosette." x 360. FIG. I5. -Iron hematoxylin stain. Shows the detailed appearance and structure of the indifferent cells. Note the smaller and larger types of cells, the fibrillo-protoplasmic syncytium in which they are embedded, and the direct division of the nucleus of one of the cells. Note also the scanty amount 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. Iron hematoxylin stain. Shows an early degree of differentiation of the indifferent cells. There is more protoplasmn in the syncytium than usual. The nuclei are more vesicular than those of the indifferent cells, and a few of them have the appearance of ganglion cell nuclei. x 360. FIG. 17.-From a metastasis in the liver, showing the appearance of the individual tumor cells about some atrophied liver tissue. Note also that the cells are larger than in other regions. x 690. FIG. I8. - From a metastasis in a lymph gland, showing the delicate protoplasmic 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 cells to polarize loosely about capillaries. x 690.

PLATE XXIII. - Photomicrographs illustrating the ganglioneuromatous portion of the tumor. FIG. 20. -Iron hematoxylin-eosin stain. Shows a small cluster of ganglion cells and a nerve entering at the left side and breaking up amnong the cells. Note that only one of the ganglion cells is encapsulated, and that only in part; also note the presence of two or more nuclei in some of the ganglion cells, and the occurrence of scattered small cells, many of which are indifferent or but slightly differentiated nerve cells. x 430. FIG. 21. - Iron hematoxylin stain. Shows a cluster of very irregular ganglion cells, lying naked in the fibrillar stroma. Many of the cells are multinucleated and some are apparently fused together. x 87. FIG. 22. -Iron hematoxylin-eosin stain. From an area of the edema in a focus of ganglion cells and granular disintegration of the fibrillar matrix, showing atypical multinucleated giant ganglion cells. Note the apparent direct division of the nucleolus of a ganglion cell in the upper left corner of the figure. Some of the giant cells consist of irregular masses of ganglion cell nuclei. Note the striking variation in size. x 430. FIG. 23.- Iron hematoxylin stain. Shows numerous ganglion cells 258 WAHL. that have become degenerated and hyaline with absence of many of the nuclei. There are also many unmedullated nerve fibers. x 87. FIG. 24. -Iron hematoxvlin stain. Shows interlacing bundles of medullated nerve fibers. x 87. FIG. 25. -Bielschowsky's stain for neurofibrille. Shows a small cluster of ganglion cells with delicate black nerve fibers entering it. Note the bundles of nerve fibers within the surrounding tissue. x 87. FIG. 26.- Bielschowsky's stain for neurofibrillhe. Shows a ganglion cell with a long process containing an axis cylinder. Note the absence of sheath 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 silver preparation showing three ganglion cells and many nerve fibers. Note the relation of the sheath cells to the nerve fibers. Note also the occasional 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 small ganglion cell, and at the other end breaking up among several ganglion cells. x 69o. FIG. 29. - Photomicrograph of several foci of ganglion cells in the capsular part of the tumor tissue. Shows considerable edema in the foci, disintegrating the ganglion cells from each other, especially marked in the upper foci, where there is a partial cyst formed. x 62. FIG. 30.-Photomicrograph from same region, but showing the cystoid structures. Note the disintegrated ganglion cells in these cystic spaces. x 62. FIG. 31.- Photomicrograph showing partial obliteration of the cystic spaces, with loose connective tissue derived from the surrounding walls. x 62. FIG. 32. - Photomicrograph illustrating the transformation of an area containing many cystic spaces into a cavernous angiomatous appearance with red cells, degenerated ganglion cells, fibrin and cellular ddbris in the lumina. x 62. FIG. 33. Photomicrograph illustrating the transformation of areas of cystoid formations to patchy areas of fibrosis. x 62. FIG. 34. - Photomicrograph of an area of indifferent cells showing the formation of embryonic nerves represented by the lighter areas with parallel running nuclei. Compare with next figure. x 4o. FIG. 35. - Photomicrograph taken of a part of the anlage of the adrenal gland in a human fetus about ten weeks old. Note the separation of the tissue on left two-thirds of figure into upper and lower parts; lower one representing the cortical part of the adrenal, the upper part the paraganglion composed of sympathetic " Bildungszellen." Note the presence of two embryonic nerves in the upper part of this section. Also note a " rosette " embedded in the lower left quadrant, indicating the migration of the cells of the paraganglion to the center of the cortical anlage in the form of " rosettes." Also note in the upper right corner a sheath-like NEUROBLASTOMATA. 259 arrangement of cells (not well focused), which is apparently the separation 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 human fetus at about io weeks. x 360.

PLATE XXV., FIGS. 37 and 38. - Photomicrograph of myeloid cells taken from an area of myeloid tissue in the capsular part of the tumor tissue. Note a mitotic figure in each photomicrograph. Note a diaster stage near the center of Fig. 37 and an equatorial plate stage in upper right corner of Fig. 38. Note variation in the size and morphology of the cells. The two large cells in the lower part of Fig. 38 contained eosinophilic granules in the cytoplasm. Note also that the cells are surrounded by a delicate reticulum. x 690. FIG. 39.- Photomicrograph of an area of myeloid tissue. Note the radial arrangement of the cells about the blood vessels. x 87. FIG. 40.- Photomicrograph of a metastasis into a lymph gland, showing lymphoid 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 striking dissimilarity between them. x 69o. FIG. 4I.- Photomicrograph of a giant megalokaryocyte present in the myeloid tissue. x 69o. FIG. 42.- Photomicrograph of a very sclerotic and thickened blood vessel in the capsular portion of the tumor tissue. Note that the lumen is almost obliterated. x 87. FIG. 43. - Camera lucida drawing of a nerve fiber, showing the relation of 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 marked elongated ribbon-like sheath nucleus frequently seen along the nerve fibers in the tumor tissue. x 1240. FIG. 45. - Camera lucida drawing of a ganglion cell with neurofibrille passing out along its single large process. Note that the latter is split in two parts at its base. Note also the presence of three neurofibrille in the nerve process, and that they disappear in the neighborhood of the nuclei. They are not equally sharply focused in one plane. Bielschow- sky preparation. x 1240. FIG. 46.- Camera lucida drawing of a ganglion cell showing partial direct division of the nucleus with the presence of three distinct nucleoli. Note the indentations of the nuclear membrane suggesting beginning division, corresponding to the three nucleoli. Bielschowsky preparation. X I240.

PLATE XXVI. - Photomicrographs illustrating the chromaffine tissues of the tumor. FIG. 47.-Iron hematoxylin stain. Shows clusters of indifferent cells and nests of chromaffine cells, embedded in a fibrillar matrix beneath the 260 WAHL. base of the pedicle of the tumor. A large nest of the chromaffine cells is shown 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 centimeter from 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 the periaortic mass. x 360. FIG. 50.- Hematoxylin and eosin stain. Shows an irregular L-shaped area of cuboidal epithelial cells (chromaffine cells), embedded in a mass of indifferent tissue in the periaortic tumor mass. Note the syncytium in the angle of the L; and that the cells are lighter and surrounded by more protoplasm than the indifferent cells at the periphery. x 87. FIG. 5I.- From same preparation as Fig. 50, showing two large chromaffine cells apparently developing from the surrounding nucleated protoplasmic 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 nests of chromaffine cells under higher magnification. Note their cuboidal shape, but obscure outlines, their tendency to a reticular arrangement, and the presence of many indifferent cells scattered among them. Note also the surrounding fibrillar matrix. x 360. JOURNAL OF MEDICAL RESEARCH VOL. XXX. PLATE XX.

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